DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ONCOLOGIC DRUGS ADVISORY COMMITTEE
ZARNESTRA (TIPIFARNIB)FILM COATED TABLETS
TIBOTEC THERAPEUTICS, A DIVISION OF ORTHO BIOTECH,
LP PROPOSED INDICATION FOR THE TREATMENT OF
ELDERLY PATIENTS WITH NEWLY DIAGNOSED POOR-RISK
ACUTE MYELOID LEUKEMIA (AML)
Thursday, May 5, 2005
5630 Fishers Land
P A R T I C I P A N T S
ADVISORY COMMITTEE REPRODUCTIVE HEALTH DRUGS
Silvana Martino, D.O. - CHAIR
Otis W. Brawley, M.D.
Ronald M. Bukowski, M.D.
Bruce D. Cheson, M.D.
Stephen L. George, Ph.D.
Pamela J. Haylock, RN [Industry Representative]
Alexandra M. Levine, M.D.
Joanne E. Mortimer, M.D.
Michael C. Perry, M.D.
Gregory H. Reaman, M.D.
Johanna M. Clifford, M.S., RN, Executive Secretary
CONSULTANTS AND GUESTS
Susan O'Brien, M.D.
Patient Representative (voting):
Acting Industry Representative (non-voting):
Guest Speaker (non-voting):
Frederick Appelbaum, M.D.
Qin Ryan, M.D.
Ramzi Dagher, M.D.
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
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
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
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,
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
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,
10 MR. FLATAU: Arthur Flatau, I'm the Patient
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.
11 For everybody that's lived in Texas, such
12 as Susan and myself--
13 VOICE: Muchas gracias.
14 DR. PAZDUR: De nada.
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.
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.
19 Hasta luego, he said. Okay.
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.
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
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?
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
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.
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.
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.
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
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
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.
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
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
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.
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.
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.
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.
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
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
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.
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
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.
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
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.
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
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.
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
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.
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.
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.
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.
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
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
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.
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.
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.
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
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.
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
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.
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.
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
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.
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.
21 The study applied standard morphologic
22 criteria of complete remission, which are listed
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.
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
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
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.
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.
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.
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
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
2 Most patients were symptomatic, either
3 from AML or from pre-existing co-morbidities.
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.
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.
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
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
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
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.
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.
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
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.
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.
21 The complete remissions were documented at
22 four of the six sites. No single institution
23 accounts for the majority of cases.
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
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.
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.
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
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.
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
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.
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.
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
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
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.
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.
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.
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
17 Patient age did not appear to have an
18 impact on the tolerability.
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
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
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.
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.
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.
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.
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
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.
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
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.
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
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
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.
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
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
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.
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
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.
10 Now, to put the CTEP-20 study into
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.
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
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
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
9 Fred Appelbaum to present. So those of you that
10 have questions please know that that will be your
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.
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.
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
11 In some cases where leukemia CRs were of
12 uncertain duration, CR was considered a surrogate
13 reasonably likely to predict clinical benefit.
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.
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.
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.
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.
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.
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.
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
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
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.
17 Zarnestra is being proposed for the
18 treatment of elderly patients with newly diagnosed
19 poor-risk acute myeloid leukemia.
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.
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.
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.
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
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.
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
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.
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.
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
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
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.
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
17 Less responders were seen in subjects with
18 unfavorable karyotypes.
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
9 Next, I will discuss the CTEP-20 safety
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
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.
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
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
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.
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
22 The median total duration of
1 hospitalization was 15 days. Ten subjects required
2 at least three hospitalizations during the study
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.
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.
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.
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
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
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.
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.
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.
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
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.
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.
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.
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,
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
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.
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
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.
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
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
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.
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.
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--
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.
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.
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
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
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
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
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
2 I'm not sure if that answers the question