1

 

                            DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                                  FOOD AND DRUG ADMINISTRATION

 

                            CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

                               ONCOLOGIC DRUGS ADVISORY COMMITTEE

 

 

 

                                           NDA 21-824

 

                           ZARNESTRA (TIPIFARNIB)FILM COATED TABLETS

 

                       TIBOTEC THERAPEUTICS, A DIVISION OF ORTHO BIOTECH,

                           LP PROPOSED INDICATION FOR THE TREATMENT OF

                         ELDERLY PATIENTS WITH NEWLY DIAGNOSED POOR-RISK

                                  ACUTE MYELOID LEUKEMIA (AML)

 

 

 

 

 

 

 

 

                                     Thursday, May 5, 2005

 

                                           8:00 a.m.

 

 

 

 

 

 

 

 

                                       5630 Fishers Land

                                           Room 1066

                                      Rockville, Maryland


 

 

 

 

 

 

                                                                             2

 

                                    P A R T I C I P A N T S

 

                  ADVISORY COMMITTEE REPRODUCTIVE HEALTH DRUGS

 

                  Silvana Martino, D.O. - CHAIR

                  Otis W. Brawley, M.D.

                  Ronald M. Bukowski, M.D.

                  Bruce D. Cheson, M.D.

                  Stephen L. George, Ph.D.

                  Pamela J. Haylock, RN [Industry Representative]

                  Alexandra M. Levine, M.D.

                  Joanne E. Mortimer, M.D.

                  Michael C. Perry, M.D.

                  Gregory H. Reaman, M.D.

 

                  Johanna M. Clifford, M.S., RN, Executive Secretary

 

 

                  CONSULTANTS AND GUESTS

 

                  Consultants (voting)

 

                  Susan O'Brien, M.D.

 

 

                  Patient Representative (voting):

 

                  Arthur Flatau

 

 

                  Acting Industry Representative (non-voting):

 

                  Roger Porter

 

 

                  Guest Speaker (non-voting):

 

                  Frederick Appelbaum, M.D.

 

 

                  FDA PARTICIPANTS

 

                  Qin Ryan, M.D.

                  Ramzi Dagher, M.D.

                  Robert Justice

                  Richard Pazdur, M.D.

                  Robert Temple, M.D.


 

 

 

 

 

 

                                                                             3

 

                                        C O N T E N T S

                                                                          PAGE

 

                  Call to Order

                            Silvana Martino, D.O., Chair                     4

 

                  Introduction of Committee                                  4

 

                  Conflict of Interest Statement

                            Johanna Clifford                                 6

 

                  Opening Remarks

                            Richard Pazdur, M.D.                             9

 

 

                  Sponsor Presentation - Tibotec Therapeutics, Inc.

                     Introduction

                             Robert DeLap, M.D., Ph.D.                      15

 

                     AML in Elderly Patients

                            Richard Stone, M.D.                             23

 

                     Clinical  Data

                            Alain Thibault, M.D.                            36

 

                     Benefit/Risk

                            Alex Zukiwski, M.D.                             62

 

                  FDA Presentation:  NDA 21-824, Zarnestra

                            Qin Ryan, M.D.                                  70

 

                  AML in Older Individuals

                            Frederick R. Appelbaum, M.D.,                   90

 

                  Open Public Hearing                                      121

 

                  Questions from the Committee                             129

 

                  Discussion of the Questions                              181


 

 

 

 

 

 

                                                                             4

 

              1                      P R O C E E D I N G S

 

              2                          Call to Order

 

              3             DR. MARTINO: Good morning, ladies and

 

 

              4   gentlemen.  I'd like to begin this meeting.

 

              5             The topic before us this morning is the

 

              6   drug Zarnestra, presented by Tibotec.  And the

 

              7   proposed indication is for the treatment of elderly

 

              8   patients with newly diagnosed poor-risk myeloid

 

 

              9   leukemia.

 

             10                    Introduction of Committee

 

             11             The first order of business is I would

 

             12   like the members of the committee to introduce

 

             13   themselves.  And I'd like to start with Dr.

 

 

             14   O'Brien, please.

 

             15             I need you all to use your microphones,

 

             16   please.

 

             17             DR. O'BRIEN: I'm from the leukemia

 

             18   department at MD Anderson.

 

 

             19             DR. CHESON: Bruce Cheson, head of

 

             20   Hematology, Georgetown University Lombardi Cancer

 

             21   Center.

 

             22             DR. GEORGE: Steve George, Duke University


 

 

 

 

 

 

                                                                             5

 

              1   Medical Center.

 

              2             DR. BRAWLEY: Otis Brawley.  I'm a medical

 

              3   oncologist and epidemiologist at the Winship Cancer

 

 

              4   Institute of Emory University.

 

              5             DR. MORTIMER: Joanne Mortimer, medical

 

              6   director, UCSD Morris Cancer Center.

 

              7             MS. HAYLOCK: Pamela Haylock, oncology

 

              8   nurse and doctoral student at UTMB, Galveston,

 

 

              9   Texas.

 

             10             MR. FLATAU: Arthur Flatau, I'm the Patient

 

             11   Representative.

 

             12             DR. REAMAN: Greg Reaman, pediatric

 

             13   oncologist, Children's Hospital, Washington, D.C.;

 

 

             14   George Washington University in the Children's

 

             15   Oncology Group.

 

             16             DR. LEVINE: Alexandra Levine, head of

 

             17   hematology at University of Southern California,

 

             18   Norris Cancer Center.

 

 

             19             DR. MARTINO: Silvana Martino, from the

 

             20   Angeles Clinic in Santa Monica, California, main

 

             21   medical oncologist.

 

             22             MS. CLIFFORD: Johanna Clifford, Executive


 

 

 

 

 

 

                                                                             6

 

              1   Secretary to the ODAC.

 

              2             DR. PERRY: Michael Perry, medical

 

              3   oncologist, University of Missouri Ellis Fischel

 

 

              4   Cancer Center, Columbia, Missouri.

 

              5             DR. PORTER: Roger Porter, retired both

 

              6   from the NIH and Wyeth, now a consultant.

 

              7             DR. BUKOWSKI: Ronald Bukowski, medical

 

              8   oncologist, Cleveland Clinic, Cleveland, Ohio.

 

 

              9             DR. DAGHER: Ramzi Dagher, Division of

 

             10   Oncology Drug Products, FDA.

 

             11             DR. JUSTICE: Robert Justice, Acting Deputy

 

             12   Director, Oncology Drug Products, FDA.

 

             13             DR. PAZDUR: Richard Pazdur, FDA.

 

 

             14             DR. TEMPLE: Bob Temple, Director, OD-1.

 

             15             DR. MARTINO: Next, I'd like Ms. Johanna

 

             16   Clifford to read the conflict of interest

 

             17   statements for the members of the panel, please.

 

             18                  Conflict of Interest Statement

 

 

             19             MS. CLIFFORD:  The following announcement

 

             20   addresses the issue of conflict of interest, and is

 

             21   made as part of the record to preclude even the

 

             22   appearance of such at this meeting.

 

             23             Based on the submitted agenda all

 

 

             24   financial interests reported by the committee

 

             25   participants, it has been determined that all


 

 

 

 

 

 

                                                                             7

 

              1   interest in firms regulated by the Center for Drug

 

              2   Evaluation and Research present no potential for an

 

              3   appearance of a conflict of interest, with the

 

 

              4   following exceptions.

 

              5             In accordance 18 USC 208(b)(3), full

 

              6   waivers have been granted to the following

 

              7   participants: Dr. Stephen George, for consultant

 

              8   for a competitor, which he received less than

 

 

              9   $10,001 per year; Dr. Ronald Bukowski, for

 

             10   consulting with a competitor, which he receives

 

             11   less than $10,001 per year.  Pamela Haylock has

 

             12   been granted waivers under 208(b)(3) and 21 USC

 

             13   505(n) for her spouse owning stock in a competitor.

 

 

             14   The stock is valued from $25,001 to $50,000.

 

             15             A copy of the waiver statements may be

 

             16   obtained by submitting a written request to the

 

             17   agency's Freedom of Information Office, Room 12A-30

 

             18   of the Parklawn Building.

 

 

             19             In addition, we would like to not that Dr.


 

 

 

 

 

 

                                                                             8

 

              1   Frederick Appelbaum, FDA's invited guest speaker,

 

              2   is participating as a representative of the Fred

 

              3   Hutchinson Cancer Research Center.  He has no

 

 

              4   financial interest in, or professional relationship

 

              5   with any of products of firms that could be

 

              6   affected by the committee's discussions.

 

              7             With respect to the FDA's invited industry

 

              8   representative, we would like to disclose that Dr.

 

 

              9   Roger Porter is participating in this meeting as

 

             10   the industry representative, acting on behalf of

 

             11   regulated industry.  Dr. Porter is a private

 

             12   consultant to industry.

 

             13             In the event that the discussions involve

 

 

             14   any other products or firms not already on the

 

             15   agenda, for which an FDA participant has a

 

             16   financial interest, the participants are aware of

 

             17   the need to exclude themselves from such

 

             18   involvement, and their exclusion will be noted for

 

 

             19   the record.

 

             20             With respect to all other participants, we

 

             21   ask, in the interest of fairness, that they address

 

             22   any current or previous financial involvement with


 

 

 

 

 

 

                                                                             9

 

              1   any firms they may wish to comment upon.

 

              2             Thank you.

 

              3             DR. MARTINO: Thank you, Ms. Clifford.

 

 

              4   And, next, Dr. Richard Pazdur will provide some

 

              5   opening remarks to this meeting.

 

              6                         Opening Remarks

 

              7             DR. PAZDUR: Thank you, Dr. Martino.

 

              8             First of all, I'd like to say Feliz Cinco

 

 

              9   de Mayo to everyone.

 

             10             [Laughter.]

 

             11             For everybody that's lived in Texas, such

 

             12   as Susan and myself--

 

             13             VOICE: Muchas gracias.

 

 

             14             DR. PAZDUR: De nada.

 

             15             [Laughter.]

 

             16             This is a big day in the State of Texas.

 

             17   And I just want to bring that up.

 

             18             I have some enjoyable issues to do to

 

 

             19   start out here, and that is to thank two members of

 

             20   our committee that will be retiring.  And I use

 

             21   that word "retiring" in quotations, because,

 

             22   because of their expertise, we probably will be


 

 

 

 

 

 

                                                                            10

 

              1   inviting them back--both to sit on ODAC special

 

              2   committees, as well as to serve as special

 

              3   consultants to us during the process that we

 

 

              4   evaluate drugs outside of the ODAC committee.

 

              5             The two individuals that will be leaving

 

              6   the committee are Stephen George and Otis Brawley.

 

              7             Stephen George is, obviously, from Duke

 

              8   University in North Carolina, and has served on the

 

 

              9   ODAC Advisory Committee as the committee

 

             10   statistician from July of 2001, to June of 2005.

 

             11   In addition to his committee participation, Dr.

 

             12   George has visited the FDA and he's given numerous

 

             13   presentations to us on various statistical issues,

 

 

             14   and has served as a consultant to us on many NDAs

 

             15   and IND matters.  So we really appreciate Dr.

 

             16   George's efforts--on this committee and also behind

 

             17   the doors here--in helping the FDA.  And we look

 

             18   forward to working with you, as you leave the

 

 

             19   committee, on a continuing basis.

 

             20             So I have this beautiful plaque here that

 

             21   I'd like to present to you.

 

             22             [Applause.]

 

             23             Thank you very much.

 

 

             24             DR. GEORGE: Thank you.  Thank you.

 

             25             DR. PAZDUR: And the gentleman that is


 

 

 

 

 

 

                                                                            11

 

              1   sitting right next to him, Dr. Otis Brawley, is

 

              2   professor of hematology and oncology and

 

              3   epidemiology, and is the Associate Director for

 

 

              4   Cancer Control at the Winship Cancer Institute at

 

              5   Emory University.

 

              6             He's an international authority in the

 

              7   field of health disparities research and prostate

 

              8   cancer.  He's served on the committee from July of

 

 

              9   2001 to 2005.  Like Dr. George, Otis has been

 

             10   involved with many of the behind-the-scenes efforts

 

             11   at the FDA; consulting with us on numerous

 

             12   applications, considerations of Phase I and Phase

 

             13   II trial designs, and Phase III trial designs also.

 

 

             14             We really have appreciated Dr. Brawley's

 

             15   work with us.  And here, again--this is not to say

 

             16   goodbye, but just as a transition to another role

 

             17   with us in the FDA.  Thank you very much.

 

             18             [Applause.]

 

 

             19             Hasta luego, he said.  Okay.

 

             20             [Laughter.]

 

             21             Recuerdos a todos--regards to everyone.

 

             22             I'm just going to make a few short

 

             23   comments about this application, because I think

 

 

             24   that the speakers will probably address all of the

 

             25   salient points, and I think we could bring up any


 

 

 

 

 

 

                                                                            12

 

              1   regulatory issues relatively succinctly during our

 

              2   presentations, and also in our discussions.

 

              3             Basically, what we have here is a

 

 

              4   single-arm study in a patient population where

 

              5   there has to be discussion that there is no other

 

              6   available therapy for this patient population--or

 

              7   the results are so impressive here that we need to

 

              8   consider the approval of the drug.

 

 

              9             We're going to be asking basically the

 

             10   question: does this drug deserve full approval?

 

             11   Okay?  And one of the reasons why we're asking this

 

             12   is that we have accepted basically a situation

 

             13   where complete response rates have equated clinical

 

 

             14   benefit.  Okay?  We believe that this is an

 

             15   established surrogate for survival.  And, in

 

             16   addition to that, we believe that application in a


 

 

 

 

 

 

                                                                            13

 

              1   complete response rate would have a reduction in

 

              2   transfusion requirements and other supportive care

 

              3   products.  So this is meaningful clinical endpoint,

 

 

              4   an established surrogate for clinical benefit.

 

              5             So, with that in mind, I'd like you to

 

              6   proceed with the discussions, and I'll turn the

 

              7   discussions--the presentations--over to Dr.

 

              8   Martino.

 

 

              9             DR. MARTINO: Rich, before I let you sit

 

             10   down, please, I just want to be sure that I'm clear

 

             11   that, in fact, the application is seeking for full

 

             12   approval, and not accelerated approval.

 

             13             DR. PAZDUR: Correct--yes.

 

 

             14             DR. MARTINO: Because, when I reviewed the

 

             15   material, I came to this with one view, and then

 

             16   when the question was presented to me, I realized

 

             17   that it was full approval.

 

             18             DR. PAZDUR: Correct.

 

 

             19             DR. MARTINO: So I just wanted to be sure

 

             20   that that is what you mean.

 

             21             DR. PAZDUR: And this is the area that I

 

             22   want to clarify here.  The issue here is: we look


 

 

 

 

 

 

                                                                            14

 

              1   at complete response rates.  And, here again,

 

              2   that's not only the response rates but response

 

              3   rates of a sufficient magnitude--okay?  So we look

 

 

              4   at both of these parameters: the response rate and

 

              5   the magnitude.  If that is sufficient, one should

 

              6   conclude that this would be an established

 

              7   surrogate for clinical benefit.  Okay?

 

              8             DR. PERRY: Do we have the option of

 

 

              9   recommending it for accelerated approval and not

 

             10   for full approval?  Or is this simply "yes" or

 

             11   "no."

 

             12             DR. PAZDUR: Yes--we would entertain any

 

             13   topics or discussions regarding that.

 

 

             14             DR. PERRY: So we've got three options

 

             15   then: yes, no--

 

             16             DR. PAZDUR: Correct.  But we'd like to

 

             17   firsts discuss that endpoint of full approval.  And

 

             18   then, if you want to deviate from that, let's

 

 

             19   please have a discussion of what. Okay?

 

             20             DR. PERRY: Okay.

 

             21             DR. MARTINO: Are there other questions for

 

             22   Dr. Pazdur at this point?  Ladies and gentlemen?


 

 

 

 

 

 

                                                                            15

 

              1   Okay.

 

              2             Turn the microphone on, please.

 

              3             DR. PAZDUR: They're right there in the

 

 

              4   plastic box.

 

              5             DR. MARTINO: A practical question, there.

 

              6   Thank you.

 

              7             At this point, I would like to turn to the

 

              8   Tibotec representatives to present their data.  And

 

 

              9   Dr. DeLap, if you would please introduce your

 

             10   subsequent speakers, as well.

 

             11           Sponsor Presentation - Tibotec Therapeutics

 

             12             DR. DeLAP: Thank you.  Madam Chair,

 

             13   members of the committee, colleagues and

 

 

             14   guests--good morning.  I'm Dr. Robert DeLap, Vice

 

             15   President of Regulatory Affairs at Johnson &

 

             16   Johnson Pharmaceutical Research.

 

             17             We are pleased to be here today to present

 

             18   data generated in National Cancer Institute and

 

 

             19   company-sponsored studies on the efficacy and

 

             20   safety of tipifarnib in poor-risk AML, and our

 

             21   application for approval of tipifarnib for use in a

 

             22   patient population that is not well served by


 

 

 

 

 

 

                                                                            16

 

              1   existing AML therapies.

 

              2             Our application proposes that tipifarnib

 

              3   will be indicated for the treatment of elderly

 

 

              4   patients with newly diagnosed, poor-risk acute

 

              5   myeloid leukemia, based on durable complete

 

              6   remissions that were observed in the CTEP-20 study.

 

              7             As noted in the agency's briefing

 

              8   materials for today's meeting, complete remissions

 

 

              9   have been used as evidence of patient benefit to

 

             10   support approval of new treatments for AML.  Thus,

 

             11   the consideration today is the use of these data to

 

             12   support the approval of tipifarnib for this

 

             13   indication.

 

 

             14             Elderly patients with AML obtain less

 

             15   benefit from the intensive induction treatment

 

             16   regimens used in younger patients, and the risks of

 

             17   severe treatment toxicities and treatment-related

 

             18   mortality rise with increasing age.  Since

 

 

             19   risk-benefit considerations for intensive-induction

 

             20   treatment are often not favorable in these

 

             21   patients, new treatments are clearly needed.

 

             22             In the clinical research to be discussed


 

 

 

 

 

 

                                                                            17

 

              1   today, tipifarnib has demonstrated meaningful

 

              2   efficacy in elderly patients as described in our

 

              3   proposed indication, with a well-characterized

 

 

              4   safety profile in outpatient treatment.

 

              5             [Slide.]

 

              6             Tipifarnib was originally synthesized in

 

              7   the Johnson & Johnson Pharmaceutical Research

 

              8   laboratories.  Clinical investigations began with

 

 

              9   solid tumor studies in 1997.  Based on mutual

 

             10   interest in this compound, the company and the NCI

 

             11   entered into a Cooperative Research and Development

 

             12   Agreement in 1999.

 

             13             Pre-clinical evidence of activity against

 

 

             14   leukemias led to clinical research in AML, with

 

             15   initiation of the CTEP-1 Phase 1 study in 1999.

 

             16   Complete clinical remissions observed in CTEP-1 led

 

             17   to further research, including the CTEP-20 Phase 2

 

             18   study in myeloid malignancies.

 

 

             19             Following consultations between the

 

             20   company, the National Cancer Institute and the FDA,

 

             21   CTEP-20 was subsequently amended and expanded to

 

             22   focus on evaluating the efficacy and safety of


 

 

 

 

 

 

                                                                            18

 

              1   tipifarnib in elderly patients with newly diagnosed

 

              2   poor-risk AML.

 

              3             Considering the unmet need in this patient

 

 

              4   population, tipifarnib has recently received orphan

 

              5   designation for AML, and has been granted

 

              6   fast-track status by FDA.

 

              7             The NDA for tipifarnib was accepted into

 

              8   FDA's Continuous Marketing Application-1 pilot

 

 

              9   program, which has allowed for expedited submission

 

             10   and review of these data.

 

             11             [Slide.]

 

             12             This slide summarized the study program

 

             13   for tipifarnib in poor-risk AML.

 

 

             14             Following the CTEP-1 study, the INT-17

 

             15   study evaluated tipifarnib in patients with

 

             16   relapsed or refractory AML.

 

             17             Today's discussions will focus on the

 

             18   CTEP-20 study, as this is the study that has

 

 

             19   evaluated efficacy and safety in the patient

 

             20   population of interest for today's discussion.

 

             21             The AML-301 study, in patients greater

 

             22   than 70 years of age with newly diagnosed leukemia


 

 

 

 

 

 

                                                                            19

 

              1   is evaluating the effect of tipifarnib versus best

 

              2   supportive care.  And that study is designed to

 

              3   establish the magnitude of the anticipated survival

 

 

              4   benefit, and is actively enrolling patients.

 

              5             The ongoing CTEP-50 study is an iterative

 

              6   trial being conducted under NCI supervision, which

 

              7   is evaluating alternative dosing regimens in

 

              8   elderly patients with newly diagnosed leukemia.

 

 

              9             Finally, the AML development program also

 

             10   includes related studies, not shown on this slide,

 

             11   in maintenance of remission and use in combination

 

             12   with other agents.  Those studies are briefly noted

 

             13   in the company's background materials for today's

 

 

             14   meeting, but will not be included in our

 

             15   presentation today, as they represent work in

 

             16   progress in other AML settings.

 

             17             [Slide.]

 

             18             The CTEP-20 study focused on patients who

 

 

             19   have generally not been represented in AML clinical

 

             20   trials, and are not well served by

 

             21   intensive-induction chemotherapy regimens.  The

 

             22   median age of the elderly patients enrolled in this


 

 

 

 

 

 

                                                                            20

 

              1   study was 75.  Most of the patients had antecedent

 

              2   myelodysplastic syndromes; 49 percent had

 

              3   unfavorable karyotypes; the remainder had

 

 

              4   intermediate karyotypes.  No patients with

 

              5   favorable karyotypes were enrolled.

 

              6             Overall, 90 percent of patients had two or

 

              7   more risk factors, considering age, antecedent

 

              8   myelodysplastic syndromes, unfavorable karyotypes,

 

 

              9   or evidence of organ dysfunction.  These are

 

             10   patients who would be expected to have poor

 

             11   tolerance for standard AML treatments, and would be

 

             12   much less likely to benefit from existing

 

             13   treatments.

 

 

             14             [Slide.]

 

             15             As you will see in today's presentation,

 

             16   tipifarnib demonstrates a favorable benefit risk

 

             17   for a more fragile patient population that

 

             18   generally does not receive standard AML therapy.

 

 

             19   Evidence of meaningful clinical efficacy has been

 

             20   observed, with a 15 percent rate of durable

 

             21   complete remissions in the planned analysis.

 

             22             Treatment safety has been well documented,


 

 

 

 

 

 

                                                                            21

 

              1   with more than 1,000 patients in monotherapy

 

              2   studies.  This includes a total of 409 patients in

 

              3   the AML studies, CTEP-20 and INT-17, as well as

 

 

              4   patients exposed at lower doses in solid tumor

 

              5   studies.

 

              6             Tipifarnib produces predictable and

 

              7   reversible myelosuppression with continued daily

 

              8   dosing, but it is myeloablative, and the incidence

 

 

              9   of life-threatening, not-hematologic toxicities has

 

             10   bene low.

 

             11             Patients in the CTEP-20 study were able to

 

             12   spend much of their time outside of the hospital.

 

             13   Thus, tipifarnib can serve as an oral out-patient

 

 

             14   treatment for these patients.

 

             15             [Slide.]

 

             16             Our agenda today includes three additional

 

             17   presentations.  In a few moments I will turn to Dr.

 

             18   Richard Stone, from the Dana-Farber Cancer

 

 

             19   Institute, who will discuss the problem of AML in

 

             20   elderly patients.

 

             21             Dr. Alain Thibault will then review the

 

             22   clinical data provided in our new drug application,


 

 

 

 

 

 

                                                                            22

 

              1   focusing on the CTEP-20 study, which has provided

 

              2   data on the efficacy and safety of tipifarnib in

 

              3   elderly poor-risk patients with newly diagnosed

 

 

              4   AML.

 

              5             Finally, Dr. Alex Zukiwski will summarize

 

              6   benefits and risks of tipifarnib treatment in this

 

              7   patient population.

 

              8             We are joined today by medical experts to

 

 

              9   contribute to the discussion, and to help address

 

             10   specific questions.  These include Dr. Karp, who

 

             11   served as principal investigator for the CTEP-20

 

             12   study; Drs. Sekeres and Stone, who have special

 

             13   expertise in AML and have experience with the use

 

 

             14   of tipifarnib; and Dr. Wright, from the NCI's

 

             15   Cancer Therapy Evaluation Program.  Unfortunately,

 

             16   Dr. Albitar from Nichols Institute, who provided an

 

             17   independent review of bone marrow slides in the

 

             18   CTEP-20 study, and had planned to be with us today,

 

 

             19   could not be here because of a family emergency.

 

             20             This concludes my introduction.  I will

 

             21   now turn the podium over to Dr. Richard Stone who

 

             22   will discuss the problem of AML in elderly


 

 

 

 

 

 

                                                                            23

 

              1   patients.

 

              2             Thank you.

 

              3                     AML in Elderly Patients

 

 

              4             DR. STONE: Dr. DeLap, thank you very much.

 

              5             Members of the panel, guests--I'll be

 

              6   spending the next few minutes discussing the

 

              7   following topic: AML in the older-age patient

 

              8   represents a therapeutic area of significant unmet

 

 

              9   need.  And this is particular true for those

 

             10   subjects who have an inferior prognosis compared to

 

             11   the average.

 

             12             [Slide.]

 

             13             Now, AML in the older population is not

 

 

             14   uncommon, and the number of cases will be

 

             15   increasing over time.  This is clearly a

 

             16   biologically and therapeutically distinct disease

 

             17   compared to AML which may occur in younger adults.

 

             18   And the reasons for this distinctive character are:

 

 

             19   number one, it's an intrinsically resistant disease

 

             20   to chemotherapy; and number two, there are markedly

 

             21   inferior outcomes to available chemotherapeutic

 

             22   agents compared to younger adults.

 

             23             Some subgroups of patients who are older

 

 

             24   adults with AML have a markedly worse than the

 

             25   average prognosis which, I think you'll see in a


 

 

 

 

 

 

                                                                            24

 

              1   minute, is quite poor to start with.  As such, many

 

              2   patients who are older with AML are not offered

 

              3   and/or refuse the standard cytotoxic induction and

 

 

              4   post-remission therapy.  As such, an efficacious,

 

              5   relatively non-toxic approach would be welcomed by

 

              6   patients and leukemia doctor's alike.

 

              7             [Slide.]

 

              8             There are approximately 12,000 new cases

 

 

              9   of AML each year in this country.  Approximately

 

             10   9,000 people die of this disease.

 

             11             In contrast to what might be the case if

 

             12   you look at a tertiary care cancer center, the

 

             13   median age of AML is at least 68.  The incidence

 

 

             14   increases markedly as people get older.  For

 

             15   example, if you're 50 years old you have a 1 in

 

             16   50,000 chance of having AML.  If you're 70, you

 

             17   have a 1 in 7,000 chance.

 

             18             [Slide.]

 

 

             19             This next slide graphically depicts the


 

 

 

 

 

 

                                                                            25

 

              1   marked increase in the incidence of AML that occurs

 

              2   as people get older.  And it's particularly

 

              3   striking once you get to the sixth, and

 

 

              4   particularly seventh, decade of life.

 

              5             [Slide.]

 

              6             Moreover, as I think everybody is aware,

 

              7   the demographics of our population are changing to

 

              8   the fact that we're getting to be older as a

 

 

              9   country.  And, as such, the number of cases of AML

 

             10   in this age cohort--or the number of cases

 

             11   total--will be increasing over the next few

 

             12   decades.

 

             13             [Slide.]

 

 

             14             Now, this slide depicts the situation that

 

             15   was true in the 1980s, when chemotherapy was

 

             16   applied the same way to younger adults and older

 

             17   adults with AML.  This is data taken from

 

             18   cooperative group trials on both sides of the

 

 

             19   Atlantic, and this required the patient to get to a

 

             20   center where they could get chemotherapy.  So, as

 

             21   I'll come back to, it may not be representative of

 

             22   what really happens in the community.

 

             23             Nonetheless, this slide makes the

 

 

             24   important point that the therapeutic outcome in

 

             25   older adults is much different than younger adults.


 

 

 

 

 

 

                                                                            26

 

              1   For example, if you're over age 65, your chance of

 

              2   achieving complete remission is only 45 percent,

 

              3   compared to 70 percent in younger adults with AML.

 

 

              4   If you achieve remission your chance for staying in

 

              5   remission is only about one in five, compared to

 

              6   about 45 percent of younger adults.

 

              7             And what's particularly striking to me as

 

              8   an oncology and a leukemia doctor taking care of

 

 

              9   these patients, is the treatment-related mortality

 

             10   rate is about one in four, and the early death rate

 

             11   is much lower in younger adults.

 

             12             The overall survival--about 10 percent,

 

             13   walking in the door.  And these are people that

 

 

             14   could get chemotherapy--compared 1 in 30 younger

 

             15   adults.

 

             16             The median survival of older adults who

 

             17   present with AML and go on clinical trials is only

 

             18   10 months--which I think we'd all agree is not

 

 

             19   someplace we'd like to be.

 

             20             [Slide.]

 

             21             There are two major reasons--as I

 

             22   indicated--for this inferior outcome.  The first

 

             23   general category is decreased host tolerance.  Of

 

 

             24   course, being older, these patients have a higher

 

             25   incidence of having co-morbid diseases such as


 

 

 

 

 

 

                                                                            27

 

              1   diabetes and vascular disease.  Perhaps because of

 

              2   that, and for just general aging features, they

 

              3   have a decreased ability to clear chemotherapy,

 

 

              4   which obviously could contribute to increased

 

              5   toxicity.

 

              6             Thirdly, it's been shown in multiple

 

              7   studies that the ability to recover from myelotoxic

 

              8   chemotherapy is diminished in older adults, and

 

 

              9   they have a longer period of neutropenia and

 

             10   thrombocytopenia--which leads to an enhanced rate

 

             11   of chemotherapy-induced complications.

 

             12             [Slide.]

 

             13             At least as important, if not more so, is

 

 

             14   the fact that the leukemias which arise in older

 

             15   adults are intrinsically resistant, biologically.

 

             16   This fact of increased intrinsic resistance is


 

 

 

 

 

 

                                                                            28

 

              1   manifested by, or associated with, these features:

 

              2   number one, there's an increased instance of what's

 

              3   called "unfavorable chromosomal abnormalities" in

 

 

              4   older patients, such as the loss of the long arm of

 

              5   the entire chromosome-5 or -7' problems at 11q23,

 

              6   and complex cytogenetic abnormalities.  These are

 

              7   the same type of abnormalities that occur in people

 

              8   who have myelodysplastic syndrome, and/or people

 

 

              9   who had prior chemotherapy for other cancers.

 

             10             There's an increased incidence of

 

             11   antecedent--either known or suspected--hematologic

 

             12   abnormalities, most particularly myelodysplastic

 

             13   syndrome.

 

 

             14             There's an increased likelihood of

 

             15   expression of genes which encode drug resistance,

 

             16   most notably the MDR-1 protein, which is a

 

             17   chemotherapy efflux pump, as well as other ones

 

             18   like MRP, LRP, MSH-2.

 

 

             19             [Slide.]

 

             20             Now, this combination of biological and

 

             21   host factors, and the inferior outcomes, led to a

 

             22   slight change in the approach of cooperative groups


 

 

 

 

 

 

                                                                            29

 

              1   in the 1990s, where separate clinical trials were

 

              2   designed for older adults compared to younger

 

              3   adults with AML.

 

 

              4             This is a representative list of trials

 

              5   conducted in the 1990s in cooperative groups in

 

              6   Europe and in America.  And even though these

 

              7   trials evaluated different novel therapeutic

 

              8   strategies, such as the use of growth factors,

 

 

              9   different chemotherapeutic drugs, and

 

             10   drug-resistance modulating drugs, the results are

 

             11   very stereotyped from trial to trial.  There are

 

             12   other trials out there which I could have picked,

 

             13   such as the recently published MRC trial, but that

 

 

             14   was largely a little bit younger patient

 

             15   population.

 

             16             The median age is 68 in all the trials.

 

             17   The complete remission rate is about 40 to 50

 

             18   percent.  And, again, the toxic death rate--and

 

 

             19   this is the 1990s--is in the 20 percent range

 

             20   throughout all the trials.  And, again, all the

 

             21   trials--median survival, nine to 10 months.

 

             22             And I want to stress one very important


 

 

 

 

 

 

                                                                            30

 

              1   point: it's that these--the patients who went on

 

              2   these trials were, number one, deemed to be

 

              3   chemotherapy candidates.  They got to a center that

 

 

              4   was participating in a cooperative group trial.

 

              5   They had to meet the eligibility criteria for these

 

              6   trials--which varied from trial to trial, there

 

              7   were subtle differences.  Most of these trials did

 

              8   not allow people with secondary AML; that is AML

 

 

              9   that occurred myelodysplastic syndrome, or after

 

             10   prior chemotherapy to go on.  Some did.  Some of

 

             11   the trials had a lower boundary of age 60, some 65,

 

             12   some 55.

 

             13             And so those are kind of the best results

 

 

             14   one can get with chemotherapy.

 

             15             [Slide.]

 

             16             The situation in the community is

 

             17   certainly much worse.  That's number one.

 

             18             Number two is: if you look into the

 

 

             19   subgroup analysis of these trials, you can find

 

             20   some important facts which suggest that you can

 

             21   identify patients that even have a worse prognosis

 

             22   than the average.  For example, if you have prior


 

 

 

 

 

 

                                                                            31

 

              1   myelodysplastic syndrome, your chance of remission

 

              2   is 24 percent compared to 52 percent if you don't.

 

              3   If you have one of those poor cytogenetic

 

 

              4   abnormalities that I mentioned, 21 percent

 

              5   likelihood of remission, compared to 55 percent if

 

              6   you don't. And these data were taken from the SWOG

 

              7   trial.

 

              8             This data from the recently published ECOG

 

 

              9   trial says that if you're over age 70, you've got a

 

             10   29 percent of going into remission, compared to 51

 

             11   percent for those younger than age 70.  However,

 

             12   only 13 percent in this trial were above age 75.

 

             13             Only 5 percent of those in the Lowenberg

 

 

             14   trial were above age 80, and in those people the

 

             15   chance for remission was only 14 percent.

 

             16             So, number one, you can find bad

 

             17   prognostic factors within these groups and, number

 

             18   two, the number of patients who are really old who

 

 

             19   go on these trials is low.

 

             20             [Slide.]

 

             21             Community data is shown in this slide

 

             22   which suggests that if you're over age 65 and you


 

 

 

 

 

 

                                                                            32

 

              1   present with AML, your median survival may be only

 

              2   in the several-month range, compared to the another

 

              3   10 months we saw for the people who went on those

 

 

              4   chemotherapy trials.

 

              5             [Slide.]

 

              6             So, given this sort of dismal outcome with

 

              7   chemotherapy, the value of chemotherapy in this age

 

              8   population is debated, particularly in those who

 

 

              9   have poor prognosis features.

 

             10             There have only been a couple of

 

             11   randomized studies--and these were done in Europe

 

             12   in the 1980s--which tried to compare early

 

             13   aggressive chemo versus less intensive approaches.

 

 

             14   And they both showed a small increase in survival

 

             15   for early intensive chemo, but there was no

 

             16   associated quality of life studies, and cost, in

 

             17   terms of up-front mortality was quite high.

 

             18             These issues are reflected in the National

 

 

             19   Cancer Center Network guidelines--it's a consensus

 

             20   panel of AML experts--which acknowledges that

 

             21   standard induction chemotherapy is an option, but

 

             22   clinical trial with either new agents or biological


 

 

 

 

 

 

                                                                            33

 

              1   agents is the preferred approach even for those

 

              2   people who have good performance status who are

 

              3   over age 60 and present with AML.

 

 

              4             [Slide.]

 

              5             How do people make this difficult decision

 

              6   between a treatment which has a 25 percent toxic

 

              7   death rate and a low cure rate, versus supportive

 

              8   care?  It's a very difficult decision.  My

 

 

              9   colleague Dr. Sekeres, when he as at the

 

             10   Dana-Farber, tried to study this by a prospective

 

             11   patient-doctor questionnaire, and among the

 

             12   findings from the study are that, number one,

 

             13   patients consistently inflate the chance of cure,

 

 

             14   compared to what is stated in medical record

 

             15   predicted by the physician; number two, despite

 

             16   documentation in the medical record that the

 

             17   doctors discussed multiple treatment options with

 

             18   the patients, the patients said, no, they didn't

 

 

             19   discuss this with me.  That may be because there

 

             20   really aren't too many options, and the options

 

             21   seem to be so stark that people feel they don't

 

             22   really have any.

 

             23             [Slide.]

 

 

             24             What happens in the community?  This slide

 

             25   suggests the choices people make.


 

 

 

 

 

 

                                                                            34

 

              1             First of all, if you're in the younger

 

              2   cohort of the overall older cohort, you only choose

 

              3   chemotherapy about half the time.  As you get

 

 

              4   older, the chance of choosing chemotherapy is quite

 

              5   low.

 

              6             What are the consequences of this

 

              7   decision?  Well, if you choose to get chemotherapy,

 

              8   you're going to spend significantly more time in

 

 

              9   the hospital than if you choose supportive care.

 

             10             What's even more important than that is

 

             11   you don't get any bang for the buck, because the

 

             12   percentage of time you spend in the hospital,

 

             13   compared to the total amount of time that you have

 

 

             14   left is still higher if you choose chemotherapy.

 

             15   So you don't seem to reap any benefit in that

 

             16   regard.

 

             17             [Slide.]

 

             18             So I think it's quite clear that the

 

 

             19   efficacy of standard chemotherapy is reduced in the


 

 

 

 

 

 

                                                                            35

 

              1   older adult with AML compared to the younger adult.

 

              2   The therapy is poorly tolerated.  There is clearly

 

              3   a high therapy-related mortality rate.  No trials

 

 

              4   that I know about have really addressed the quality

 

              5   of life cost of chemotherapy.

 

              6             If there is a small improvement in

 

              7   survival with chemotherapy, it's quite likely to be

 

              8   offset by an increase in hospitalization and other

 

 

              9   negative QOL factors.  And it's moot for many

 

             10   patients, because two-thirds of patients who are

 

             11   older than age 65 don't choose chemotherapy as

 

             12   their primary treatment modality.

 

             13             So non-chemotherapeutic approaches,

 

 

             14   besides supportive care, which may have efficacy

 

             15   and low toxicity, are badly needed.

 

             16             [Slide.]

 

             17             In summary, it's clear that AML in the

 

             18   older adult is a biologically and clinically

 

 

             19   distinct entity.  Even in the so-called "best"

 

             20   patients who go on chemotherapy trials, the chance

 

             21   for treatment-related death with induction

 

             22   chemotherapy is actually greater than the chance


 

 

 

 

 

 

                                                                            36

 

              1   for cure.  In those poor prognosis patients who

 

              2   have--in the older part of this group--who have

 

              3   prior MDS, adverse cytogenics, the advisability of

 

 

              4   chemotherapy must be considered very low.

 

              5             Patients and doctors are often choosing a

 

              6   non-intensive approach, but currently there is

 

              7   really no such therapy in this category which

 

              8   offers and appreciable chance for remission.

 

 

              9             So I'd like to thank you for your

 

             10   attention.  And I'll be happy introduce Alain

 

             11   Thibault from Johnson & Johnson Pharmaceutical

 

             12   Research & Development to talk about CTEP-20.

 

             13                          Clinical Data

 

 

             14             DR. THIBAULT: Thank you, Dr. Stone.

 

             15             Good morning.  My name is Alain Thibault.

 

             16   I'm responsible for the clinical development of

 

             17   tipifarnib worldwide.

 

             18             I will first describe key features of

 

 

             19   tipifarnib, then I will present the results of

 

             20   CTEP-20, which was a trial sponsored by the Cancer

 

             21   Therapy and Evaluation Program of the National

 

             22   Cancer Institute.  These data are presented in


 

 

 

 

 

 

                                                                            37

 

              1   support of our application for the approval of

 

              2   tipifarnib in the treatment of newly diagnosed

 

              3   elderly patients with poor-risk AML.

 

 

              4             [Slide.]

 

              5             Tipifarnib is a selective and competitive

 

              6   inhibitor of the enzyme farnesyl transferase.  The

 

              7   enzyme processes more than a hundred proteins

 

              8   intracellularly--some of which are shown here, and

 

 

              9   many of which are involved in signaling pathways

 

             10   linked to the control of cell growth.  Other

 

             11   extensive research has been conducted.  To this

 

             12   date, the specific pathways associated with the

 

             13   anti-leukemic activity in AML are still the subject

 

 

             14   of ongoing research.

 

             15             [Slide.]

 

             16             Tipifarnib is an oral treatment.  So,

 

             17   after oral administration, plasma and bone marrow

 

             18   concentrations rapidly exceed the IC50 of AML cell

 

 

             19   lines as determined in vitro.  Tipifarnib is

 

             20   metabolized in the liver by several pathways.  The

 

             21   major metabolites are biologically inactive.

 

             22   Tipifarnib is not a substrate from drug efflux pump


 

 

 

 

 

 

                                                                            38

 

              1   encoded by the MDR-1 gene.

 

              2             The diversity of metabolic routes may

 

              3   explain why tipifarnib has demonstrated a low

 

 

              4   potential for drug interactions in several

 

              5   pharmacology studies that have been carried out to

 

              6   date.

 

              7             [Slide.]

 

              8             The recommended dosing regimen is 600

 

 

              9   milligrams po BID, given for 21 days in four-week

 

             10   cycles.  This was established by a classical dose

 

             11   escalating Phase I trial conducted in 34 patients

 

             12   with poor-risk leukemias, most of whom had AML.

 

             13             The 21-day administration is required to

 

 

             14   maintain sustained inhibition of the target so as

 

             15   to maximize efficacy.  And the seven-day rest

 

             16   period is required to reduce the incidence of

 

             17   peripheral neuropathy, which had been observed when

 

             18   continuous, uninterrupted dosing was used.

 

 

             19             The 600 milligram BID dose is associated

 

             20   with consistent farnesyl transferase inhibition;

 

             21   plasma and bone marrow concentrations that exceed

 

             22   the IC50, and acceptable patient tolerability.

 

             23             [Slide.]

 

 

             24             Let's now turn to the description of the

 

             25   study design.  I'll first describe the rationale in


 

 

 

 

 

 

                                                                            39

 

              1   design, then I'll go over demographics, indices,

 

              2   characteristics.  Then we'll go over efficacy and

 

              3   safety.

 

 

              4             CTEP-20 was part of a research agreement

 

              5   established between Johnson & Johnson and the

 

              6   National Cancer Institute.  This was a single-arm

 

              7   study.  It was conducted at six sites across the

 

              8   United States, and Johns Hopkins University was the

 

 

              9   coordinating center.

 

             10             From the very beginning, the aim of the

 

             11   investigators was to study tipifarnib in patients

 

             12   with poor-risk myeloid neoplasms--I'll go over them

 

             13   in a few minutes.  And this was a very critical

 

 

             14   feature of the study from the very outset--that

 

             15   study of patients with poor-risk myeloid disorders.

 

             16             [Slide.]

 

             17             So--newly diagnosed patients, with

 

             18   high-risk MDS--myelodysplastic syndrome--chronic

 

 

             19   myelomonocytic leukemia, and acute myeloid leukemia


 

 

 

 

 

 

                                                                            40

 

              1   were initially enrolled.  Specifically regarding

 

              2   AML, the diagnosis of AML was based on WHO

 

              3   criteria.  No prior therapy for AML was

 

 

              4   allowed--with the exception of hydroxyurea, which

 

              5   could be used to control counts prior to the

 

              6   patient's entering the study.

 

              7             With respect to age, the study initially

 

              8   enrolled patients age 18 to 65, with risk factors

 

 

              9   such as unfavorable cytogenetics, prior MDS, or

 

             10   prior exposure to chemotherapy.  On the other hand,

 

             11   patients aged 65 and above could enter the study

 

             12   with or without risk factors.  These were the

 

             13   initial age requirements for AML patients.

 

 

             14             The patients had to have approximate

 

             15   status of 0 to 2 on the ECOG scale.  And this was

 

             16   chosen because it would enable them to receive

 

             17   treatment in the outpatient setting.

 

             18             [Slide.]

 

 

             19             After consultation and discussion and

 

             20   input from the FDA in July of 2003, the study

 

             21   protocol was amended: it was amended to focus on a

 

             22   more homogeneous population of elderly patients who


 

 

 

 

 

 

                                                                            41

 

              1   had AML, who were not candidates to receive

 

              2   intensive induction chemotherapy because the

 

              3   associated risks were felt to outweigh the

 

 

              4   benefits.

 

              5             Therefore, after this amendment, the age

 

              6   requirements were raised. Patients aged 65 to 74

 

              7   had to have a prior history of MDS, while patients

 

              8   75 years or older could enter the study in the

 

 

              9   absence of other risk factors.

 

             10             So these are the patients that Dr. Stone

 

             11   described as commonly excluded from trials that are

 

             12   commonly reported in the literature.

 

             13             [Slide.]

 

 

             14             The primary endpoint of the study was

 

             15   complete remission, assessed by the investigators.

 

             16             Duration of CR, partial remission,

 

             17   hematological improvement, and overall survival

 

             18   were evaluated as secondary endpoints.  Then the

 

 

             19   safety profile was characterized.

 

             20             [Slide.]

 

             21             The study applied standard morphologic

 

             22   criteria of complete remission, which are listed


 

 

 

 

 

 

                                                                            42

 

              1   here.

 

              2             To achieve a complete remission, a patient

 

              3   had to demonstrate less that 5 percent leukemic

 

 

              4   blasts in the bone marrow; full recovery of

 

              5   peripheral counts--without, obviously, circulating

 

              6   blasts or any evidence of extramedullary AML.

 

              7             [Slide.]

 

              8             Partial responses were defined as:

 

 

              9   complete recovery of counts in the presence of

 

             10   residual blasts--5 to 19 percent, following at

 

             11   least a 50 percent decline from baseline values.

 

             12   Then, hematology improvement was defined as partial

 

             13   recovery of peripheral counts, with the same bone

 

 

             14   marrow context.

 

             15             So these responses can be viewed as broad

 

             16   indicators of anti-leukemic activity, even though

 

             17   their correlation with survival is not well

 

             18   established.

 

 

             19             [Slide.]

 

             20             Treatment with tipifarnib as an outpatient

 

             21   monotherapy regimen--to ensure patient safety all

 

             22   patients were monitored weekly for toxicity.  All


 

 

 

 

 

 

                                                                            43

 

              1   patients had a bone marrow aspirate and biopsy

 

              2   performed prior to study entry.  And this procedure

 

              3   was repeated at the end of each treatment cycle.

 

 

              4             Unless they had dose-limiting toxicity,

 

              5   patients continued to receive tipifarnib in a

 

              6   cyclical fashion until disease progression or

 

              7   relapse.

 

              8             The only exception concerns patients who

 

 

              9   achieved a complete remission.  These patients had

 

             10   the option to stop treatment after three additional

 

             11   cycles, and then be re-treated at the time of

 

             12   relapse.  And I will go over the outcome of this

 

             13   maneuver, as well.

 

 

             14             [Slide.]

 

             15             In response to adverse events, the

 

             16   investigators could individualize treatment using

 

             17   three strategies: either dose reductions, treatment

 

             18   interruptions within a cycle, or treatment delays

 

 

             19   between cycles.

 

             20             Each cycle was to include a minimum of 21

 

             21   days of tipifarnib.  The minimum rest period was

 

             22   seven days, which could be extended by a maximum of


 

 

 

 

 

 

                                                                            44

 

              1   35 days if needed.  The total cycle duration could

 

              2   not exceed 63 days.

 

              3             [Slide.]

 

 

              4             So let's go over the details of the

 

              5   population right now.

 

              6             So, CTEP-20 started as a study of

 

              7   tipifarnib in high-risk MDS, CMMD and AML.  Of the

 

              8   171 patients that were enrolled, 158 were

 

 

              9   considered to be poor-risk AML patients.  The 137

 

             10   elderly poor-risk patients were strictly defined in

 

             11   the final protocol--as I outlined earlier.  And

 

             12   from now on, the presentation will focus on the 136

 

             13   patients who were actually treated.

 

 

             14             The 61 patients aged 65 to 74, with prior

 

             15   MDS; and the 75 patients aged 75 or more make up a

 

             16   unique population.

 

             17             [Slide.]

 

             18             The median age of the patient population

 

 

             19   is 75 years.  The male to female ratio is similar

 

             20   to that of the general elderly AML population, and

 

             21   appears to reflect the higher incidence of MDS in

 

             22   men.

 

             23             The major of patients were Caucasians--or

 

 

             24   White.  Among the seven non-Caucasians, three were

 

             25   African-Americans, two Asians, and two were


 

 

 

 

 

 

                                                                            45

 

              1   Hispanics.

 

              2             Most patients were symptomatic, either

 

              3   from AML or from pre-existing co-morbidities.

 

 

              4             [Slide.]

 

              5             Now, using the age-specific incidence of

 

              6   AML that Dr. Stone referred to earlier, if we use

 

              7   this as a comparator, CTEP-20 appears to be more

 

              8   representative of the general AML population than

 

 

              9   what is found in most other trials, in that the

 

             10   median age of the CTEP-20 patient was 75 years old.

 

             11   And this exceeds that of the major cooperative

 

             12   group studies by approximately 10 years.

 

             13             [Slide.]

 

 

             14             Now, we know that many issues underlie the

 

             15   assessment of AML patients, especially in the

 

             16   elderly.  The chance of cure, the risk of toxicity,

 

             17   the need for hospital stays all have an impact on

 

             18   treatment options that are offered to these

 

 

             19   patients.  This has been reviewed by Dr. Stone.

 

             20             What this slide lists are the clinical

 

             21   reasons given by the investigators--the six

 

             22   principal investigators of this study--for

 

             23   including the patients on the trial rather than

 

 

             24   administering intensive chemotherapy to them.

 

             25             Age and the presence of risk factors were


 

 

 

 

 

 

                                                                            46

 

              1   most commonly invoked.  Patient preference over

 

              2   physician preference of experimental treatment over

 

              3   chemotherapy played a minor role.

 

 

              4             [Slide.]

 

              5             Now, the clinical rationales I've just

 

              6   reviewed can be more objectively described in terms

 

              7   of the risk factors that are classically associated

 

              8   with poor outcome from chemotherapy So the CTEP-20

 

 

              9   patients had, by design, one of the highest

 

             10   prevalence of risk factors ever reported in the

 

             11   literature.  Prior MDS was documented in 82 percent

 

             12   of the patients.  Forty-nine percent of the

 

             13   patients harbored unfavorable cytogenetics, such as

 

 

             14   deletion of chromosome-5 or -7.  The other patients

 

             15   had intermediate karyotypes.  Patients with

 

             16   favorable karyotypes, such as inversion-16, were


 

 

 

 

 

 

                                                                            47

 

              1   not enrolled on this study.

 

              2             All in all, 41 percent--this number is not

 

              3   on the slide--had both MDS and unfavorable

 

 

              4   cytogenetics.

 

              5             Now, in terms of increased morbidity

 

              6   risks, 55 percent were age 75 or older--more than

 

              7   half; and 61 percent had evidence of organ

 

              8   dysfunction.  This was manifested by two or more

 

 

              9   active medical conditions other than the AML, on

 

             10   either history, physical examination or laboratory

 

             11   findings.

 

             12             [Slide.]

 

             13             Looking at the number of risk factors per

 

 

             14   patient is also very interesting: 44 percent of the

 

             15   patients had two risk factors; 35 percent had

 

             16   three; 11 percent had four of these risk factors.

 

             17   So, overall, 90 percent of the trial population

 

             18   entered with two or more risk factors on this

 

 

             19   trial.

 

             20             [Slide.]

 

             21             The full spectrum of leukemic burden was

 

             22   represented also in this study.  The median bone


 

 

 

 

 

 

                                                                            48

 

              1   marrow blasts count at diagnosis was 46 percent.

 

              2   All patients met the WHO criteria--as I

 

              3   mentioned--except for one, who was nevertheless

 

 

              4   included because he was clearly evolving from MDS.

 

              5   This patient, who did not achieve a CR was excluded

 

              6   by the FDA.  But, for the sake of this

 

              7   presentation, I'm reporting the results based on

 

              8   the investigator's assessment.

 

 

              9             [Slide.]

 

             10             The majority of the patients were severely

 

             11   myelosuppressed--as would be expected--prior to

 

             12   study entry.  The median neutrophil count was 636,

 

             13   with 61 percent having Grade 3 or 4

 

 

             14   myelosuppression at the time of entry.  Fifty-six

 

             15   percent of the patients had a similar degree of

 

             16   thrombocytopenia, with a median platelet count

 

             17   value of 41,500.

 

             18             [Slide.]

 

 

             19             So, in summary, the 136 patients accrued

 

             20   to this study represent a population with a high

 

             21   incidence of risk factors, and they routinely do

 

             22   poorly with available treatment.

 

             23             So, it is in this context that I'd like to

 

 

             24   review the efficacy of tipifarnib for the next few

 

             25   minutes.


 

 

 

 

 

 

                                                                            49

 

              1             [Slide.]

 

              2             Complete remissions were documented by the

 

              3   investigators at the research sites in 20 patients,

 

 

              4   for a complete remission rate of 15 percent.  The

 

              5   associated 95 percent confidence interval ranges

 

              6   from 9 to 22 percent.

 

              7             Partial remissions and hematologic

 

              8   improvements were documented in 10 additional

 

 

              9   patients.  So, in total, tipifarnib reduced the

 

             10   leukemic burden of 30 patients, or 22 percent of

 

             11   the study population.

 

             12             [Slide.]

 

             13             In general, the data shows consistency

 

 

             14   across risk groups.  And this is what we illustrate

 

             15   here on this slide.

 

             16             For example, the complete remission rate

 

             17   in the 111 patients with prior MDS, secondary AML,

 

             18   was 16 percent; and the response rate in the

 

 

             19   patients aged 75 years or more was 12 percent.

 

             20             [Slide.]

 

             21             The complete remissions were documented at

 

             22   four of the six sites.  No single institution

 

             23   accounts for the majority of cases.

 

 

             24             [Slide.]

 

             25             And as a specific quality control feature


 

 

 

 

 

 

                                                                            50

 

              1   of the study, the complete remissions were sought

 

              2   to be confirmed by the investigators, even though

 

              3   the primary endpoint of the study was achieving a

 

 

              4   CR.

 

              5             So what this slide shows here, is that the

 

              6   primary endpoint of the study was complete

 

              7   remission, and that of the 20 patients who achieved

 

              8   a complete remission, 17 were confirmed by repeat

 

 

              9   bone marrow biopsy at one month.  The three that

 

             10   were not confirmed include one patient who relapsed

 

             11   early, one patient who died while in CR, and one

 

             12   patient who refused further follow-up with bone

 

             13   marrow biopsies--and I will go over them in some

 

 

             14   detail for you.

 

             15             [Slide.]

 

             16             Patient 318 was an 81-year-old man with 90


 

 

 

 

 

 

                                                                            51

 

              1   percent blasts at baseline.  He achieved a complete

 

              2   remission but had evidence of early relapse by

 

              3   peripheral counts on day 58.

 

 

              4             Patient 336 was an 80-year-old man who

 

              5   achieved also a CR following one cycle of

 

              6   tipifarnib at the recovery of counts at the end of

 

              7   the cycle.  Upon re-treatment with a second cycle,

 

              8   he developed drug-induced myelosuppression.  This

 

 

              9   was complicated by neutropenic fungal sepsis, and

 

             10   then the patient died in CR on day 67.

 

             11             And, finally, patient 508 was a

 

             12   79-year-old man with 90 percent blasts at the time

 

             13   of study entry.  He entered a CR which was

 

 

             14   established by bone marrow biopsy.  He then refused

 

             15   further bone marrow assessments, but was maintained

 

             16   in CR by continuous treatment for 121 days, based

 

             17   on peripheral counts.

 

             18             [Slide.]

 

 

             19             Another aspect of the quality control

 

             20   measure was an independent review which was

 

             21   performed by Dr. Albitar.  This reviewer was

 

             22   blinded to patient outcome.

 

             23             This review involved a retrospective

 

 

             24   collection of the baseline diagnostic bone marrow

 

             25   slides from the 136 patients, and in addition, the


 

 

 

 

 

 

                                                                            52

 

              1   key aspirate slides which were obtained from

 

              2   patients on treatment.  This included slides from

 

              3   18 of the 20 patients who achieved a CR, so that

 

 

              4   the independent reviewer had access to a large

 

              5   proportion, although not all, of the CRs.

 

              6             So his findings are summarized on this

 

              7   slide.

 

              8             [Slide.]

 

 

              9             As a result of his review, all 18

 

             10   CRs--this is the first bullet--all 18 CRs that were

 

             11   available for him were agreed upon, for a

 

             12   concordance rate of 100 percent.

 

             13             The reviewer--and this is the second

 

 

             14   bullet--the reviewer also agreed that 15 of the 16

 

             15   confirmed CRs that were available for his

 

             16   review--there were 17 by the investigators, 16

 

             17   available.  And therefore, from his review of the

 

             18   16, he verified that 15 were indeed maintained at

 

 

             19   one month.

 

             20             The one disagreement is in the patient on

 

             21   whom there was agreement that he achieved a CR, but

 

             22   there was a disagreement as to the number of blasts

 

             23   in the follow-up period.  The investigators

 

 

             24   assessed as less than 5 percent, and the

 

             25   independent reviewer assessed it variously between


 

 

 

 

 

 

                                                                            53

 

              1   6 percent and 9 percent.  Both agreed on the time

 

              2   of relapse.

 

              3             [Slide.]

 

 

              4             Now, most patients who achieved a complete

 

              5   remission on this study had more than one risk

 

              6   factor.  These complete remissions, but also

 

              7   partial remissions and heme improvements were

 

              8   documented regardless of the number of risk factors

 

 

              9   present in any given patients.  And so the overall

 

             10   rates of anti-leukemic activity ranged from 19

 

             11   percent to 29 percent, irrespective of the number

 

             12   of risk factors.  There is no trend that can be

 

             13   identified.

 

 

             14             [Slide.]

 

             15             On this Kaplan-Myer plot, the x-axis is

 

             16   labeled in days.  The complete remissions were


 

 

 

 

 

 

                                                                            54

 

              1   durable.  They range from 33 to 376 days, with a

 

              2   median duration of 220 days.  This is slightly more

 

              3   than seven months.

 

 

              4             The 95 percent confidence interval around

 

              5   this is 154 up to 275 days.

 

              6             Duration of complete remissions was

 

              7   calculated starting from the first documentation of

 

              8   CR until time of relapse.  And the dots represent

 

 

              9   patients that were censored at the time of clinical

 

             10   cut-off, or the time of death, if they were still

 

             11   in CR.

 

             12             [Slide.]

 

             13             Now, turning your attention to survival,

 

 

             14   on this Kaplan-Myer plot, and on the one that will

 

             15   follow, patients were censored at the time of

 

             16   clinical cut-off or last follow-up.  131 patients

 

             17   have complete follow-up, and five patients had

 

             18   follow-up--at least partial follow-up.

 

 

             19             The median survival of the patients who

 

             20   achieved a CR was 433 days.  This is in excess of a

 

             21   year.  Two patients were alive at two and three

 

             22   years, respectively.  And these data suggest that


 

 

 

 

 

 

                                                                            55

 

              1   complete remissions are indeed associated with

 

              2   survival benefit in this patient population.

 

              3             This potential effect on survival is being

 

 

              4   investigated in a 301 trial that Dr. DeLap

 

              5   described at the beginning of this presentation.

 

              6             [Slide.]

 

              7             Finally, the overall survival of the 136

 

              8   patients is depicted here.  The median survival was

 

 

              9   164 days, or approximately five to five-and-a-half

 

             10   months.

 

             11             [Slide.]

 

             12             The information collected by the

 

             13   investigators concerned tipifarnib administration,

 

 

             14   obviously, but also treatment administered after

 

             15   failing the first course of treatment.

 

             16             This slide shows the re-treatment of

 

             17   patients who achieved a CR--seven of the 20

 

             18   patients who achieved a CR chose to stop after

 

 

             19   three cycles.  They were re-treated with tipifarnib

 

             20   at relapse.  One of these seven patients achieved a

 

             21   second complete remission of similar duration to

 

             22   the first one: approximately six months.

 

             23             So these data suggest that patients may

 

 

             24   remain sensitive to tipifarnib at the time of

 

             25   relapse.


 

 

 

 

 

 

                                                                            56

 

              1             [Slide.]

 

              2             The use of chemotherapy after tipifarnib

 

              3   in the 136 patients was also recorded.  The

 

 

              4   majority of the patients went on to receive

 

              5   palliative care only.

 

              6             Only 12 patients, most of whom were less

 

              7   than 75, were able to receive intensive

 

              8   chemotherapy, usually anthra-cycline plus Ara-C.

 

 

              9             [Slide.]

 

             10             So, in summary, tipifarnib is active in

 

             11   elderly, poor-risk AML.  The CTEP investigators

 

             12   documented a 15 percent complete remission rate,

 

             13   which is the primary endpoint of the study.

 

 

             14             Most of the complete remissions were

 

             15   confirmed at one month by the investigators, and

 

             16   verified by the independent reviewer.  Complete

 

             17   remissions were durable, lasting 220 days, or 7.2

 

             18   months.  The median survival of patients with

 

 

             19   complete remission was 433 days, or 14.2 months.

 

             20             [Slide.]

 

             21             This enters the final section of the

 

             22   presentation, which concerns safety.

 

             23             In terms of drug exposure, the median

 

 

             24   treatment cycle duration was 38 days.  47 percent

 

             25   of the patients received two or more cycles.  So


 

 

 

 

 

 

                                                                            57

 

              1   this includes patients with complete remissions,

 

              2   partial remissions, and hematologic

 

              3   improvement--but also several patients who

 

 

              4   maintained stable disease for s several months.

 

              5             [Slide.]

 

              6             The need for treatment interruptions or

 

              7   delays explained the median cycle duration of 38

 

              8   days which I just presented.  Those reductions were

 

 

              9   implemented in 35 percent of the patients.

 

             10   Reductions were implemented in approximately half

 

             11   of the patients who received two or more cycles,

 

             12   such as the patients who achieved a CR.

 

             13             The most common reason for dose reductions

 

 

             14   were related to myelosuppression, gastrointestinal,

 

             15   CNS--and, rarely, renal or dermatological signs and

 

             16   symptoms.

 

             17             Patient age did not appear to have an

 

             18   impact on the tolerability.

 

 

             19             [Slide.]

 

             20             So, as expected in a population with AML,

 

             21   the adverse events were common: 61 percent of the

 

             22   population experienced drug-related adverse events.

 

             23   These were mostly related to myelosuppression--in

 

 

             24   the background of, of course, severe

 

             25   myelosuppression.


 

 

 

 

 

 

                                                                            58

 

              1             In contrast, only 10 percent of the

 

              2   patients were withdrawn for drug adverse event.

 

              3   And adverse events were also associated with a low

 

 

              4   mortality rate.  Only nine patients in whom an

 

              5   adverse event--of the nine patients, actually, in

 

              6   whom an adverse event led to death, only one was

 

              7   assessed by the investigators as related to

 

              8   tipifarnib.

 

 

              9             [Slide.]

 

             10             To go into more details, a majority of

 

             11   patients experienced Grade 3 or 4 myelosuppression

 

             12   by peripheral count assessments.  Fewer patients

 

             13   went on to develop clinical adverse events in the


 

 

 

 

 

 

                                                                            59

 

              1   form of sepsis or bleeding complications.

 

              2             And, as I mentioned, approximately

 

              3   two-thirds had Grade 3 myelosuppression at the time

 

 

              4   of study entry, and so the overall incidence has to

 

              5   be interpreted in this context.

 

              6             [Slide.]

 

              7             Turning our attention to non-hematologic

 

              8   adverse events--that is, events excluding

 

 

              9   myelosuppression and its complications--the overall

 

             10   rate of life-threatening or Grade 4 events was low:

 

             11   2 percent.  Most events were reversible following

 

             12   treatment interruption.

 

             13             The GI tract was most commonly involved.

 

 

             14   Nausea, diarrhea, vomiting were most often mild to

 

             15   moderate.  The incidence of drug-related mucositis

 

             16   was only 3 percent.  This is what this shows--5

 

             17   percent, and 3 percent if we consider Grade 3 or 4

 

             18   in severity.

 

 

             19             Now, given that mucositis is a major

 

             20   contributor of morbidity and death in

 

             21   myelosuppressed patients, this is probably the most

 

             22   important--the most important safety advantage of


 

 

 

 

 

 

                                                                            60

 

              1   tipifarnib in this older population.

 

              2             [Slide.]

 

              3             Rare adverse events affecting the renal

 

 

              4   and CNS systems were documented.  Few reached Grade

 

              5   3 or 4 severity.  All these adverse events were

 

              6   managed appropriately by protocol-defined treatment

 

              7   interruption and dose reductions. Many appeared in

 

              8   the context of sepsis, and were of short duration.

 

 

              9   Rapid ejaculation, the median duration of CNS

 

             10   events was two to three days.

 

             11             [Slide.]

 

             12             Very few patients--as we show here--were

 

             13   removed from the study because of these events.

 

 

             14             Indeed, the adverse events that led to the

 

             15   termination of treatment were varied.  No one AE

 

             16   appears to be a major contributor.  The most common

 

             17   causes were elevation of serum creatinine and skin

 

             18   rash, both of which were reversible.

 

 

             19             [Slide.]

 

             20             This study did not have a specific module

 

             21   collecting data on quality of life as we would

 

             22   have.  So, hospitalization data provides a valuable


 

 

 

 

 

 

                                                                            61

 

              1   perspective on the safety profile and the patient

 

              2   tolerability of this drug.  And what it suggests is

 

              3   that outpatient treatment of this elderly

 

 

              4   population is feasible.

 

              5             Up to 40 percent of the patients received

 

              6   their full course of treatment as outpatients.  The

 

              7   majority of patients who were hospitalized were

 

              8   hospitalized only once or twice.

 

 

              9             The median duration of combined hospital

 

             10   stay was 15 days--all hospitalizations.  And this

 

             11   represents 14 percent of the patients spent on

 

             12   study.

 

             13             [Slide.]

 

 

             14   Finally, few patients died from adverse events on

 

             15   this study.  No single cause appears to account for

 

             16   the majority of cases, most of which appear related

 

             17   to a complication of AML.

 

             18             In the opinion of the investigators, only

 

 

             19   one death from neutropenic fungal sepsis was

 

             20   related to tipifarnib.

 

             21             [Slide.]

 

             22             So how can we best summarize CTEP-20?


 

 

 

 

 

 

                                                                            62

 

              1   First of all, CTEP-20 was a study of patients with

 

              2   significant unmet medical need, determined by the

 

              3   advanced age, and the high prevalence of risk

 

 

              4   factors which are associated with poor patient

 

              5   outcome.

 

              6             In this patient population, tipifarnib

 

              7   induced as a monotherapy a 15 percent complete

 

              8   remission rate that was both durable and

 

 

              9   independent of risk factors.

 

             10             The safety profile of tipifarnib allowed

 

             11   outpatient treatment.  This might be due to a very

 

             12   low rate of life-threatening non-hematological

 

             13   toxicity, especially when one considers mucositis.

 

 

             14             So, consequently, the time spent in

 

             15   hospital represented a small fraction of the total

 

             16   study time: approximately 14 percent.  Only one

 

             17   death was attributable to tipifarnib.

 

             18             This concludes my review.  And Dr. Alex

 

 

             19   Zukiwski will deliver the closing presentation for

 

             20   Johnson & Johnson.

 

             21                           Benefit/Risk

 

             22             DR. ZUKIWSKI: Thank you, Dr. Thibault.

 

             23             Good morning.  I'm Alex Zukiwski from the

 

 

             24   Oncology Development Group at Johnson & Johnson

 

             25   Pharmaceutical Research and Development.  I'm going


 

 

 

 

 

 

                                                                            63

 

              1   to conclude the presentation today with a summary.

 

              2             The proposed indication is: tipifarnib is

 

              3   indicated for the treatment of elderly patients

 

 

              4   with newly diagnosed poor-risk acute myeloid

 

              5   leukemia.  The basis of this approval is complete

 

              6   remissions-- an accepted efficacy endpoint in AML

 

              7   which has been shown to correlate with overall

 

              8   survival.

 

 

              9             [Slide.]

 

             10             It is evidence that elderly patients with

 

             11   poor-risk AML have limited therapeutic options.  As

 

             12   noted in Dr. Stone's presentation, select elderly

 

             13   patients should be considered for chemotherapy,

 

 

             14   although older patients do not do as well as

 

             15   younger patients.  These patients who receive

 

             16   induction chemotherapy were described as having the

 

             17   best ability to tolerate and benefit from such

 

             18   treatment.

 

 

             19             In the United States, approximately


 

 

 

 

 

 

                                                                            64

 

              1   two-thirds of the patients greater that 65 years of

 

              2   age do not receive IV chemotherapy.  This is due to

 

              3   an unfavorable benefit-risk.  These patients have

 

 

              4   risk factors which predispose to decreased

 

              5   efficacy, including antecedent hematological

 

              6   disorders such as myelodysplastic syndrome, and

 

              7   also have unfavorable cytogenetics.

 

              8             They also have factors which predispose

 

 

              9   them to increased toxicity, such as co-morbidities

 

             10   and compromised performance status.

 

             11             As indicated in the NCCN guidelines,

 

             12   options available for this under served patient

 

             13   population include investigational studies,

 

 

             14   low-intensity chemotherapy, and--unfortunately for

 

             15   many of these patients--it is simply best

 

             16   supportive care.

 

             17             [Slide.]

 

             18             The patients enrolled in CTEP-20 were felt

 

 

             19   not be well-served by standard induction

 

             20   chemotherapy.  And this represents a unique patient

 

             21   population which is not well represented in the

 

             22   literature. For example, the CALGB and ECOG studies


 

 

 

 

 

 

                                                                            65

 

              1   mentioned in Dr. Stone's presentation enrolled

 

              2   patients who were good candidates for induction

 

              3   chemotherapy, and many of these studies excluded

 

 

              4   those patients with prior myelodysplastic syndrome.

 

              5             The median age of the CTEP study

 

              6   population was 75 years, and 90 percent of the

 

              7   CTEP-20 patients had two or more risk factors which

 

              8   predisposed them to decreased efficacy and

 

 

              9   increased toxicity from conventional anti-leukemic

 

             10   therapies.

 

             11             [Slide.]

 

             12             The complete remission rate in this very

 

             13   difficult to treat patient population was 15

 

 

             14   percent by investigators' assessment.  As per the

 

             15   key academic investigators involved in the CTEP

 

             16   study, this response rate is meaningful in a

 

             17   patient population that is often excluded from AML

 

             18   studies, and many times receives palliative care

 

 

             19   only.

 

             20             Of the 20 complete remissions as assessed

 

             21   by the investigators, the independent reviewer was

 

             22   able to confirm and verify 15 complete remissions


 

 

 

 

 

 

                                                                            66

 

              1   for quality control purposes.  While the other five

 

              2   cases could not be verified for a variety of

 

              3   reasons, there is evidence of substantial

 

 

              4   anti-leukemic activity in these five patients.

 

              5             The median duration of complete remissions

 

              6   was 220 days, and complete remissions were observed

 

              7   across all risk groups.

 

              8             The exploratory analysis of survival--as

 

 

              9   outlined by Dr. Thibault--is encouraging, and will

 

             10   be further examined in an AML study specifically

 

             11   designed to evaluate a survival endpoint.

 

             12             [Slide.]

 

             13             The anti-leukemic activity observed in the

 

 

             14   CTEP-20 study has to be considered in the overall

 

             15   treatment context as presented by DR. Stone.  Even

 

             16   in the "best" patients who can receive induction

 

             17   chemotherapy, individual risk factors which were

 

             18   very prominent in the CTEP-20 study have a negative

 

 

             19   impact on complete remission rates.

 

             20             As shown in this slide, a reduction of

 

             21   complete remission rates by approximately one-half

 

             22   is observed in patients with prior myelodysplastic


 

 

 

 

 

 

                                                                            67

 

              1   syndrome, unfavorable cytogenetics, or advanced

 

              2   age--with even the most effective chemotherapeutic

 

              3   agents.

 

 

              4             The early death rates in these trials,

 

              5   which includes the more younger and fit patient

 

              6   populations, is approximately 20 to 25 percent,

 

              7   with the majority of these deaths associated with

 

              8   bone marrow aplasia and severe mucositis.

 

 

              9                            [Slide.]

 

             10             Now, to put the CTEP-20 study into

 

             11   context.

 

             12             These are patients which experienced AML

 

             13   investigators felt were not the best candidates for

 

 

             14   combination chemotherapy.  They had an 83 percent

 

             15   incidents of myelodysplastic syndrome; a 49 percent

 

             16   incidence of unfavorable cytogenetics, and a median

 

             17   age of 75.

 

             18             What would be the anticipated complete

 

 

             19   remission rate in this patient population with

 

             20   combination chemotherapy?

 

             21             The anticipated early death rate in this

 

             22   patient population with combination chemotherapy


 

 

 

 

 

 

                                                                            68

 

              1   would most likely be at least double the 12 percent

 

              2   early death rate observed in the CTEP-20 trial.

 

              3             [Slide.]

 

 

              4             In the patient population studied in

 

              5   CTEP-20, advanced age, with its associated

 

              6   co-morbidity co-morbidities, and the underlying

 

              7   disease complicates any treatment efforts.

 

              8             Despite this, a management and predictable

 

 

              9   safety profile was observed in the patients treated

 

             10   with tipifarnib.  Adverse events were managed with

 

             11   supportive care measures.  As the scheduled

 

             12   treatment was for 21 days, dose

 

             13   modifications--including dose interruptions and

 

 

             14   dose reductions--could be quickly implemented to

 

             15   address any emerging toxicities.

 

             16             Forty percent of the patients did not

 

             17   require hospitalization.  And for those who were

 

             18   hospitalized, the median duration was approximately

 

 

             19   15 days.  The limited time spent in hospital is an

 

             20   important feature of this outpatient treatment.

 

             21             Twelve percent of the patients died on

 

             22   study within 30 days of the first dose of


 

 

 

 

 

 

                                                                            69

 

              1   tipifarnib.  And only one treatment-related death

 

              2   was reported by the investigators during the study.

 

              3   This data indicates that tipifarnib has been shown

 

 

              4   to safely treat a unique elderly patient

 

              5   population.

 

              6             [Slide.]

 

              7             In conclusion, the application under

 

              8   review is focused on a difficult to treat patient

 

 

              9   population for whom an unmet medical need exists,

 

             10   and alternative treatments are required.

 

             11   Approximately one in seven to one in nine of the

 

             12   patients treated with tipifarnib developed a

 

             13   durable complete remission.

 

 

             14             This novel targeted therapy is

 

             15   administered as an oral tablet which allows for

 

             16   flexible outpatient dosing.  As presented here

 

             17   today, there is a positive benefit-risk evidence

 

             18   with tipifarnib treatment.

 

 

             19             Approval of tipifarnib for this orphan

 

             20   indication will provide a new treatment for elderly

 

             21   patients with poor-risk AML.  These patients are

 

             22   currently not well served.  Standard induction


 

 

 

 

 

 

                                                                            70

 

              1   chemotherapy has a high degree of toxicity and a

 

              2   lower degree of efficacy in this patient

 

              3   population.

 

 

              4             This concludes the sponsor's presentation.

 

              5             DR. MARTINO: Thank you.

 

              6             Ladies and gentlemen, I will not allow

 

              7   questions until we have also allowed the FDA and

 

              8   Dr.

 

 

              9   Fred Appelbaum to present.  So those of you that

 

             10   have questions please know that that will be your

 

             11   opportunity.

 

             12             Dr. Ryan, representing the FDA, will

 

             13   present next.

 

 

             14                         FDA Presentation

 

             15                      NDA 21-824, Zarnestra

 

             16             DR. RYAN: Good morning.  I'm Qin Ryan,

 

             17   medical officer in the Division of Oncology Drug

 

             18   Products.  I'm here today to present the main

 

 

             19   findings from our review of Zarnestra NDA 21824.

 

             20             [Slide.]

 

             21             My presentation will cover the relevant

 

             22   regulatory background; clinical development


 

 

 

 

 

 

                                                                            71

 

              1   overview and proposed indication; CTEP-20 study

 

              2   design, efficacy and safety findings.

 

              3             [Slide.]

 

 

              4             First, the relevant regulatory background.

 

              5             In oncology, clinical benefit has been

 

              6   defined as a longer life, a better life or an

 

              7   effect on an established surrogate for either.

 

              8             In acute leukemias, durable complete

 

 

              9   remission--CR--has been considered evidence of

 

             10   benefit.

 

             11             In some cases where leukemia CRs were of

 

             12   uncertain duration, CR was considered a surrogate

 

             13   reasonably likely to predict clinical benefit.

 

 

             14             [Slide.]

 

             15             Here are some examples.  As first-line

 

             16   indications for acute myeloid leukemia --AML--both

 

             17   idarubicin and daunorubicin were regular approvals

 

             18   based on demonstration of durable remissions in

 

 

             19   randomized trials.  In addition, idarubicin also

 

             20   demonstrated a survival advantage in two

 

             21   comparative studies.

 

             22             In the case of gemtuzumab, accelerated


 

 

 

 

 

 

                                                                            72

 

              1   approval was granted for patients aged 60 or older

 

              2   with CD-33 positive disease who are not candidates

 

              3   for second-line cytotoxic chemotherapy.  Approval

 

 

              4   was based on a pooled complete remission rate from

 

              5   three single-arm studies. Of 277 patients enrolled

 

              6   into these three studies, 157 were 60 years or

 

              7   older.  Although relaxed free survival was

 

              8   evaluated, the ratio of remission could not be

 

 

              9   reliably ascertained, as 45 percent of patients who

 

             10   achieved remission also received additional

 

             11   anti-leukemic therapy.

 

             12             [Slide.]

 

             13             Next, I will discuss the clinical

 

 

             14   background for this NDA.

 

             15             Patients with newly-diagnosed AML, if not

 

             16   treated, will progress rapidly to a fatal outcome.

 

             17   The standard induction therapy for newly diagnosed

 

             18   AML, such as 3+7 regimen of cytarabine and

 

 

             19   daunorubicin can be expected to achieve 60 to 75

 

             20   percent complete remission.  And the

 

             21   treatment-related death rate, less than 10 to 20

 

             22   percent in adult AML patients younger than age 60.

 

             23             [Slide.]

 

 

             24             One follow-up study indicated that 30 to

 

             25   40 percent of patients in this age group will


 

 

 

 

 

 

                                                                            73

 

              1   survive three years or more.  However, clinical

 

              2   outcome would depend on multiple factors.

 

              3   Unfavorable outcome is usually associated with

 

 

              4   multiple poor-risk factors, such as poor

 

              5   performance status, organ dysfunction, or

 

              6   significant co-morbidity, older age, unfavorable

 

              7   karyotype, prior MDS, disease resistance

 

              8   or patient intolerance to cytotoxic therapy.

 

 

              9             Although the incidence of adult AML

 

             10   increases with age, the chance for patients to

 

             11   receive treatment decreases.

 

             12             [Slide.]

 

             13             Menzin, et al., analyzed a data base of

 

 

             14   over 2,600 AML patients aged 65 or older,

 

             15   identified by Medicare claims.  Overall, only 30

 

             16   percent of those patients received some form of

 

             17   chemotherapy.  Asa shown here, the percentage of

 

             18   patients receiving chemotherapy decreased

 

 

             19   drastically with increasing age.

 

             20             [Slide.]

 

             21             Menzin, et al., also estimated survival

 

             22   for these patients.  As indicated by the curve with

 

             23   diamond points, the median survival for all

 

 

             24   identified patients was two months, with a two-year

 

             25   survival of 6 percent.


 

 

 

 

 

 

                                                                            74

 

              1             [Slide.]

 

              2             Compared to younger adults, elderly AML

 

              3   patients usually present with other risk factors,

 

 

              4   such as poor performance status, organ dysfunction,

 

              5   co-morbidity, unfavorable karyotype, prior MDS, and

 

              6   drug resistant disease, as mentioned before.  The

 

              7   less tolerant to standard induction therapy the

 

              8   elderly poor-risk AML patients are, the more likely

 

 

              9   they are to be a therapeutic challenge.

 

             10             [Slide.]

 

             11             One review pointed out that

 

             12   treatment-related mortality in elderly patients

 

             13   with poor-risk AML may be as high as 25 percent,

 

 

             14   and the complete remission rate may be less than 50

 

             15   percent.

 

             16             In a study of AML patients at least 80


 

 

 

 

 

 

                                                                            75

 

              1   years of age, the mortality rate at one month as 48

 

              2   percent, and the complete remission rate was less

 

              3   than 30 percent.

 

 

              4             Few elderly AML patients are expected to

 

              5   live free of disease after standard cytotoxic

 

              6   chemotherapy.

 

              7             [Slide.]

 

              8             Next, I will discuss the clinical program.

 

 

              9             Zarnestra is a farnesyl transferase

 

             10   inhibitor.  It is formulated in film coat 100 mg

 

             11   tablets.  In the CTEP-20 study, Zarnestra was

 

             12   tested as first-line AML induction therapy.  It was

 

             13   administered hourly with food, at a dose of 600 mg

 

 

             14   twice daily for 21 days, followed by a rest period

 

             15   of seven to 42 days.

 

             16             [Slide.]

 

             17             Zarnestra is being proposed for the

 

             18   treatment of elderly patients with newly diagnosed

 

 

             19   poor-risk acute myeloid leukemia.

 

             20             [Slide.]

 

             21             Eleven studies relevant to safety and dose

 

             22   findings have been submitted in this NDA.  Among


 

 

 

 

 

 

                                                                            76

 

              1   those, the studies relevant to efficacy and safety

 

              2   in AML are summarized here.  The most relevant

 

              3   population for the proposed indication is a

 

 

              4   subgroup of subjects in Study CTEP-20, accounting

 

              5   of 79 percent of CTEP-20 enrollment.

 

              6             The studies INT-17 and CTEP-1 are less

 

              7   relevant to the proposed indication.  Therefore we

 

              8   will focus our discussion on CTEP 20.

 

 

              9             I will now go over the CTEP-20 study

 

             10   design in the next few slides.

 

             11             [Slide.]

 

             12             This open-label, single-arm, multicenter

 

             13   study which opened on October 10, 2001, was

 

 

             14   originally designed to assess the efficacy and

 

             15   safety of Zarnestra in subjects with previously

 

             16   untreated, poor-risk hematologic malignancies.

 

             17   After enrolling 110 patients, Amendment 6 was

 

             18   implemented on September 16, 2003.  The target

 

 

             19   population as redefined as subjects either 75 years

 

             20   or older with newly diagnosed AML, or 65 to 74

 

             21   years of age with AML arising from prior

 

             22   myelodysplastic syndrome.

 

             23             [Slide.]

 

 

             24             The original primary objective was to

 

             25   determine response rate, which included CR and PR.


 

 

 

 

 

 

                                                                            77

 

              1   As mentioned, after the 6th Amendment, the primary

 

              2   objective changed to determining the complete

 

              3   remission rate in elderly subjects with previously

 

 

              4   untreated, poor-risk acute myeloid leukemia.

 

              5             Secondary objectives were to determine the

 

              6   progression-free survival, overall survival,

 

              7   duration of response, and safety profile.

 

              8             [Slide.]

 

 

              9             After Amendment 6, the major inclusion

 

             10   criteria can be described as follows: untreated

 

             11   newly diagnosed AML patients, 75 years or older, or

 

             12   65 to 74 years of age with prior MDS.

 

             13             Our eligible subjects should have

 

 

             14   pathologic confirmation of AML showing equal or

 

             15   more than 20 percent marrow or peripheral blasts.

 

             16   Patients must have an ECOG performance score of

 

             17   zero or one-- which was changed from the original

 

             18   zero to two--with adequate renal and liver

 

 

             19   function.

 

             20             Patients with the following conditions

 

             21   were excluded: hypoleukocytosis despite

 

             22   leukopheresis or hydroxyurea; acute promyelocytic

 

             23   leukemia; previous anti-leukemic chemotherapy other

 

 

             24   than hydroxyurea; disseminated intravascular

 

             25   coagulation, or leukemia involvement of the central


 

 

 

 

 

 

                                                                            78

 

              1   nervous system.

 

              2             [Slide.]

 

              3             Leukemia assessments were conducted at

 

 

              4   baseline and the end of each cycle, ranging from 29

 

              5   to 64 days.  This included medical history,

 

              6   physical examination, bone marrow aspiration and

 

              7   biopsy, CBC and chemistry.

 

              8             The criteria for response assessment were

 

 

              9   based on NCI-sponsored workshop on definition of

 

             10   diagnosis and response in acute myeloid leukemia.

 

             11             Per protocol, CR is defined as marrow

 

             12   showing less than 5 percent myeloblasts, with

 

             13   normal maturation of all cell lines; an ANC of at

 

 

             14   least 1,000 per micro liter; a platelet count of

 

             15   100,000 per micro liter; absence of blasts in

 

             16   peripheral blood; absence of identifiable leukemic


 

 

 

 

 

 

                                                                            79

 

              1   in the bone marrow; clearance of disease-associated

 

              2   cytogenetic abnormalities; and clearance of any

 

              3   previously existing extramedullary disease.

 

 

              4             In addition, CR must be confirmed four to

 

              5   six weeks after initial documentation; at least one

 

              6   bone marrow biopsy should be performed to confirm

 

              7   CR.

 

              8             Subjects who achieved a complete remission

 

 

              9   could receive additional Zarnestra treatment until

 

             10   disease progression, or receive up to three

 

             11   additional cycles and stop.

 

             12             Re-treatment with Zarnestra was allowed.

 

             13   Subjects with progressive disease at any time

 

 

             14   during the Zarnestra administration were withdrawn

 

             15   from the study.  The first follow-up occurred 30

 

             16   days after treatment termination for subjects who

 

             17   did not have a documented progression, or had not

 

             18   started subsequent therapy; every 90 days after

 

 

             19   documentation of progressive disease or start of

 

             20   subsequent therapy.

 

             21             In the next few slides, I will discuss the

 

             22   CTEP-20 patient population efficacy data.

 

             23             [Slide.]

 

 

             24             Of the total 171 patients enrolled in

 

             25   CTEP-20, 158 of them had AML.  At the time of


 

 

 

 

 

 

                                                                            80

 

              1   clinical cutoff, 157 AML subjects were treated with

 

              2   at least one cycle of Zarnestra.  Of those, 136

 

              3   were elderly subjects with poor-risk AML, and are

 

 

              4   most relevant to the proposed indication.

 

              5             Please note that one of the elderly

 

              6   subjects with poor-risk AML was excluded from FDA's

 

              7   efficacy analysis, but not safety analysis.  The

 

              8   reason for this exclusion was that this patient's

 

 

              9   baseline blast count was less than 20,000 per cubic

 

             10   milliliter, as assessed by both the investigator

 

             11   and the sponsor's central review.  This patient did

 

             12   not respond to Zarnestra treatment.

 

             13             This resulted in 156 evaluable patients in

 

 

             14   the all-treated AML population, and 135 patients in

 

             15   the elderly poor-risk AML population.

 

             16             Two thirds of subjects had a performance

 

             17   status of one, and a quarter of them had a

 

             18   performance status of zero.  There were

 

 

             19   approximately 10 percent of patients who were


 

 

 

 

 

 

                                                                            81

 

              1   enrolled before Amendment 6, with a performance

 

              2   status of two.  As per investigators, all 136

 

              3   patients were ineligible for standard chemotherapy

 

 

              4   for at least one reason.

 

              5             Of patients aged 75 or older, 96 percent

 

              6   were considered ineligible due to age, whereas in

 

              7   the 65 to 74-year-old group, approximately 50

 

              8   percent of patients had age or other risk factors

 

 

              9   as a reason for ineligibility.

 

             10             [Slide.]

 

             11             Based on the sponsor-provided data, risk

 

             12   factors in the CTEP-20 elderly poor-risk AML

 

             13   population are summarized by category and number.

 

 

             14             Eighty-two percent of patients had prior

 

             15   MDS; more than half of the patients were older than

 

             16   75 years, or with poor organ function as defined by

 

             17   the sponsor; and two-thirds of patients had

 

             18   unfavorable karyotypes; 44 percent and 35 percent

 

 

             19   of patients had at least two or three of these risk

 

             20   factors, respectively.  About 10 percent of

 

             21   patients had either one or four risk factors.

 

             22             Complete responders were initially


 

 

 

 

 

 

                                                                            82

 

              1   assessed by the site investigators. The sponsor

 

              2   appointed an independent reviewer to reassess the

 

              3   complete remissions.  FDA requested all available

 

 

              4   bone marrow slides of CRs from the sponsor, and

 

              5   reviewed them with an FDA-appointed hematology

 

              6   consultant.

 

              7             [Slide.]

 

              8             The assessment of CR by the study

 

 

              9   investigator, the independent reviewer, and FDA are

 

             10   summarized here.  Of the three unconfirmed CRs, the

 

             11   FDA and independent reviewer agreed with the

 

             12   investigator that two could not be confirmed due to

 

             13   death and disease progression.  FDA also agrees

 

 

             14   with the independent reviewer that on CR by

 

             15   investigator assessment was unconfirmed due to

 

             16   insufficient data.  In addition, slides of two

 

             17   subjects were not available for response assessment

 

             18   by the sponsor's independent reviewer or FDA

 

 

             19   consultant.

 

             20             [Slide.]

 

             21             FDA agrees with the sponsor-appointed

 

             22   independent reviewer's assessment of complete


 

 

 

 

 

 

                                                                            83

 

              1   remission; that is, 15 subjects were confirmed

 

              2   complete remission from the FDA-identified elderly

 

              3   poor-risk AML patient subgroup.

 

 

              4             FDA assessment of the confirmed complete

 

              5   remission rate is 11.1 percent, with a 95 percent

 

              6   confidence interval of 6.6 to 18 percent.

 

              7             [Slide.]

 

              8             Based on FDA exploratory subgroup

 

 

              9   analysis, patients older than age 74 have a lower

 

             10   tendency to achieve complete remission than do

 

             11   patients age 65 to 74, with a rate of 6.7 percent

 

             12   versus 16.4 percent, respectively.

 

             13             In addition, of the 25 patients older than

 

 

             14   74 years with de novo AML who enrolled in CTEP-20,

 

             15   only one patient achieved complete remission with

 

             16   confirmation.

 

             17             Less responders were seen in subjects with

 

             18   unfavorable karyotypes.

 

 

             19             [Slide.]

 

             20             The FDA has explored the duration of

 

             21   confirmed CR as a secondary endpoint of study

 

             22   CTEP-20.  Per protocol, no anti-leukemic therapy


 

 

 

 

 

 

                                                                            84

 

              1   other than Zarnestra was given to patients who

 

              2   achieved a response until after disease progression

 

              3   and removal from the study.

 

 

              4             At the time of cut-off, progression of

 

              5   disease or death occurred in seven of 15 patients,

 

              6   giving a median remission duration of 275 days,

 

              7   with 95 percent confidence interval of 127 to 376

 

              8   days.

 

 

              9             Next, I will discuss the CTEP-20 safety

 

             10   data.

 

             11             [Slide.]

 

             12             In CTEP-20, all of the elderly poor-risk

 

             13   AML patients received at least Zarnestra during

 

 

             14   first cycle; 47 percent of them were treated for a

 

             15   second cycle, and 20 percent received a third

 

             16   cycle.

 

             17             The median duration of these cycles was 36

 

             18   to 38 days.  The mean intensity for the first cycle

 

 

             19   was 749.4 mg per day, which is approximately 63

 

             20   percent of the planned 1,200 mg per day dose.

 

             21             The calculated dose intensity may not

 

             22   reflect true drug exposure, since the Zarnestra


 

 

 

 

 

 

                                                                            85

 

              1   exposure measurements were primarily based on the

 

              2   pharmacy dispensation record.  A patient medication

 

              3   diary was not planned for CTEP-20.

 

 

              4             [Slide.]

 

              5             Ninety-eight percent of CTEP-20 subjects

 

              6   experienced adverse events.  The most frequently

 

              7   reported non-hematological adverse events were

 

              8   diarrhea, fatigue, nausea, skin rash, fever,

 

 

              9   anorexia, constipation, vomiting and dyspnea.

 

             10   Dizziness, and  ataxia or abnormal gait were the

 

             11   most frequently seen nervous system adverse events.

 

             12   In addition, confusion was the most commonly seen

 

             13   psychiatric adverse event.  This may be related to

 

 

             14   age and hospitalization.

 

             15             The most common dermatological and

 

             16   infection-related adverse event were neutropenia,

 

             17   with or without fever; purpurea, thrombocytopenia,

 

             18   anemia, bacterial infection, candida and other

 

 

             19   fungal infections.

 

             20             The most frequent metabolic disturbances

 

             21   were increased creatinine, hypokalemia, and

 

             22   hyponatremia.

 

             23             Of 136 subjects, 21, 47 and 56 subjects

 

 

             24   had at least one adverse event leading to treatment

 

             25   termination, dose reduction, and temporary


 

 

 

 

 

 

                                                                            86

 

              1   interruption of Zarnestra, respectively.  The top

 

              2   three adverse events leading to changing treatment

 

              3   were neutropenia, increased creatinine and rash.

 

 

              4             FDA agrees with the sponsor that 113

 

              5   subjects, or 83 percent of the elderly poor-risk

 

              6   AML group, experienced Grade 3 or 4 adverse events.

 

              7   The most frequent treatment-emergent Grade 3 or 4

 

              8   adverse events were secondary to myelosuppression,

 

 

              9   including neutropenia, with or without fever,

 

             10   infection, thrombocytopenia, and anemia.

 

             11             Other frequent severe adverse events were

 

             12   fatigue, rash, dyspnea, confusion, diarrhea, and

 

             13   hypokalemia.

 

 

             14             [Slide.]

 

             15             Thirty-one of the 136 elderly poor-risk

 

             16   AML subjects in CTEP-20 died, either within 30 days

 

             17   of treatment termination, or within 30 days of

 

             18   receiving the first dose of medication.  The death

 

 

             19   rate within 30 days of the first dose was 12


 

 

 

 

 

 

                                                                            87

 

              1   percent. Based on the sponsor-provided data, we

 

              2   verified the sponsor's summary and agree that 19 of

 

              3   31 deaths were due to disease progression, and nine

 

 

              4   of them were due to adverse events.  The deaths due

 

              5   to adverse events were 7 percent with causes such

 

              6   as cardiac failure and various infections.

 

              7             One death due to adverse event was thought

 

              8   to be drug-related by the investigator.  This was a

 

 

              9   patient who had a neutropenic fever, fungal

 

             10   infection, and renal dysfunction.

 

             11             There were three of 31 deaths attributed

 

             12   to adverse events or progression of disease on

 

             13   subsequent treatment, after patients progressed

 

 

             14   from Zarnestra, which the sponsor categorized as

 

             15   "other" cause of death.

 

             16             [Slide.]

 

             17             Eighty-one subjects, or 60 percent of the

 

             18   total 136 patients, were hospitalized during the

 

 

             19   study.  Fourteen percent of the subjects received

 

             20   Zarnestra treatment in the outpatient setting

 

             21   completely.

 

             22             The median total duration of


 

 

 

 

 

 

                                                                            88

 

              1   hospitalization was 15 days.  Ten subjects required

 

              2   at least three hospitalizations during the study

 

              3   period.

 

 

              4             [Slide.]

 

              5             In summary, durable complete remission has

 

              6   been accepted as an endpoint supportive of regular

 

              7   approval in AML.  Zarnestra efficacy findings

 

              8   should be considered in the context of a poor-risk

 

 

              9   AML population and the toxicity profile observed.

 

             10   Although the remission rate does not compare

 

             11   favorably with that reported with cytotoxic

 

             12   therapy, the one-month's mortality and treatment

 

             13   related date rate of 12 percent and 7 percent,

 

 

             14   respectively, compare favorably with the greater

 

             15   than 25 percent treatment-related death rate

 

             16   reported in the literature for patients age 60 or

 

             17   older, with or without other risk factors, who had

 

             18   adequate organ function to receive chemotherapy.

 

 

             19             We will have one question for the

 

             20   committee to discuss: does the risk-benefit

 

             21   analysis support regular approval of Zarnestra for

 

             22   the treatment of elderly patients with AML?

 

             23             Thank you very much for your attention.

 

 

             24             DR. MARTINO: Thank you, Dr. Ryan.

 

             25             At this point, ladies and gentlemen, we


 

 

 

 

 

 

                                                                            89

 

              1   have one additional speaker, and that is Dr. Fred

 

              2   Appelbaum, who will present via videoconference at

 

              3   a quarter to the hour.

 

 

              4             So, at this point, I'm going to give you

 

              5   about 15, 20 minutes of a break, and we'll be back

 

              6   here at 10:45 for his video presentation.  We will

 

              7   take questions subsequently.

 

              8                            [Off the record.]

 

 

              9             DR. MARTINO: Back on the record.

 

             10             The next presentation is Dr. Fred

 

             11   Appelbaum.  He's going to speak to us via

 

             12   videoconference.  He is the Director of Clinical

 

             13   Research at Fred Hutchinson Cancer Center.  And I

 

 

             14   don't know if we are actually ready to go.

 

             15             Ms. Clifford?  Are we ready to go with Dr.

 

             16   Appelbaum?

 

             17             MS. CLIFFORD: I think so.

 

             18             DR. MARTINO: I someone going to clue him

 

 

             19   in?  Or shall Dr. Martino simply say: "Action."

 

             20                     AML in Older Individuals

 

             21                     [Via videoconferencing]

 

             22             DR. APPELBAUM: I couldn't hear anything

 

             23   you were saying.  Can you see my slides?

 

 

             24             VOICE: [Off mike.] [Inaudible.]

 

             25             You won't be able to follow the pointer,


 

 

 

 

 

 

                                                                            90

 

              1   is that right?

 

              2             Well, thank you for inviting me to say a

 

              3   few words about AML in older individuals.  I was

 

 

              4   asked by the FDA just to provide a general

 

              5   background.  I am not speaking particularly about

 

              6   this product or any of the information that was

 

              7   presented about the product, but rather just a

 

              8   global picture of AML in the elderly.  Some of this

 

 

              9   was probably already gone over this morning, so I

 

             10   will be relatively brief.

 

             11             [Slide.]

 

             12             The problem of AML in the elderly is a

 

             13   substantial one because the disease, as you can see

 

 

             14   from the first slide, in terms of incidence, goes

 

             15   up quite rapidly once patients are in their sixth

 

             16   decade.  Before that, it is relatively uncommon.


 

 

 

 

 

 

                                                                            91

 

              1   But once patients pass the age of 50, the incidence

 

              2   of AML goes up quite markedly.

 

              3             The problem of AML in the elderly--or the

 

 

              4   older individual--is different than AML in the

 

              5   younger individual for two primary reasons.  First,

 

              6   the patients are different and, secondly, the

 

              7   disease is different.

 

              8             In terms of patients being

 

 

              9   different--well, older patients are older.  And,

 

             10   with that comes an increased incidence

 

             11   co-morbidities and decreased performance status.

 

             12             [Slide.]

 

             13             This next slide shows you a typical

 

 

             14   picture of patients that were entered onto a

 

             15   protocol for patients with AML above age 55, using

 

             16   a standard induction regimen of daunomycin and

 

             17   Ara-C.

 

             18             As you can see from the performance status

 

 

             19   and the age, patients under age 60, a relatively

 

             20   small proportion of them--about 8 percent--will

 

             21   have a very poor performance status of 3 or

 

             22   greater; whereas once patients are over age 75,


 

 

 

 

 

 

                                                                            92

 

              1   that incidence at least doubles.

 

              2             Yet, even on those over age 75, at least

 

              3   60 percent--on this Southwest Oncology Group Study,

 

 

              4   which was the last one performed--had a performance

 

              5   status of zero or one, indicating relatively good

 

              6   performance.

 

              7             These statistics almost certainly

 

              8   understate the problem of decreased performance

 

 

              9   status in the elderly, because these are patients

 

             10   that the doctors chose to enter onto the trial.

 

             11   And it may be that, particularly among the elderly,

 

             12   there's a substantial proportion who were not

 

             13   entered onto the trial because of decreased

 

 

             14   performance status.

 

             15             I know of no easy--or no way, in fact, at

 

             16   all--that we can get data which truly reflects the

 

             17   performance status on a population basis of the

 

             18   elderly patients with AML.  This is almost

 

 

             19   certainly an underestimate of the difficulty.

 

             20             [Slide.]

 

             21             The next slide shows, I think, a very

 

             22   important principle that hasn't been talked


 

 

 

 

 

 

                                                                            93

 

              1   about--or it hasn't been published, to my

 

              2   knowledge, quite in this way--and that is the very

 

              3   great interaction between performance status and

 

 

              4   age.  So that this looks at patients, again,

 

              5   treated with a standard induct of Daunomycin-45 x 3

 

              6   and Ara-C, and a chance of dying within the first

 

              7   month of being entered onto study, based on the

 

              8   performance status and age.

 

 

              9             So that older patients--that is, those

 

             10   that are over age 70, have a relatively low chance

 

             11   of dying within the first 30 days if they have a

 

             12   good performance status--only 9 percent, which is

 

             13   not substantially different than what you'd see in

 

 

             14   patients even under age 50.

 

             15             Yet once patients get older, and their

 

             16   performance status goes done, then you see a marked

 

             17   interaction.  So that if you're both over age 70

 

             18   and have a performance status of 3, the chance of

 

 

             19   dying within the first 30 days is 62 percent, which

 

             20   is very, obviously, substantial.  So there's this

 

             21   interaction which is--both of performance status,

 

             22   because the younger patients don't have that high


 

 

 

 

 

 

                                                                            94

 

              1   chance of dying, even with a poor performance

 

              2   standard.  That's only 17 percent.  So you can see

 

              3   there's this interaction with both age and

 

 

              4   performance status, which are cumulative.

 

              5             [Slide.]

 

              6             This, of course, reflects what would

 

              7   happen with the overall complete response rate--I'm

 

              8   sorry, this slide simply shows what I just told

 

 

              9   you, but in a different graphic form.  That is

 

             10   performance status and age being cumulative in

 

             11   terms of the chance of early death, with 62

 

             12   percent--that's in the back right, versus a very

 

             13   low chance, in the front left, if you are young and

 

 

             14   have a good performance status.

 

             15             [Slide.]

 

             16             This clearly reflects--on complete

 

             17   response rates, which are shown in the next slide,

 

             18   so that if you're over age 70 treated with standard

 

 

             19   chemotherapy and have a good performance status,

 

             20   you have a relatively good chance--50 percent or

 

             21   greater--of getting a complete response.  But if

 

             22   you're older and have a poor performance status, it


 

 

 

 

 

 

                                                                            95

 

              1   deteriorates to, in this study, 29 percent.

 

              2   Whereas if you're younger and have a poor

 

              3   performance status, the interaction doesn't seem to

 

 

              4   be as great.  The numbers in these individual cells

 

              5   get fairly small with a total n of 500.

 

              6             So, the first way that AML in the elderly

 

              7   or the older patient differs is that the patients

 

              8   are older, they tend to have a poor performance

 

 

              9   status, and a poor performance status is a clear

 

             10   bad prognostic factor for getting a CR and for

 

             11   early death.

 

             12             The second way that AML in the older

 

             13   patient differs is that is biologically is

 

 

             14   different from AML in the younger patient--in

 

             15   general; not in each specific case, but as a

 

             16   population it differs.

 

             17             AML in the older patient is more often

 

             18   preceded by myelodysplasia.  It is a less

 

 

             19   proliferative disease.  It's more frequently

 

             20   associated with unfavorable cytogenetics, and it

 

             21   more often expresses multidrug resistence.

 

             22             And I'll show you data about each of


 

 

 

 

 

 

                                                                            96

 

              1   these.

 

              2             First, as far as "preceded by

 

              3   myelodysplasia"--and here one has to be careful

 

 

              4   about the definitions.  If one takes a strict

 

              5   definition of having a documented hematologic

 

              6   disorder preceding the diagnosis of AML by at least

 

              7   three months, generally this is seen in about 15 to

 

              8   18 percent of patients who are over age 55, and

 

 

              9   seen in about half that number in patients who are

 

             10   less than age 55.

 

             11             [Slide.]

 

             12             As far as "less proliferative" is

 

             13   concerned, that's shown on the slide you now have

 

 

             14   in front of you.  And this is a large number of

 

             15   patients--about 900 patients on three sequential

 

             16   studies--and it just shows that the white count, at

 

             17   diagnosis for AML, in patients who were less than

 

             18   age 55 is about 17,000, but it goes down to about

 

 

             19   12,000 when you're over age 75.  And the percent

 

             20   blasts if you're less than age 55 tends to be

 

             21   higher, at 39 percent; but if you're over age 75 it

 

             22   drops to about 26 percent--not marked differences,


 

 

 

 

 

 

                                                                            97

 

              1   but there is a biologic difference here which

 

              2   suggests that AML in the very old patient tends to

 

              3   be a less highly proliferative disease.

 

 

              4             [Slide.]

 

              5             The next slide shows the marked difference

 

              6   in cytogenetics as patients age in AML.

 

              7             The blue bars at the very top are the

 

              8   percent of AML patients with unfavorable

 

 

              9   cytogenetics, according to age.  So that if you're

 

             10   less than age 55, about 21 percent of patients will

 

             11   have unfavorable cytogenetics, using the SWOG--or

 

             12   Southwest Oncology Group--criteria for cytogenetic

 

             13   risk group--which is very similar, but not quite

 

 

             14   identical, to the MRC's definition.

 

             15             If patients are over age 75, the incidence

 

             16   of unfavorable cytogenetics increases markedly from

 

             17   21 percent to 52 percent; and, conversely, the dark

 

             18   bar at the bottom, the percent with favorable

 

 

             19   cytogenetics--that's 8;21, inversion 16, or 15, 17,

 

             20   then that drops from 20 percent in patients who are

 

             21   less than age 56, to only 4 percent if you're over

 

             22   age 75.

 

             23             The particular cytogenetic abnormalities

 

 

             24   which are seen more frequently as one ages are

 

             25   shown on the next slide.


 

 

 

 

 

 

                                                                            98

 

              1             [Slide.]

 

              2             And they are of marked increase in the

 

              3   incidence in the loss of -5, or part -5, on the

 

 

              4   long arm, or loss of -7 or part of 7 on the long

 

              5   arm, where either one of these was seen in either 6

 

              6   to 8 percent in patients age less than 56, but if

 

              7   you're over age 75, you see this in a three or

 

              8   four-fold higher incidence, with 26 or 22 percent,

 

 

              9   respectively.

 

             10             Similarly, a loss of the short arm of 17

 

             11   is seen in only 2 percent less than age 56, and

 

             12   greater than 11 percent in those age greater than

 

             13   75.  And all those p-values you can see are .0001.

 

 

             14             Conversely, as I've already mentioned,

 

             15   inversion 16, and 8;21s drop as you get older,

 

             16   among the favorable cytogenetic risk group.

 

             17             It is, I think, just intellectually

 

             18   interesting to speculate why we see this particular

 

 

             19   differences with age.  We don't, in fact, know the


 

 

 

 

 

 

                                                                            99

 

              1   answer.

 

              2             Some have argued that AML in the elderly

 

              3   is more the result of multiple cytogenetic or

 

 

              4   mutational [technical difficulty] a myelodysplasia

 

              5   with a subsequent alternations.

 

              6             An alternative hypothesis is that our stem

 

              7   cells get older, and getting a leukemia stem cell

 

              8   is a bad thing to do and the disease, therefore

 

 

              9   behaves differently in the elderly.  And there is

 

             10   some data for each of those arguments.

 

             11             [Slide.]

 

             12             MRK is one way of measuring multidrug

 

             13   resistance.  It may not be the best.  It's a

 

 

             14   simple, reproducible one.  But whether one uses MRK

 

             15   staining, or one uses actual drug efflux, which is

 

             16   cyclosporin inhibitable, in either way that you

 

             17   measure it, you will find that, as patients age,

 

             18   there is a higher incidence of multidrug

 

 

             19   resistance.

 

             20             In this--which included about 600

 

             21   patients--if you were less than age 56, about 33

 

             22   percent would have a bright MRK staining.  If you


 

 

 

 

 

 

                                                                           100

 

              1   were over age 75, it's about twice that number.

 

              2             [Slide.]

 

              3             Now, if you take all of these possible

 

 

              4   changes, and you look at the likelihood of getting

 

              5   a complete response, in univariate analysis--this

 

              6   is a study that we did in the Southwest Oncology

 

              7   Group--in univariate analysis you can see that

 

              8   these make a big difference in outcome.  AML, if

 

 

              9   you have a secondary AML--that is, secondary to

 

             10   primary myelodysplasia; this isn't treatment

 

             11   related, which is another kind of secondary AML.

 

             12   But this is secondary to primary

 

             13   myelodysplasia--the CR rates are half as much as if

 

 

             14   you have a de novo disease, if you are CD34

 

             15   positive in some, but not all studies, in this one,

 

             16   that seemed to give a lower incidence of complete

 

             17   response rates.

 

             18             As I obviously mentioned, MRK staining--if

 

 

             19   you have a bright, you have half as much chance of

 

             20   getting a CR as if you're negative.

 

             21             Unfavorable cytogenetics--again, about

 

             22   half as much a chance of getting CRs as if you have


 

 

 

 

 

 

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              1   intermediate or favorable.  And functional drug

 

              2   efflux, like MRK staining, also predicts for CR

 

              3   rates.

 

 

              4             [Slide.]

 

              5             Now, this is in univariate analysis.  When

 

              6   we looked in multivariate analysis, we found three

 

              7   factors-- and that's shown on the next slide that

 

              8   predicted for complete response rate: and that is

 

 

              9   whether you had secondary AML; if you had

 

             10   unfavorable cytogenetics, and then if you had MDR1

 

             11   expression--either by functional drug efflux or MRK

 

             12   staining.  And each one of these were independently

 

             13   significant in this multivariate analysis.

 

 

             14             And if you had all three factors present,

 

             15   you had almost no chance of getting a CR; that is,

 

             16   if you had secondary AML, with unfavorable

 

             17   cytogenetics and MDR1 expression, the chance of CR

 

             18   was 11 percent.  But even if you're over age 65, if

 

 

             19   you had none of the three factors, you'd have an 81

 

             20   percent chance of getting a complete response--much

 

             21   like you would expect in a younger patient with

 

             22   AML.

 

             23             [Slide.]

 

 

             24             Now, we're not the only ones that have

 

             25   seen this.  This has been seen by others.  One of


 

 

 

 

 

 

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              1   the largest studies of treatment of AML was the MRC

 

              2   AML 11 Study.  It looked at three different

 

              3   preparative regimens: a classic daunomycin-Ara-C

 

 

              4   and 6TG regimen, versus the daunomycin-Ara-C VP-16

 

              5   regimen, versus a mitoxantrone-Ara-C regimen--and

 

              6   then also randomized to giving G-CSF after

 

              7   induction.  And they also had a randomization and

 

              8   consolidation of two, versus six, cycles.

 

 

              9             The study itself isn't what I"ll be

 

             10   talking very much about, since none of these

 

             11   factors had a major impact on outcome.  But I

 

             12   would--just to look at this study-- which was

 

             13   published in Blood in 2001--for the general

 

 

             14   principles of treatment of AML.  And, as I said,

 

             15   this was a large study--it will show on the next

 

             16   slide--with over 1,300 patients.  And they had ages

 

             17   between 56 and up to above 90 years old.

 

             18             [Slide.]

 

 

             19             As I said, in the Southwest Oncology


 

 

 

 

 

 

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              1   Group, we see about a 15 to 18 percent incidence of

 

              2   secondary AML, which is exactly what the MRC study

 

              3   saw.  And they had a 4 percent incidence of

 

 

              4   treatment-related disease.  Ours was a bit higher

 

              5   in SWOG--about 6 percent.  But these are very

 

              6   typical numbers for AML in the older individual.

 

              7             [Slide.]

 

              8             In their study, they had a 62 percent

 

 

              9   complete response rate.  They had a 7 percent death

 

             10   in incomplete response.  They had a relapse rate of

 

             11   78 percent, and they had disease-free survival at

 

             12   five years of 15 percent.

 

             13             These results are fairly typical of most

 

 

             14   studies of chemotherapy for patients over age 55.

 

             15             As I have tried to make the point--and

 

             16   will make it again--

 

             17             [Slide.]

 

             18             --oh, this shows you the outcome by

 

 

             19   treatment group.  And, as you can see, there is

 

             20   essentially no difference among the three groups,

 

             21   with a median survival that is between nine and 11

 

             22   months, and a five-year survival which is down


 

 

 

 

 

 

                                                                           104

 

              1   around 15 percent on these studies.

 

              2             Now, the point I've tried to make

 

              3   repetitively is that AML in older patients is a

 

 

              4   very heterogeneous disease.

 

              5             [Slide.]

 

              6             And this shows you--the next slide shows

 

              7   you--what the MRC found.  And they found

 

              8   essentially the same thing that we had previously

 

 

              9   reported in SWOG--and other have reported, as

 

             10   well--and that is that cytogenetics, age, whether

 

             11   you have primary or secondary disease, performance

 

             12   status and--in their hands--also white count at

 

             13   diagnosis were powerful predictors.  And you can

 

 

             14   see, with a large study of over 1,300 patients, how

 

             15   powerful these are.  Those p-values are 10-14 or

 

             16   10-6, or 10-7--so that's a lot zeros, suggesting

 

             17   that these are very powerful predictors.  So that

 

             18   unfavorable cytogenetics--both for complete

 

 

             19   response rate and overall survival--is a bad fact;

 

             20   having a high white count likewise gives you a low

 

             21   chance of CR or overall survival.  As you age,

 

             22   things get worse.  If you have secondary disease


 

 

 

 

 

 

                                                                           105

 

              1   and if you have a poor performance status--the same

 

              2   things that we had previously reported.

 

              3             [Slide.]

 

 

              4             So, in summary then, using conventional

 

              5   chemotherapy, if you take a large cohort of

 

              6   patients that are over age 60--or 55, depending on

 

              7   the particular study--complete response rates of 50

 

              8   to 60 percent can be expected; a median survival of

 

 

              9   9 months can be also expected in this cohort of

 

             10   patients; and perhaps 10 to 15 percent may continue

 

             11   to be alive after four to five years.

 

             12             However--and this is the most important

 

             13   point--the patient and disease-related factors very

 

 

             14   greatly, among this population, and heavily

 

             15   influence treatment outcome.  In my mind,

 

             16   particularly important in considering any patient

 

             17   group are age, performance status, primary versus

 

             18   secondary presentation, cytogenetics and the MDR

 

 

             19   status.

 

             20             And these facts have been relatively

 

             21   unchanged over the last several decades because our

 

             22   therapies for AML in the elderly haven't changed


 

 

 

 

 

 

                                                                           106

 

              1   very much over the last several decades.  And there

 

              2   clearly is a need for new and effective agents for

 

              3   this patient population.

 

 

              4             I'd be happy to answer any questions about

 

              5   this relatively brief and perhaps superficial

 

              6   presentation.

 

              7             Thank you.

 

              8             DR. MARTINO: Fred, Thank you.  And ladies

 

 

              9   and gentlemen, it is my understanding that we are

 

             10   able to handle some questions to Dr.

 

             11   Appelbaum--from a technical perspective.  So, if

 

             12   there are questions to him directly, this would be

 

             13   your opportunity.

 

 

             14             Dr. Mortimer?

 

             15             DR. MORTIMER: Yes, Fred--this is Joan

 

             16   Mortimer.  I wonder if you could just make a

 

             17   comment on the role of growth factors.  I presume

 

             18   that since you didn't talk about it in the MRC

 

 

             19   trial that there is no advantage or disadvantage to

 

             20   the use of growth factors?

 

             21             DR. APPELBAUM: In the MRC trial there was

 

             22   no advantage or disadvantage for the use of growth


 

 

 

 

 

 

                                                                           107

 

              1   factors.  There have been--as you know, probably

 

              2   better than anyone on the planet, Joan--I think at

 

              3   least a dozen studies of the use of growth factors

 

 

              4   after chemotherapy for AML in older individuals.

 

              5             And the vast majority of those studies

 

              6   show that the use of growth factors shorten the

 

              7   duration of neutropenia quite consistently by five

 

              8   to seven days.  They are more variable in whether

 

 

              9   that shortening of neutropenia changes the risk of

 

             10   significant infection; and only, as I'm aware, two

 

             11   studies showed a change in survival or complete

 

             12   response rate.  The majority of them showed no

 

             13   effect on CR rates or survival, but did show an

 

 

             14   important shortening of the period of

 

             15   pancytopenia--that's after induction.  And then

 

             16   after consolidation, the results are a little more

 

             17   consistent that you shorten neutropenia and

 

             18   decrease the incidence of infections--again, with

 

 

             19   no change in survival.

 

             20             DR. MARTINO: Dr. Brawley, you're next.

 

             21             DR. BRAWLEY: Yes, Otis Brawley here.

 

             22             Dr. Appelbaum, in the studies that you


 

 

 

 

 

 

                                                                           108

 

              1   presented, and all the data that we've reviewed, it

 

              2   seems like the goal is always to get a complete

 

              3   remission, as if the complete remission is a

 

 

              4   surrogate for patient benefit in terms of increased

 

              5   survival.

 

              6             Has anyone ever tried any studies that

 

              7   look at the possibility of a drug that might sort

 

              8   of suppress a smoldering factor, where the goal is

 

 

              9   not complete remission but suppression of the

 

             10   leukemia, and perhaps try to determine of that

 

             11   actually increases survival--especially in an

 

             12   older, sickly population?

 

             13             DR. APPELBAUM: That's an excellent

 

 

             14   question, Dr. Brawley.  And the lessons that had

 

             15   been learned in acute leukemia in younger patients,

 

             16   where it's a much more proliferative disease, have

 

             17   sort of given the indication that you really have

 

             18   to get a complete response if patients are going to

 

 

             19   survive for any length of time, because the disease

 

             20   is so very proliferative.

 

             21             Now, on the other hand, if you take the

 

             22   totally other tack of looking at myelodysplasia as


 

 

 

 

 

 

                                                                           109

 

              1   being a sort of symbol for a less aggressive

 

              2   disease--we now have data that a drug which doesn't

 

              3   get complete response rates, so that it

 

 

              4   phibezacytadine by perhaps a slowing--some people

 

              5   can argue why phibezacytadine works.  Some people

 

              6   believe it's a differentiation factor.  Other

 

              7   people believe that it actually is working as a

 

              8   cytotoxic.  But, without getting complete

 

 

              9   responses, it appears that it may prolong survival.

 

             10             Years ago, the way that many

 

             11   patients--very old patients with AML--were treated

 

             12   was with much less aggressive therapy using oral

 

             13   6MP, or using daily or weekly VP16, trying to keep

 

 

             14   the cap on things.  And I believe that there were

 

             15   some suggestions--not proven in randomized trials

 

             16   ever, but suggestions that there was improvement in

 

             17   survival.

 

             18             You are, I thin, correct that it is

 

 

             19   possible that there will be drugs--maybe many

 

             20   drugs--that could cause differentiation, slowing

 

             21   down the proliferation, and be of some benefit to

 

             22   the patient without getting a complete response.

 

             23             But the lessons from the more aggressive

 

 

             24   disease is that generally those effects are

 

             25   temporary and not as lasting as physicians would


 

 

 

 

 

 

                                                                           110

 

              1   like.

 

              2             I'm not sure if that answers the question

 

              3   adequately.