FOOD AND DRUG ADMINISTRATION










                               ONCOLOGIC DRUGS ADVISORY COMMITTEE




                                           NDA 21-824







                                  ACUTE MYELOID LEUKEMIA (AML)









                                     Thursday, May 5, 2005


                                           8:00 a.m.









                                       5630 Fishers Land

                                           Room 1066

                                      Rockville, Maryland









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




                  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.









                                        C O N T E N T S



                  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.


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


                     AML in Elderly Patients

                            Richard Stone, M.D.                             23


                     Clinical  Data

                            Alain Thibault, M.D.                            36



                            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









              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









              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









              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









              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.









              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









              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









              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









              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









              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









              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









              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?









              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









              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









              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









              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









              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









              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,









              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,









              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









              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









              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









              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.









              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









              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









              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









              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









              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









              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









              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









              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.









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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.









              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









              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









              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









              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









              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









              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









              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.









              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









              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.









              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









              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









              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









              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?









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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.









              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









              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









              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.









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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,









              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.









              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,









              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









              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









              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









              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









              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,









              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.









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              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









              1   like.


              2             I'm not sure if that answers the question


              3   adequately.