1
DEPARTMENT OF
HEALTH AND HUMAN SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG
EVALUATION AND RESEARCH
ONCOLOGIC DRUGS
ADVISORY COMMITTEE
NDA
21-824
ZARNESTRA
(TIPIFARNIB)FILM COATED TABLETS
TIBOTEC THERAPEUTICS, A
DIVISION OF ORTHO BIOTECH,
LP PROPOSED
INDICATION FOR THE TREATMENT OF
ELDERLY PATIENTS WITH
NEWLY DIAGNOSED POOR-RISK
ACUTE MYELOID
LEUKEMIA (AML)
Thursday,
May 5, 2005
8:00
a.m.
5630
Fishers Land
Room
1066
Rockville, Maryland
2
P A R T I C
I P A N T S
ADVISORY COMMITTEE
REPRODUCTIVE HEALTH DRUGS
Silvana Martino, D.O. - CHAIR
Otis W. Brawley, M.D.
Ronald M. Bukowski, M.D.
Bruce D. Cheson, M.D.
Stephen L. George, Ph.D.
Pamela J. Haylock, RN [Industry
Representative]
Alexandra M. Levine, M.D.
Joanne E. Mortimer, M.D.
Michael C. Perry, M.D.
Gregory H. Reaman, M.D.
Johanna M. Clifford, M.S.,
RN, Executive Secretary
CONSULTANTS AND GUESTS
Consultants (voting)
Susan O'Brien, M.D.
Patient Representative
(voting):
Arthur Flatau
Acting Industry Representative
(non-voting):
Roger Porter
Guest Speaker (non-voting):
Frederick Appelbaum, M.D.
FDA PARTICIPANTS
Qin Ryan, M.D.
Ramzi Dagher, M.D.
Robert Justice
Richard Pazdur, M.D.
Robert Temple, M.D.
3
C O N T
E N T S
PAGE
Call to Order
Silvana Martino,
D.O., Chair 4
Introduction of
Committee 4
Conflict of Interest
Statement
Johanna
Clifford
6
Opening Remarks
Richard Pazdur,
M.D. 9
Sponsor Presentation -
Tibotec Therapeutics, Inc.
Introduction
Robert DeLap,
M.D., Ph.D. 15
AML in Elderly Patients
Richard Stone, M.D. 23
Clinical Data
Alain Thibault,
M.D. 36
Benefit/Risk
Alex Zukiwski,
M.D. 62
FDA Presentation: NDA 21-824, Zarnestra
Qin Ryan, M.D. 70
AML in Older Individuals
Frederick R. Appelbaum,
M.D., 90
Open Public Hearing 121
Questions from the
Committee 129
Discussion of the
Questions 181
4
1 P R O C E E D I N G S
2 Call to Order
3 DR. MARTINO: Good morning, ladies
and
4 gentlemen.
I'd like to begin this meeting.
5 The topic before us this morning
is the
6 drug Zarnestra, presented by Tibotec. And the
7 proposed indication is for the treatment of
elderly
8 patients with newly diagnosed poor-risk
myeloid
9 leukemia.
10 Introduction of Committee
11 The first order of business is I
would
12 like the members of the committee to
introduce
13 themselves.
And I'd like to start with Dr.
14 O'Brien, please.
15 I need you all to use your
microphones,
16
please.
17 DR. O'BRIEN: I'm from the leukemia
18 department at MD Anderson.
19 DR. CHESON: Bruce Cheson, head of
20 Hematology, Georgetown University Lombardi Cancer
21 Center.
22 DR. GEORGE: Steve George, Duke
University
5
1 Medical Center.
2 DR. BRAWLEY: Otis Brawley. I'm a medical
3 oncologist and epidemiologist at the Winship
Cancer
4 Institute of Emory University.
5 DR. MORTIMER: Joanne Mortimer,
medical
6 director, UCSD Morris Cancer Center.
7 MS. HAYLOCK: Pamela Haylock,
oncology
8 nurse and doctoral student at UTMB,
Galveston,
9 Texas.
10 MR. FLATAU: Arthur Flatau, I'm the
Patient
11 Representative.
12 DR. REAMAN: Greg Reaman, pediatric
13 oncologist, Children's Hospital, Washington,
D.C.;
14 George Washington University in the
Children's
15
Oncology Group.
16 DR. LEVINE: Alexandra Levine, head
of
17 hematology at University of Southern
California,
18 Norris Cancer Center.
19 DR. MARTINO: Silvana Martino, from
the
20 Angeles Clinic in Santa Monica, California,
main
21 medical oncologist.
22 MS. CLIFFORD: Johanna Clifford,
Executive
6
1 Secretary to the ODAC.
2 DR. PERRY: Michael Perry, medical
3 oncologist, University of Missouri Ellis
Fischel
4 Cancer Center, Columbia, Missouri.
5 DR. PORTER: Roger Porter, retired
both
6 from the NIH and Wyeth, now a consultant.
7 DR. BUKOWSKI: Ronald Bukowski,
medical
8 oncologist, Cleveland Clinic, Cleveland,
Ohio.
9 DR. DAGHER: Ramzi Dagher, Division
of
10 Oncology Drug Products, FDA.
11 DR. JUSTICE: Robert Justice,
Acting Deputy
12 Director, Oncology Drug Products, FDA.
13
DR. PAZDUR: Richard Pazdur, FDA.
14 DR. TEMPLE: Bob Temple, Director,
OD-1.
15 DR. MARTINO: Next, I'd like Ms.
Johanna
16 Clifford to read the conflict of interest
17
statements for the members of the panel, please.
18 Conflict of Interest
Statement
19 MS. CLIFFORD: The following announcement
20 addresses the issue of conflict of interest,
and is
21 made as part of the record to preclude even
the
22 appearance of such at this meeting.
23 Based on the submitted agenda all
24 financial interests reported by the committee
25 participants, it has been determined that
all
7
1 interest in firms regulated by the Center
for Drug
2 Evaluation and Research present no potential
for an
3 appearance of a conflict of interest, with
the
4 following exceptions.
5 In accordance 18 USC 208(b)(3),
full
6 waivers have been granted to the following
7 participants: Dr. Stephen George, for
consultant
8 for a competitor, which he received less
than
9 $10,001 per year; Dr. Ronald Bukowski, for
10 consulting with a competitor, which he
receives
11 less than $10,001 per year. Pamela Haylock has
12 been granted waivers under 208(b)(3) and 21
USC
13 505(n) for her spouse owning stock in a
competitor.
14
The stock is valued from $25,001
to $50,000.
15 A copy of the waiver statements
may be
16 obtained by submitting a written request to
the
17 agency's Freedom of Information Office, Room
12A-30
18
of the Parklawn Building.
19 In addition, we would like to not
that Dr.
8
1 Frederick Appelbaum, FDA's invited guest
speaker,
2 is participating as a representative of the
Fred
3 Hutchinson Cancer Research Center. He has no
4 financial interest in, or professional
relationship
5 with any of products of firms that could be
6 affected by the committee's discussions.
7 With respect to the FDA's invited
industry
8 representative, we would like to disclose
that Dr.
9 Roger Porter is participating in this
meeting as
10 the industry representative, acting on
behalf of
11 regulated industry. Dr. Porter is a private
12 consultant to industry.
13 In the event that the discussions
involve
14 any other products or firms not already on
the
15 agenda, for which an FDA participant has a
16 financial interest, the participants are
aware of
17 the need to exclude themselves from such
18 involvement, and their exclusion will be
noted for
19 the record.
20 With respect to all other
participants, we
21 ask, in the interest of fairness, that they
address
22 any current or previous financial
involvement with
9
1 any firms they may wish to comment upon.
2 Thank you.
3 DR. MARTINO: Thank you, Ms.
Clifford.
4 And, next, Dr. Richard Pazdur will provide
some
5 opening remarks to this meeting.
6 Opening Remarks
7 DR. PAZDUR: Thank you, Dr.
Martino.
8 First of all, I'd like to say
Feliz Cinco
9 de Mayo to everyone.
10 [Laughter.]
11 For everybody that's lived in
Texas, such
12 as Susan and myself--
13 VOICE: Muchas gracias.
14 DR. PAZDUR: De nada.
15 [Laughter.]
16 This is a big day in the State of
Texas.
17 And I just want to bring that up.
18 I have some enjoyable issues to do
to
19 start out here, and that is to thank two
members of
20 our committee that will be retiring. And I use
21 that word "retiring" in
quotations, because,
22 because of their expertise, we probably will
be
10
1 inviting them back--both to sit on ODAC
special
2 committees, as well as to serve as special
3 consultants to us during the process that we
4 evaluate drugs outside of the ODAC committee.
5 The two individuals that will be
leaving
6 the committee are Stephen George and Otis
Brawley.
7 Stephen George is, obviously, from
Duke
8 University in North Carolina, and has served
on the
9 ODAC Advisory Committee as the committee
10 statistician from July of 2001, to June of
2005.
11 In addition to his committee participation,
Dr.
12 George has visited the FDA and he's given
numerous
13 presentations to us on various statistical
issues,
14 and has served as a consultant to us on many
NDAs
15 and IND matters. So we really appreciate Dr.
16
George's efforts--on this committee and also behind
17 the doors here--in helping the FDA. And we look
18 forward to working with you, as you leave
the
19 committee, on a continuing basis.
20 So I have this beautiful plaque
here that
21 I'd like to present to you.
22 [Applause.]
23 Thank you very much.
24 DR. GEORGE: Thank you. Thank you.
25 DR. PAZDUR: And the gentleman that
is
11
1 sitting right next to him, Dr. Otis Brawley,
is
2 professor of hematology and oncology and
3 epidemiology, and is the Associate Director
for
4 Cancer Control at the Winship Cancer
Institute at
5 Emory University.
6 He's an international authority in
the
7 field of health disparities research and
prostate
8 cancer.
He's served on the committee from July of
9 2001 to 2005. Like Dr. George, Otis has been
10 involved with many of the behind-the-scenes
efforts
11 at the FDA; consulting with us on numerous
12 applications, considerations of Phase I and
Phase
13 II trial designs, and Phase III trial
designs also.
14
We really have appreciated Dr. Brawley's
15 work with us. And here, again--this is not to say
16 goodbye, but just as a transition to another
role
17 with us in the FDA. Thank you very much.
18 [Applause.]
19 Hasta luego, he said. Okay.
20 [Laughter.]
21 Recuerdos a todos--regards to
everyone.
22 I'm just going to make a few short
23 comments about this application, because I
think
24 that the speakers will probably address all
of the
25 salient points, and I think we could bring
up any
12
1 regulatory issues relatively succinctly
during our
2 presentations, and also in our discussions.
3 Basically, what we have here is a
4 single-arm study in a patient population
where
5 there has to be discussion that there is no
other
6 available therapy for this patient
population--or
7 the results are so impressive here that we
need to
8 consider the approval of the drug.
9 We're going to be asking basically
the
10 question: does this drug deserve full
approval?
11 Okay?
And one of the reasons why we're asking this
12 is that we have accepted basically a
situation
13 where complete response rates have equated
clinical
14 benefit.
Okay? We believe that this is an
15 established surrogate for survival. And, in
16 addition to that, we believe that
application in a
13
1 complete response rate would have a
reduction in
2 transfusion requirements and other
supportive care
3 products.
So this is meaningful clinical endpoint,
4 an established surrogate for clinical
benefit.
5 So, with that in mind, I'd like
you to
6 proceed with the discussions, and I'll turn
the
7 discussions--the presentations--over to Dr.
8 Martino.
9 DR. MARTINO: Rich, before I let
you sit
10
down, please, I just want to be sure that I'm clear
11 that, in fact, the application is seeking
for full
12 approval, and not accelerated approval.
13 DR. PAZDUR: Correct--yes.
14 DR. MARTINO: Because, when I
reviewed the
15 material, I came to this with one view, and
then
16 when the question was presented to me, I
realized
17 that it was full approval.
18 DR. PAZDUR: Correct.
19 DR. MARTINO: So I just wanted to
be sure
20 that that is what you mean.
21 DR. PAZDUR: And this is the area
that I
22 want to clarify here. The issue here is: we look
14
1 at complete response rates. And, here again,
2 that's not only the response rates but
response
3 rates of a sufficient magnitude--okay? So we look
4 at both of these parameters: the response
rate and
5 the magnitude. If that is sufficient, one should
6 conclude that this would be an established
7 surrogate for clinical benefit. Okay?
8 DR. PERRY: Do we have the option
of
9 recommending it for accelerated approval and
not
10 for full approval? Or is this simply "yes" or
11 "no."
12 DR. PAZDUR: Yes--we would
entertain any
13 topics or discussions regarding that.
14 DR. PERRY: So we've got three
options
15
then: yes, no--
16 DR. PAZDUR: Correct. But we'd like to
17 firsts discuss that endpoint of full
approval. And
18 then, if you want to deviate from that,
let's
19 please have a discussion of what. Okay?
20 DR. PERRY: Okay.
21 DR. MARTINO: Are there other
questions for
22 Dr. Pazdur at this point? Ladies and gentlemen?
15
1 Okay.
2 Turn the microphone on, please.
3 DR. PAZDUR: They're right there in
the
4 plastic box.
5 DR. MARTINO: A practical question, there.
6 Thank you.
7 At this point, I would like to
turn to the
8 Tibotec representatives to present their
data. And
9 Dr. DeLap, if you would please introduce
your
10 subsequent speakers, as well.
11 Sponsor Presentation - Tibotec
Therapeutics
12 DR. DeLAP: Thank you. Madam Chair,
13 members of the committee, colleagues and
14 guests--good morning. I'm Dr. Robert DeLap, Vice
15 President of Regulatory Affairs at Johnson
&
16 Johnson Pharmaceutical Research.
17 We are pleased to be here today to
present
18 data generated in National Cancer Institute
and
19 company-sponsored studies on the efficacy
and
20 safety of tipifarnib in poor-risk AML, and
our
21 application for approval of tipifarnib for
use in a
22 patient population that is not well served
by
16
1 existing AML therapies.
2 Our application proposes that
tipifarnib
3 will be indicated for the treatment of
elderly
4 patients with newly diagnosed, poor-risk
acute
5 myeloid leukemia, based on durable complete
6 remissions that were observed in the CTEP-20
study.
7 As noted in the agency's briefing
8 materials for today's meeting, complete
remissions
9 have been used as evidence of patient
benefit to
10
support approval of new treatments for AML. Thus,
11 the consideration today is the use of these
data to
12 support the approval of tipifarnib for this
13 indication.
14 Elderly patients with AML obtain less
15 benefit from the intensive induction
treatment
16 regimens used in younger patients, and the
risks of
17 severe treatment toxicities and
treatment-related
18
mortality rise with increasing age.
Since
19 risk-benefit considerations for
intensive-induction
20 treatment are often not favorable in these
21 patients, new treatments are clearly needed.
22 In the clinical
research to be discussed
17
1 today, tipifarnib has demonstrated
meaningful
2 efficacy in elderly patients as described in
our
3 proposed indication, with a
well-characterized
4 safety profile in outpatient treatment.
5 [Slide.]
6 Tipifarnib was originally synthesized
in
7 the Johnson & Johnson Pharmaceutical
Research
8 laboratories. Clinical investigations began with
9 solid tumor studies in 1997. Based on mutual
10 interest in this compound, the company and
the NCI
11 entered into a Cooperative Research and
Development
12 Agreement in 1999.
13 Pre-clinical evidence of activity
against
14 leukemias led to clinical research in AML,
with
15 initiation of the CTEP-1 Phase 1 study in
1999.
16 Complete clinical remissions observed in
CTEP-1 led
17 to further research, including the CTEP-20
Phase 2
18 study in myeloid malignancies.
19 Following consultations between
the
20 company, the National Cancer Institute and
the FDA,
21 CTEP-20 was subsequently amended and
expanded to
22 focus on evaluating the efficacy and safety
of
18
1 tipifarnib in elderly patients with newly
diagnosed
2 poor-risk AML.
3 Considering the unmet need in this
patient
4 population, tipifarnib has recently received
orphan
5 designation for AML, and has been granted
6 fast-track status by FDA.
7 The NDA for tipifarnib was
accepted into
8 FDA's Continuous Marketing Application-1
pilot
9 program, which has allowed for expedited
submission
10 and review of these data.
11 [Slide.]
12 This slide summarized the study
program
13 for tipifarnib in poor-risk AML.
14 Following the CTEP-1 study, the
INT-17
15 study evaluated tipifarnib in patients with
16
relapsed or refractory AML.
17 Today's discussions will focus on
the
18 CTEP-20 study, as this is the study that has
19 evaluated efficacy and safety in the patient
20 population of interest for today's
discussion.
21 The AML-301 study, in patients
greater
22 than 70 years of age with newly diagnosed
leukemia
19
1 is evaluating the effect of tipifarnib
versus best
2 supportive care. And that study is designed to
3 establish the magnitude of the anticipated
survival
4 benefit, and is actively enrolling patients.
5 The ongoing CTEP-50 study is an
iterative
6 trial being conducted under NCI supervision,
which
7 is evaluating alternative dosing regimens in
8 elderly patients with newly diagnosed
leukemia.
9 Finally, the AML development
program also
10 includes related studies, not shown on this
slide,
11 in maintenance of remission and use in
combination
12 with other agents. Those studies are briefly noted
13 in the company's background materials for
today's
14 meeting, but will not be included in our
15 presentation today, as they represent work
in
16 progress in other AML settings.
17 [Slide.]
18 The CTEP-20 study focused on
patients who
19 have generally not been represented in AML
clinical
20
trials, and are not well served by
21 intensive-induction chemotherapy
regimens. The
22 median age of the elderly patients enrolled
in this
20
1 study was 75. Most of the patients had antecedent
2 myelodysplastic syndromes; 49 percent had
3 unfavorable karyotypes; the remainder had
4 intermediate karyotypes. No patients with
5 favorable karyotypes were enrolled.
6 Overall, 90 percent of patients
had two or
7 more risk factors, considering age,
antecedent
8 myelodysplastic syndromes, unfavorable
karyotypes,
9 or evidence of organ dysfunction. These are
10 patients who would be expected to have poor
11 tolerance for standard AML treatments, and
would be
12 much less likely to benefit from existing
13 treatments.
14 [Slide.]
15 As you will see in today's
presentation,
16 tipifarnib demonstrates a favorable benefit
risk
17 for a more fragile patient population that
18 generally does not receive standard AML
therapy.
19 Evidence of meaningful clinical efficacy has
been
20 observed, with a 15 percent rate of durable
21 complete remissions in the planned analysis.
22 Treatment safety has been well
documented,
21
1 with more than 1,000 patients in monotherapy
2 studies.
This includes a total of 409 patients in
3 the AML studies, CTEP-20 and INT-17, as well
as
4 patients exposed at lower doses in solid
tumor
5 studies.
6
Tipifarnib produces predictable and
7 reversible myelosuppression with continued
daily
8 dosing, but it is myeloablative, and the
incidence
9 of life-threatening, not-hematologic
toxicities has
10 bene low.
11 Patients in the CTEP-20 study were
able to
12 spend much of their time outside of the
hospital.
13 Thus, tipifarnib can serve as an oral
out-patient
14
treatment for these patients.
15 [Slide.]
16 Our agenda today includes three
additional
17 presentations. In a few moments I will turn to Dr.
18 Richard Stone, from the Dana-Farber Cancer
19 Institute, who will discuss the problem of
AML in
20 elderly patients.
21 Dr. Alain Thibault will then
review the
22 clinical data provided in our new drug
application,
22
1 focusing on the CTEP-20 study, which has
provided
2 data on the efficacy and safety of
tipifarnib in
3 elderly poor-risk patients with newly
diagnosed
4 AML.
5 Finally, Dr. Alex Zukiwski will
summarize
6 benefits and risks of tipifarnib treatment
in this
7 patient population.
8 We are joined today by medical
experts to
9 contribute to the discussion, and to help
address
10 specific questions. These include Dr. Karp, who
11 served as principal investigator for the
CTEP-20
12 study; Drs. Sekeres and Stone, who have
special
13 expertise in AML and have experience with
the use
14 of tipifarnib; and Dr. Wright, from the
NCI's
15 Cancer Therapy Evaluation Program. Unfortunately,
16 Dr. Albitar from Nichols Institute, who
provided an
17 independent review of bone marrow slides in
the
18 CTEP-20 study, and had planned to be with us
today,
19
could not be here because of a family emergency.
20 This concludes my
introduction. I will
21 now turn the podium over to Dr. Richard
Stone who
22 will discuss the problem of AML in elderly
23
1 patients.
2 Thank you.
3 AML in Elderly Patients
4 DR. STONE: Dr. DeLap, thank you
very much.
5 Members of the panel, guests--I'll
be
6 spending the next few minutes discussing the
7 following topic: AML in the older-age
patient
8 represents a therapeutic area of significant
unmet
9 need.
And this is particular true for those
10 subjects who have an inferior prognosis
compared to
11 the average.
12 [Slide.]
13 Now, AML in the older population
is not
14 uncommon, and the number of cases will be
15 increasing over time. This is clearly a
16 biologically and therapeutically distinct
disease
17 compared to AML which may occur in younger
adults.
18 And the reasons for this distinctive
character are:
19 number one, it's an intrinsically resistant
disease
20 to chemotherapy; and number two, there are
markedly
21 inferior outcomes to available
chemotherapeutic
22 agents compared to younger adults.
23 Some subgroups of patients who are
older
24 adults with AML have a markedly worse than
the
25 average prognosis which, I think you'll see
in a
24
1 minute, is quite poor to start with. As such, many
2 patients who are older with
AML are not offered
3 and/or refuse the standard cytotoxic
induction and
4 post-remission therapy. As such, an efficacious,
5 relatively non-toxic approach would be
welcomed by
6 patients and leukemia doctor's alike.
7 [Slide.]
8 There are approximately 12,000 new
cases
9 of AML each year in this country. Approximately
10
9,000 people die of this disease.
11 In contrast to what might be the
case if
12 you look at a tertiary care cancer center,
the
13 median age of AML is at least 68. The incidence
14 increases markedly as people get older. For
15 example, if you're 50 years old you have a 1
in
16 50,000 chance of having AML. If you're 70, you
17 have a 1 in 7,000 chance.
18 [Slide.]
19 This next slide graphically
depicts the
25
1 marked increase in the incidence of AML that
occurs
2
as people get older. And it's
particularly
3 striking once you get to the sixth, and
4 particularly seventh, decade of life.
5 [Slide.]
6 Moreover, as I think everybody is
aware,
7 the demographics of our population are
changing to
8 the fact that we're getting to be older as a
9 country.
And, as such, the number of cases of AML
10 in this age cohort--or the number of cases
11 total--will be increasing over the next few
12 decades.
13 [Slide.]
14 Now, this slide depicts the
situation that
15 was true in the 1980s, when chemotherapy was
16 applied the same way to younger adults and
older
17 adults with AML. This is data taken from
18 cooperative group trials on both sides of
the
19
Atlantic, and this required the patient to get to a
20 center where they could get
chemotherapy. So, as
21 I'll come back to, it may not be
representative of
22 what really happens in the community.
23 Nonetheless, this
slide makes the
24 important point that the therapeutic outcome
in
25 older adults is much different than younger
adults.
26
1 For example, if you're over age 65, your
chance of
2 achieving complete remission is only 45
percent,
3 compared to 70 percent in younger adults
with AML.
4 If you achieve remission your chance for
staying in
5 remission is only about one in five,
compared to
6 about 45 percent of younger adults.
7 And what's particularly striking
to me as
8
an oncology and a leukemia doctor taking care of
9 these patients, is the treatment-related
mortality
10 rate is about one in four, and the early
death rate
11 is much lower in younger adults.
12 The overall
survival--about 10 percent,
13 walking in the door. And these are people that
14 could get chemotherapy--compared 1 in 30
younger
15 adults.
16 The median survival of older adults who
17 present with AML and go on clinical trials
is only
18 10 months--which I think we'd all agree is
not
19 someplace we'd like to be.
20 [Slide.]
21 There are two major reasons--as I
22 indicated--for this inferior outcome. The first
23 general category is decreased host
tolerance. Of
24 course, being older, these patients have a
higher
25 incidence of having co-morbid diseases such
as
27
1 diabetes and vascular disease. Perhaps because of
2
that, and for just general aging features, they
3 have a decreased ability to clear
chemotherapy,
4 which obviously could contribute to
increased
5 toxicity.
6 Thirdly, it's been shown in
multiple
7 studies that the ability to recover from
myelotoxic
8 chemotherapy is diminished in older adults,
and
9 they have a longer period of neutropenia and
10 thrombocytopenia--which leads to an enhanced
rate
11 of chemotherapy-induced complications.
12 [Slide.]
13 At least as important, if not more
so, is
14 the fact that the leukemias which arise in
older
15 adults are intrinsically resistant,
biologically.
16 This fact of increased intrinsic resistance
is
28
1
manifested by, or associated with, these features:
2 number one, there's an increased instance of
what's
3 called "unfavorable chromosomal
abnormalities" in
4 older patients, such as the loss of the long
arm of
5 the entire chromosome-5 or -7' problems at
11q23,
6 and complex cytogenetic abnormalities. These are
7 the same type of abnormalities that occur in
people
8 who have myelodysplastic syndrome, and/or
people
9 who had prior chemotherapy for other
cancers.
10 There's an increased incidence of
11 antecedent--either known or
suspected--hematologic
12 abnormalities, most particularly
myelodysplastic
13 syndrome.
14 There's an increased likelihood of
15 expression of genes which encode drug
resistance,
16 most notably the MDR-1 protein, which is a
17 chemotherapy efflux pump, as well as other
ones
18 like MRP, LRP, MSH-2.
19 [Slide.]
20 Now, this combination of
biological and
21 host factors, and the inferior outcomes, led
to a
22 slight change in the approach of cooperative
groups
29
1 in the 1990s, where separate clinical trials
were
2 designed for older adults compared to
younger
3 adults with AML.
4 This is a representative list of
trials
5 conducted in the 1990s in cooperative groups
in
6
Europe and in America. And even
though these
7 trials evaluated different novel therapeutic
8 strategies, such as the use of growth
factors,
9 different chemotherapeutic drugs, and
10
drug-resistance modulating drugs, the results are
11 very stereotyped from trial to trial. There are
12 other trials out there which I could have
picked,
13 such as the recently published MRC trial,
but that
14 was largely a little bit younger patient
15 population.
16 The median age is 68 in all the
trials.
17 The complete remission rate is about 40 to
50
18 percent.
And, again, the toxic death rate--and
19 this is the 1990s--is in the 20 percent
range
20 throughout all the trials. And, again, all the
21 trials--median survival, nine to 10 months.
22 And I want to stress one very
important
30
1 point: it's that these--the patients who
went on
2 these trials were, number one, deemed to be
3 chemotherapy candidates. They got to a center that
4 was participating in a cooperative group
trial.
5 They had to meet the eligibility criteria
for these
6 trials--which varied from trial to trial,
there
7 were subtle differences. Most of these trials did
8 not allow people with secondary AML; that is
AML
9 that occurred myelodysplastic syndrome, or
after
10
prior chemotherapy to go on. Some
did. Some of
11 the trials had a lower boundary of age 60,
some 65,
12 some 55.
13 And so those are kind of the best
results
14 one can get with chemotherapy.
15 [Slide.]
16 The situation in the community is
17 certainly much worse. That's number one.
18 Number two is: if you look into
the
19
subgroup analysis of these trials, you can find
20 some important facts which suggest that you
can
21 identify patients that even have a worse
prognosis
22 than the average. For example, if you have prior
31
1 myelodysplastic syndrome, your chance of
remission
2 is 24 percent compared to 52 percent if you
don't.
3 If you have one of those poor cytogenetic
4 abnormalities that I mentioned, 21 percent
5 likelihood of remission, compared to 55
percent if
6 you don't. And these data were taken from
the SWOG
7
trial.
8 This data from the recently
published ECOG
9 trial says that if you're over age 70,
you've got a
10 29 percent of going into remission, compared
to 51
11 percent for those younger than age 70. However,
12 only 13 percent in this trial were above age
75.
13 Only 5 percent of those in the
Lowenberg
14 trial were above age 80, and in those people
the
15
chance for remission was only 14 percent.
16 So, number one, you can find bad
17 prognostic factors within these groups and,
number
18 two, the number of patients who are really
old who
19 go on these trials is low.
20 [Slide.]
21 Community data is shown in this
slide
22 which suggests that if you're over age 65
and you
32
1 present with AML, your median survival may
be only
2 in the several-month range, compared to the
another
3 10 months we saw for the people who went on
those
4 chemotherapy trials.
5 [Slide.]
6 So, given this sort of dismal
outcome with
7 chemotherapy, the value of chemotherapy in
this age
8 population is debated, particularly in those
who
9 have poor prognosis features.
10 There have only been a couple of
11 randomized studies--and these were done in
Europe
12 in the 1980s--which tried to compare early
13 aggressive chemo versus less intensive
approaches.
14 And they both showed a small increase in
survival
15 for early intensive chemo, but there was no
16 associated quality of life studies, and
cost, in
17 terms of up-front mortality was quite high.
18 These issues are reflected in the
National
19 Cancer Center Network guidelines--it's a
consensus
20
panel of AML experts--which acknowledges that
21 standard induction chemotherapy is an
option, but
22 clinical trial with either new agents or
biological
33
1 agents is the preferred approach even for
those
2 people who have good performance status who
are
3 over age 60 and present with AML.
4 [Slide.]
5 How do people make
this difficult decision
6 between a treatment which has a 25 percent
toxic
7 death rate and a low cure rate, versus
supportive
8 care?
It's a very difficult decision.
My
9 colleague Dr. Sekeres, when he as at the
10 Dana-Farber, tried to study this by a
prospective
11 patient-doctor questionnaire, and among the
12 findings from the study are that, number
one,
13 patients consistently inflate the chance of
cure,
14 compared to what is stated in medical record
15 predicted by the physician; number two,
despite
16 documentation in the medical record that the
17 doctors discussed multiple treatment options
with
18 the patients, the patients said, no, they
didn't
19 discuss this with me. That may be because there
20 really aren't too many options, and the
options
21 seem to be so stark that people feel they
don't
22 really have any.
23 [Slide.]
24 What happens in the
community? This slide
25 suggests the choices people make.
34
1 First of all, if you're in the
younger
2 cohort of the overall older cohort, you only
choose
3 chemotherapy about half the time. As you get
4 older, the chance of choosing chemotherapy
is quite
5 low.
6 What are the consequences of this
7
decision? Well, if you choose to
get chemotherapy,
8 you're going to spend significantly more
time in
9 the hospital than if you choose supportive
care.
10 What's even more important than
that is
11 you don't get any bang for the buck, because
the
12 percentage of time you spend in the
hospital,
13 compared to the total amount of time that
you have
14 left is still higher if you choose
chemotherapy.
15 So you don't seem to reap any benefit in
that
16 regard.
17 [Slide.]
18 So I think it's quite clear that
the
19 efficacy of standard chemotherapy is reduced
in the
35
1 older adult with AML compared to the younger
adult.
2 The therapy is poorly tolerated. There is clearly
3 a high therapy-related mortality rate. No trials
4 that I know about have really addressed the
quality
5 of life cost of chemotherapy.
6 If there is a small improvement in
7 survival with chemotherapy, it's quite
likely to be
8 offset by an increase in hospitalization and
other
9 negative QOL factors. And it's moot for many
10 patients, because two-thirds of patients who
are
11 older than age 65 don't choose chemotherapy
as
12 their primary treatment modality.
13 So non-chemotherapeutic
approaches,
14 besides supportive care, which may have
efficacy
15 and low toxicity, are badly needed.
16 [Slide.]
17 In summary, it's clear that AML in
the
18 older adult is a biologically and clinically
19
distinct entity. Even in the
so-called "best"
20 patients who go on chemotherapy trials, the
chance
21 for treatment-related death with induction
22 chemotherapy is actually greater than the
chance
36
1 for cure.
In those poor prognosis patients who
2 have--in the older part of this group--who
have
3 prior MDS, adverse cytogenics, the
advisability of
4 chemotherapy must be considered very low.
5 Patients and doctors are often
choosing a
6 non-intensive approach, but currently there
is
7 really no such therapy in this category
which
8 offers and appreciable chance for remission.
9 So I'd like to thank you for your
10 attention.
And I'll be happy introduce Alain
11
Thibault from Johnson &
Johnson Pharmaceutical
12 Research & Development to talk about
CTEP-20.
13 Clinical Data
14 DR. THIBAULT: Thank you, Dr.
Stone.
15 Good morning. My name is Alain Thibault.
16 I'm responsible for the clinical development
of
17 tipifarnib worldwide.
18 I will first describe key features
of
19 tipifarnib, then I will present the results
of
20 CTEP-20, which was a trial sponsored by the
Cancer
21 Therapy and Evaluation Program of the
National
22 Cancer Institute. These data are presented in
37
1 support of our application for the approval
of
2 tipifarnib in the treatment of newly
diagnosed
3 elderly patients with poor-risk AML.
4 [Slide.]
5 Tipifarnib is a selective and
competitive
6 inhibitor of the enzyme farnesyl
transferase. The
7 enzyme processes more than a hundred
proteins
8
intracellularly--some of which are shown here, and
9 many of which are involved in signaling
pathways
10 linked to the control of cell growth. Other
11 extensive research has been conducted. To this
12 date, the specific pathways associated with
the
13 anti-leukemic activity in AML are still the
subject
14 of ongoing research.
15 [Slide.]
16 Tipifarnib is an oral
treatment. So,
17 after oral administration, plasma and bone
marrow
18 concentrations rapidly exceed the IC50 of
AML cell
19 lines as determined in vitro. Tipifarnib is
20 metabolized in the liver by several
pathways. The
21 major metabolites are biologically inactive.
22 Tipifarnib is not a substrate from drug
efflux pump
38
1 encoded by the MDR-1 gene.
2 The diversity of metabolic routes
may
3 explain why tipifarnib has demonstrated a
low
4 potential for drug interactions in several
5 pharmacology studies that have been carried
out to
6 date.
7 [Slide.]
8 The recommended dosing regimen is
600
9 milligrams po BID, given for 21 days in
four-week
10 cycles.
This was established by a classical dose
11 escalating Phase I trial conducted in 34
patients
12 with poor-risk leukemias, most of whom had
AML.
13 The 21-day administration is
required to
14 maintain sustained inhibition of the target
so as
15 to maximize efficacy. And the seven-day rest
16 period is required to reduce the incidence
of
17 peripheral neuropathy, which had been
observed when
18 continuous, uninterrupted dosing was used.
19 The 600 milligram BID dose is
associated
20 with consistent farnesyl transferase
inhibition;
21
plasma and bone marrow concentrations that exceed
22 the IC50, and acceptable patient
tolerability.
23 [Slide.]
24 Let's now turn to the description
of the
25 study design. I'll first describe the rationale in
39
1 design, then I'll go over demographics,
indices,
2 characteristics. Then we'll go over efficacy and
3 safety.
4 CTEP-20 was part of a research
agreement
5 established between Johnson & Johnson
and the
6 National Cancer Institute. This was a single-arm
7
study. It was conducted at six
sites across the
8 United States, and Johns Hopkins University
was the
9 coordinating center.
10 From the very beginning, the aim
of the
11
investigators was to study tipifarnib in patients
12 with poor-risk myeloid neoplasms--I'll go
over them
13 in a few minutes. And this was a very critical
14 feature of the study from the very outset--that
15 study of patients with poor-risk myeloid
disorders.
16 [Slide.]
17 So--newly diagnosed patients, with
18 high-risk MDS--myelodysplastic
syndrome--chronic
19
myelomonocytic leukemia, and acute myeloid leukemia
40
1 were initially enrolled. Specifically regarding
2 AML, the diagnosis of AML was based on WHO
3 criteria.
No prior therapy for AML was
4 allowed--with the exception of hydroxyurea,
which
5 could be used to control counts prior to the
6 patient's entering the study.
7 With respect to age, the study
initially
8 enrolled patients age 18 to 65, with risk
factors
9 such as unfavorable cytogenetics, prior MDS,
or
10 prior exposure to chemotherapy. On the other hand,
11 patients aged 65 and above could enter the
study
12 with or without risk factors. These were the
13 initial age requirements for AML patients.
14 The patients had to have
approximate
15 status of 0 to 2 on the ECOG scale. And this was
16 chosen because it would enable them to
receive
17 treatment in the outpatient setting.
18 [Slide.]
19 After consultation and discussion
and
20 input from the FDA in July of 2003, the
study
21 protocol was amended: it was amended to
focus on a
22 more homogeneous population of elderly
patients who
41
1 had AML, who were not candidates to receive
2 intensive induction chemotherapy because the
3 associated risks were felt to outweigh the
4 benefits.
5 Therefore, after this amendment,
the age
6 requirements were raised. Patients aged 65
to 74
7 had to have a prior history of MDS, while
patients
8 75 years or older could enter the study in
the
9 absence of other risk factors.
10 So these are the patients that Dr.
Stone
11 described as commonly excluded from trials
that are
12 commonly reported in the literature.
13 [Slide.]
14 The primary endpoint of the study
was
15 complete remission, assessed by the investigators.
16 Duration of CR, partial remission,
17 hematological improvement, and overall
survival
18 were evaluated as secondary endpoints. Then the
19 safety profile was characterized.
20 [Slide.]
21 The study applied standard
morphologic
22 criteria of complete remission, which are
listed
42
1 here.
2 To achieve a complete remission, a
patient
3 had to demonstrate less that 5 percent
leukemic
4 blasts in the bone marrow; full recovery of
5 peripheral counts--without, obviously,
circulating
6 blasts or any evidence of extramedullary
AML.
7 [Slide.]
8 Partial responses were defined as:
9 complete recovery of counts in the presence
of
10 residual blasts--5 to 19 percent, following
at
11 least a 50 percent decline from baseline
values.
12 Then, hematology improvement was defined as
partial
13 recovery of peripheral counts, with the same
bone
14 marrow context.
15 So these responses can be viewed
as broad
16 indicators of anti-leukemic activity, even
though
17 their correlation with survival is not well
18 established.
19 [Slide.]
20 Treatment with tipifarnib as an
outpatient
21 monotherapy regimen--to ensure patient
safety all
22 patients were monitored weekly for
toxicity. All
43
1 patients had a bone marrow aspirate and
biopsy
2 performed prior to study entry. And this procedure
3 was repeated at the end of each treatment
cycle.
4 Unless they had dose-limiting
toxicity,
5 patients continued to receive tipifarnib in
a
6 cyclical fashion until disease progression
or
7 relapse.
8 The only exception concerns
patients who
9 achieved a complete remission. These patients had
10 the option to stop treatment after three
additional
11 cycles, and then be re-treated at the time
of
12 relapse.
And I will go over the outcome of this
13 maneuver, as well.
14 [Slide.]
15 In response to adverse events, the
16 investigators could individualize treatment
using
17 three strategies: either dose reductions,
treatment
18 interruptions within a cycle, or treatment
delays
19
between cycles.
20 Each cycle was to include a
minimum of 21
21 days of tipifarnib. The minimum rest period was
22 seven days, which could be extended by a
maximum of
44
1 35 days if needed. The total cycle duration could
2 not exceed 63 days.
3 [Slide.]
4 So let's go over the details of
the
5 population right now.
6 So, CTEP-20 started as a study of
7 tipifarnib in high-risk MDS, CMMD and
AML. Of the
8 171 patients that were enrolled, 158 were
9 considered to be poor-risk AML
patients. The 137
10 elderly poor-risk patients were strictly
defined in
11 the final protocol--as I outlined
earlier. And
12 from now on, the presentation will focus on
the 136
13 patients who were actually treated.
14 The 61 patients aged 65 to 74,
with prior
15 MDS; and the 75 patients aged 75 or more
make up a
16 unique population.
17 [Slide.]
18 The median age of the patient
population
19 is 75 years.
The male to female ratio is similar
20 to that of the general elderly AML
population, and
21
appears to reflect the higher incidence of MDS in
22 men.
23 The major of patients were
Caucasians--or
24 White.
Among the seven non-Caucasians, three were
25 African-Americans, two Asians, and two were
45
1 Hispanics.
2 Most patients were symptomatic,
either
3 from AML or from pre-existing
co-morbidities.
4 [Slide.]
5 Now, using the age-specific
incidence of
6 AML that Dr. Stone referred to earlier, if
we use
7 this as a comparator, CTEP-20 appears to be
more
8 representative of the general AML population
than
9 what is found in most other trials, in that
the
10 median age of the CTEP-20 patient was 75
years old.
11 And this exceeds that of the major
cooperative
12 group studies by approximately 10 years.
13 [Slide.]
14 Now, we know that many issues
underlie the
15 assessment of AML patients, especially in
the
16 elderly.
The chance of cure, the risk of toxicity,
17 the need for hospital stays all have an
impact on
18 treatment options that are offered to these
19 patients.
This has been reviewed by Dr. Stone.
20 What this slide lists are the
clinical
21 reasons given by the investigators--the six
22 principal investigators of this study--for
23 including the patients on the trial rather
than
24 administering intensive chemotherapy to
them.
25 Age and the presence of risk
factors were
46
1 most commonly invoked. Patient preference over
2 physician preference of experimental
treatment over
3 chemotherapy played a minor role.
4 [Slide.]
5 Now, the clinical rationales I've just
6 reviewed can be more objectively described
in terms
7 of the risk factors that are classically
associated
8 with poor outcome from chemotherapy So the
CTEP-20
9 patients had, by design, one of the highest
10 prevalence of risk factors ever reported in
the
11 literature.
Prior MDS was documented in 82 percent
12 of the patients. Forty-nine percent of the
13 patients harbored unfavorable cytogenetics,
such as
14 deletion of chromosome-5 or -7. The other patients
15 had intermediate karyotypes. Patients with
16 favorable karyotypes, such as inversion-16,
were
47
1 not enrolled on this study.
2 All in all, 41 percent--this
number is not
3 on the slide--had both MDS and unfavorable
4 cytogenetics.
5 Now, in terms of increased
morbidity
6 risks, 55 percent were age 75 or older--more
than
7 half; and 61 percent had evidence of organ
8 dysfunction.
This was manifested by two or more
9 active medical conditions other than the
AML, on
10 either history, physical examination or
laboratory
11 findings.
12 [Slide.]
13 Looking at the number of risk
factors per
14 patient is also very interesting: 44 percent
of the
15 patients had two risk factors; 35 percent
had
16 three; 11 percent had four of these risk
factors.
17 So, overall, 90 percent of the trial
population
18 entered with two or more risk factors on
this
19 trial.
20 [Slide.]
21 The full spectrum of leukemic
burden was
22 represented also in this study. The median bone
48
1 marrow blasts count at diagnosis was 46
percent.
2 All patients met the WHO criteria--as I
3 mentioned--except for one, who was
nevertheless
4 included because he was clearly evolving
from MDS.
5 This patient, who did not achieve a CR was
excluded
6 by the FDA.
But, for the sake of this
7 presentation, I'm reporting the results
based on
8 the investigator's assessment.
9 [Slide.]
10 The majority of the patients were
severely
11 myelosuppressed--as would be expected--prior
to
12 study entry.
The median neutrophil count was 636,
13 with 61 percent having Grade 3 or 4
14 myelosuppression at the time of entry. Fifty-six
15 percent of the patients had a similar degree
of
16 thrombocytopenia, with a median platelet
count
17 value of 41,500.
18 [Slide.]
19 So, in summary, the 136 patients
accrued
20 to this study represent a population with a
high
21 incidence of risk factors, and they
routinely do
22 poorly with available treatment.
23 So, it is in this context that I'd
like to
24 review the efficacy of tipifarnib for the
next few
25 minutes.
49
1 [Slide.]
2 Complete remissions were
documented by the
3 investigators at the research sites in 20
patients,
4 for a complete remission rate of 15
percent. The
5 associated 95 percent confidence interval
ranges
6 from 9 to 22 percent.
7 Partial remissions and hematologic
8 improvements were documented in 10 additional
9 patients.
So, in total, tipifarnib reduced the
10 leukemic burden of 30 patients, or 22
percent of
11 the study population.
12 [Slide.]
13 In general, the data shows
consistency
14 across risk groups. And this is what we illustrate
15 here on this slide.
16 For example, the complete
remission rate
17 in the 111 patients with prior MDS,
secondary AML,
18 was 16 percent; and the response rate in the
19 patients aged 75 years or more was 12
percent.
20 [Slide.]
21 The complete remissions were
documented at
22 four of the six sites. No single institution
23 accounts for the majority of cases.
24 [Slide.]
25 And as a specific quality control
feature
50
1 of the study, the complete remissions were
sought
2 to be confirmed by the investigators, even
though
3 the primary endpoint of the study was
achieving a
4 CR.
5 So what this slide shows here, is
that the
6 primary endpoint of the study was complete
7 remission, and that of the 20 patients who
achieved
8 a complete remission, 17 were confirmed by
repeat
9 bone marrow biopsy at one month. The three that
10 were not confirmed include one patient who
relapsed
11 early, one patient who died while in CR, and
one
12 patient who refused further follow-up with
bone
13 marrow biopsies--and I will go over them in
some
14 detail for you.
15 [Slide.]
16 Patient 318 was an 81-year-old man with 90
51
1 percent blasts at baseline. He achieved a complete
2 remission but had evidence of early relapse
by
3 peripheral counts on day 58.
4 Patient 336 was an 80-year-old man
who
5 achieved also a CR following one cycle of
6 tipifarnib at the recovery of counts at the end
of
7 the cycle.
Upon re-treatment with a second cycle,
8 he developed drug-induced
myelosuppression. This
9 was complicated by neutropenic fungal
sepsis, and
10 then the patient died in CR on day 67.
11 And, finally, patient 508 was a
12 79-year-old man with 90 percent blasts at
the time
13 of study entry. He entered a CR which was
14 established by bone marrow biopsy. He then refused
15 further bone marrow assessments, but was
maintained
16 in CR by continuous treatment for 121 days,
based
17 on peripheral counts.
18 [Slide.]
19 Another aspect of the quality
control
20 measure was an independent review which was
21 performed by Dr. Albitar. This reviewer was
22 blinded to patient outcome.
23 This review involved a retrospective
24 collection of the baseline diagnostic bone
marrow
25 slides from the 136 patients, and in
addition, the
52
1 key aspirate slides which were obtained from
2 patients on treatment. This included slides from
3 18 of the 20 patients who achieved a CR, so
that
4 the independent reviewer had access to a
large
5 proportion, although not all, of the CRs.
6 So his findings are summarized on
this
7 slide.
8 [Slide.]
9 As a result of his review, all 18
10 CRs--this is the first bullet--all 18 CRs
that were
11 available for him were agreed upon, for a
12 concordance rate of 100 percent.
13 The reviewer--and this is the
second
14 bullet--the reviewer also agreed that 15 of
the 16
15 confirmed CRs that were available for his
16 review--there were 17 by the investigators,
16
17 available.
And therefore, from his review of the
18 16, he verified that 15 were indeed
maintained at
19 one month.
20 The one disagreement is in the
patient on
21 whom there was agreement that he achieved a
CR, but
22 there was a disagreement as to the number of
blasts
23 in the follow-up period. The investigators
24 assessed as less than 5 percent, and the
25 independent reviewer assessed it variously
between
53
1 6 percent and 9 percent. Both agreed on the time
2 of relapse.
3 [Slide.]
4 Now, most patients who achieved a
complete
5 remission on this study had more than one
risk
6 factor.
These complete remissions, but also
7 partial remissions and heme improvements were
8 documented regardless of the number of risk
factors
9 present in any given patients. And so the overall
10 rates of anti-leukemic activity ranged from
19
11 percent to 29 percent, irrespective of the
number
12 of risk factors. There is no trend that can be
13 identified.
14 [Slide.]
15 On this Kaplan-Myer plot, the
x-axis is
16 labeled in days. The complete remissions were
54
1 durable.
They range from 33 to 376 days, with a
2 median duration of 220 days. This is slightly more
3 than seven months.
4 The 95 percent confidence interval
around
5 this is 154 up to 275 days.
6 Duration of complete remissions
was
7 calculated starting from the first
documentation of
8 CR until time of relapse. And the dots represent
9 patients that were censored at the time of
clinical
10 cut-off, or the time of death, if they were
still
11 in CR.
12 [Slide.]
13 Now, turning your attention to
survival,
14 on this Kaplan-Myer plot, and on the one
that will
15 follow, patients were censored at the time
of
16 clinical cut-off or last follow-up. 131 patients
17 have complete follow-up, and five patients
had
18 follow-up--at least partial follow-up.
19 The median survival of the
patients who
20 achieved a CR was 433 days. This is in excess of a
21 year.
Two patients were alive at two and three
22 years, respectively. And these data suggest that
55
1 complete remissions are indeed associated
with
2 survival benefit in this patient population.
3 This potential effect on survival
is being
4 investigated in a 301 trial that Dr. DeLap
5 described at the beginning of this
presentation.
6 [Slide.]
7 Finally, the overall survival of
the 136
8
patients is depicted here. The
median survival was
9 164 days, or approximately five to
five-and-a-half
10 months.
11 [Slide.]
12 The information collected by the
13 investigators concerned tipifarnib
administration,
14 obviously, but also treatment administered
after
15 failing the first course of treatment.
16 This slide shows the re-treatment
of
17 patients who achieved a CR--seven of the 20
18 patients who achieved a CR chose to stop
after
19 three cycles. They were re-treated with tipifarnib
20 at relapse.
One of these seven patients achieved a
21 second complete remission of similar
duration to
22 the first one: approximately six months.
23 So these data suggest that
patients may
24 remain sensitive to tipifarnib at the time
of
25 relapse.
56
1 [Slide.]
2 The use of chemotherapy after
tipifarnib
3 in the 136 patients was also
recorded. The
4 majority of the patients went on to receive
5 palliative care only.
6 Only 12 patients, most of whom
were less
7 than 75, were able to receive intensive
8 chemotherapy, usually anthra-cycline plus
Ara-C.
9 [Slide.]
10 So, in summary, tipifarnib is
active in
11 elderly, poor-risk AML. The CTEP investigators
12 documented a 15 percent complete remission
rate,
13 which is the primary endpoint of the study.
14 Most of the complete remissions
were
15 confirmed at one month by the investigators,
and
16 verified by the independent reviewer. Complete
17 remissions were durable, lasting 220 days,
or 7.2
18 months.
The median survival of patients with
19
complete remission was 433 days,
or 14.2 months.
20 [Slide.]
21 This enters the final section of
the
22 presentation, which concerns safety.
23 In terms of drug exposure, the
median
24 treatment cycle duration was 38 days. 47 percent
25 of the patients received two or more
cycles. So
57
1
this includes patients with complete remissions,
2 partial remissions, and hematologic
3 improvement--but also several patients who
4 maintained stable disease for s several
months.
5
[Slide.]
6 The need for treatment
interruptions or
7 delays explained the median cycle duration
of 38
8 days which I just presented. Those reductions were
9 implemented in 35 percent of the patients.
10 Reductions were implemented in approximately
half
11 of the patients who received two or more
cycles,
12 such as the patients who achieved a CR.
13 The most common reason for dose
reductions
14 were related to myelosuppression,
gastrointestinal,
15 CNS--and, rarely, renal or dermatological
signs and
16 symptoms.
17 Patient age did not appear to have
an
18 impact on the tolerability.
19 [Slide.]
20 So, as expected in a population
with AML,
21 the adverse events were common: 61 percent
of the
22 population experienced drug-related adverse
events.
23 These were mostly related to
myelosuppression--in
24 the background of, of course, severe
25 myelosuppression.
58
1 In contrast, only 10 percent of
the
2 patients were withdrawn for drug adverse
event.
3 And adverse events were also associated with
a low
4 mortality rate. Only nine patients in whom an
5 adverse event--of the nine patients,
actually, in
6 whom an adverse event led to death, only one
was
7 assessed by the investigators as related to
8 tipifarnib.
9 [Slide.]
10 To go into more details, a
majority of
11 patients experienced Grade 3 or 4
myelosuppression
12 by peripheral count assessments. Fewer patients
13 went on to develop clinical adverse events
in the
59
1 form of sepsis or bleeding complications.
2 And, as I mentioned, approximately
3 two-thirds had Grade 3 myelosuppression at
the time
4 of study entry, and so the overall incidence
has to
5 be interpreted in this context.
6 [Slide.]
7 Turning our attention to
non-hematologic
8 adverse events--that is, events excluding
9 myelosuppression and its complications--the
overall
10
rate of life-threatening or Grade 4 events was low:
11 2 percent.
Most events were reversible following
12 treatment interruption.
13 The GI tract was most commonly
involved.
14
Nausea, diarrhea, vomiting were most often mild to
15 moderate.
The incidence of drug-related mucositis
16 was only 3 percent. This is what this shows--5
17 percent, and 3 percent if we consider Grade
3 or 4
18 in severity.
19 Now, given that mucositis is a
major
20 contributor of morbidity and death in
21 myelosuppressed patients, this is probably
the most
22
important--the most important
safety advantage of
60
1 tipifarnib in this older population.
2 [Slide.]
3 Rare adverse events affecting the renal
4 and CNS systems were documented. Few reached Grade
5 3 or 4 severity. All these adverse events were
6 managed appropriately by protocol-defined
treatment
7 interruption and dose
reductions. Many appeared in
8 the context of sepsis, and were of short
duration.
9 Rapid ejaculation, the median duration of
CNS
10 events was two to three days.
11 [Slide.]
12 Very few patients--as we show
here--were
13 removed from the study because of these
events.
14 Indeed, the adverse events that
led to the
15
termination of treatment were varied.
No one AE
16 appears to be a major contributor. The most common
17 causes were elevation of serum creatinine
and skin
18 rash, both of which were reversible.
19 [Slide.]
20 This study did not have a specific
module
21 collecting data on quality of life as we
would
22 have.
So, hospitalization data provides a valuable
61
1 perspective on the safety profile and the
patient
2 tolerability of this drug. And what it suggests is
3 that outpatient treatment of this elderly
4 population is feasible.
5 Up to 40 percent of the patients
received
6 their full course of treatment as
outpatients. The
7 majority of patients who were hospitalized
were
8 hospitalized only once or twice.
9 The median duration of combined
hospital
10 stay was 15 days--all hospitalizations. And this
11 represents 14 percent of the patients spent
on
12 study.
13 [Slide.]
14 Finally, few patients died from adverse
events on
15 this study.
No single cause appears to account for
16 the majority of cases, most of which appear
related
17 to a complication of AML.
18 In the opinion of the
investigators, only
19 one death from neutropenic fungal sepsis was
20 related to tipifarnib.
21 [Slide.]
22 So how can we best summarize
CTEP-20?
62
1 First of all, CTEP-20 was a study of patients
with
2 significant unmet medical need, determined
by the
3 advanced age, and the high prevalence of
risk
4 factors which are associated with poor
patient
5 outcome.
6 In this patient population,
tipifarnib
7 induced as a monotherapy a 15 percent
complete
8 remission rate that was both durable and
9 independent of risk factors.
10 The safety profile of tipifarnib allowed
11 outpatient treatment. This might be due to a very
12 low rate of life-threatening
non-hematological
13 toxicity, especially when one considers
mucositis.
14 So, consequently, the time spent
in
15 hospital represented a small fraction of the
total
16 study time: approximately 14 percent. Only one
17 death was attributable to tipifarnib.
18 This concludes my review. And Dr. Alex
19 Zukiwski will deliver the closing
presentation for
20 Johnson & Johnson.
21 Benefit/Risk
22 DR. ZUKIWSKI: Thank you, Dr. Thibault.
23 Good morning. I'm Alex Zukiwski from the
24 Oncology Development Group at Johnson &
Johnson
25 Pharmaceutical Research and
Development. I'm going
63
1 to conclude the presentation today with a
summary.
2 The proposed indication is:
tipifarnib is
3 indicated for the treatment of elderly
patients
4 with newly diagnosed poor-risk acute myeloid
5 leukemia.
The basis of this approval is complete
6 remissions-- an accepted efficacy endpoint
in AML
7 which has been shown to correlate with
overall
8 survival.
9 [Slide.]
10 It is evidence that elderly
patients with
11 poor-risk AML have limited therapeutic
options. As
12 noted in Dr. Stone's presentation, select
elderly
13 patients should be considered for
chemotherapy,
14 although older patients do not do as well as
15 younger patients. These patients who receive
16 induction chemotherapy were described as
having the
17 best ability to tolerate and benefit from
such
18 treatment.
19 In the United States,
approximately
64
1 two-thirds of the patients greater that 65
years of
2 age do not receive IV chemotherapy. This is due to
3 an unfavorable benefit-risk. These patients have
4 risk factors which predispose to decreased
5 efficacy, including antecedent hematological
6 disorders such as myelodysplastic syndrome,
and
7 also have unfavorable cytogenetics.
8 They also have factors which
predispose
9 them to increased toxicity, such as
co-morbidities
10 and compromised performance status.
11 As indicated in the NCCN
guidelines,
12 options available for this under served
patient
13 population include investigational studies,
14 low-intensity chemotherapy,
and--unfortunately for
15 many of these patients--it is simply best
16 supportive care.
17 [Slide.]
18 The patients enrolled in CTEP-20
were felt
19 not be well-served by standard induction
20 chemotherapy. And this represents a unique patient
21 population which is not well represented in
the
22 literature. For example, the CALGB and ECOG
studies
65
1 mentioned in Dr. Stone's presentation
enrolled
2 patients who were good candidates for
induction
3 chemotherapy, and many of these studies
excluded
4 those patients with prior myelodysplastic
syndrome.
5 The median age of the CTEP study
6 population was 75 years, and 90 percent of
the
7 CTEP-20 patients had two or more risk
factors which
8 predisposed them to decreased efficacy and
9 increased toxicity from conventional
anti-leukemic
10 therapies.
11 [Slide.]
12 The complete remission rate in
this very
13 difficult to treat patient
population was 15
14 percent by investigators' assessment. As per the
15 key academic investigators involved in the
CTEP
16 study, this response rate is meaningful in a
17 patient population that is often excluded
from AML
18 studies, and many times receives palliative
care
19 only.
20 Of the 20 complete remissions as
assessed
21 by the investigators, the independent
reviewer was
22 able to confirm and verify 15 complete
remissions
66
1 for quality control purposes. While the other five
2 cases could not be verified for a variety of
3 reasons, there is evidence of substantial
4 anti-leukemic activity in these five
patients.
5 The median duration of complete
remissions
6 was 220 days, and complete remissions were
observed
7 across all risk groups.
8 The exploratory analysis of
survival--as
9 outlined by Dr. Thibault--is encouraging,
and will
10 be further examined in an AML study
specifically
11 designed to evaluate a survival endpoint.
12 [Slide.]
13 The anti-leukemic activity observed
in the
14 CTEP-20 study has to be considered in the
overall
15 treatment context as presented by DR.
Stone. Even
16 in the "best" patients who can
receive induction
17 chemotherapy, individual risk factors which
were
18 very prominent in the CTEP-20 study have a
negative
19 impact on complete remission rates.
20 As shown in this slide, a
reduction of
21 complete remission rates by approximately
one-half
22 is observed in patients with prior
myelodysplastic
67
1 syndrome, unfavorable cytogenetics, or
advanced
2 age--with even the most effective
chemotherapeutic
3 agents.
4 The early death rates in these
trials,
5 which includes the more younger and fit
patient
6
populations, is approximately 20 to 25 percent,
7 with the majority of these deaths associated
with
8 bone marrow aplasia and severe mucositis.
9 [Slide.]
10 Now, to put the CTEP-20 study into
11 context.
12 These are patients which
experienced AML
13 investigators felt were not the best
candidates for
14 combination chemotherapy. They had an 83 percent
15 incidents of myelodysplastic syndrome; a 49
percent
16 incidence of unfavorable cytogenetics, and a
median
17 age of 75.
18 What would be the anticipated
complete
19 remission rate in this patient population
with
20 combination chemotherapy?
21 The anticipated early death rate
in this
22 patient population with combination chemotherapy
68
1 would most likely be at least double the 12
percent
2 early death rate observed in the CTEP-20
trial.
3 [Slide.]
4 In the patient population studied
in
5 CTEP-20, advanced age, with its associated
6 co-morbidity co-morbidities, and the
underlying
7 disease complicates any treatment efforts.
8 Despite this, a management and
predictable
9 safety profile was observed in the patients
treated
10 with tipifarnib. Adverse events were managed with
11 supportive care measures. As the scheduled
12 treatment was for 21 days, dose
13 modifications--including dose interruptions
and
14 dose reductions--could be quickly
implemented to
15 address any emerging toxicities.
16 Forty percent of the patients did
not
17 require hospitalization. And for those who were
18 hospitalized, the median duration was
approximately
19 15 days. The limited time spent in hospital is an
20 important feature of this outpatient
treatment.
21 Twelve percent of the patients
died on
22 study within 30 days of the first dose of
69
1 tipifarnib.
And only one treatment-related death
2 was reported by the investigators during the
study.
3 This data indicates that tipifarnib has been
shown
4 to safely treat a unique elderly patient
5 population.
6 [Slide.]
7 In conclusion, the application
under
8 review is focused on a difficult to treat
patient
9 population for whom an unmet medical need
exists,
10 and alternative treatments are required.
11 Approximately one in seven to one in nine of
the
12 patients treated with tipifarnib developed a
13 durable complete remission.
14 This novel targeted therapy is
15 administered as an oral tablet which allows
for
16 flexible outpatient dosing. As presented here
17 today, there is a positive benefit-risk
evidence
18 with tipifarnib treatment.
19 Approval of tipifarnib for this
orphan
20 indication will provide a new treatment for
elderly
21 patients with poor-risk AML. These patients are
22 currently not well served. Standard induction
70
1 chemotherapy has a high degree of toxicity
and a
2 lower degree of efficacy in this patient
3 population.
4 This concludes the sponsor's
presentation.
5 DR. MARTINO: Thank you.
6 Ladies and gentlemen, I will not
allow
7 questions until we have also allowed the FDA
and
8 Dr.
9 Fred Appelbaum to present. So those of you that
10 have questions please know that that will be
your
11 opportunity.
12 Dr. Ryan, representing the FDA,
will
13 present next.
14 FDA Presentation
15 NDA 21-824, Zarnestra
16 DR. RYAN: Good morning. I'm Qin Ryan,
17 medical officer in the Division of Oncology
Drug
18 Products.
I'm here today to present the main
19
findings from our review of Zarnestra NDA 21824.
20 [Slide.]
21 My presentation will cover the
relevant
22 regulatory background; clinical development
71
1 overview and proposed indication; CTEP-20
study
2 design, efficacy and safety findings.
3 [Slide.]
4 First, the relevant regulatory
background.
5 In oncology, clinical benefit has
been
6 defined as a longer life, a better life or
an
7 effect on an established surrogate for
either.
8 In acute leukemias, durable
complete
9 remission--CR--has been considered evidence
of
10 benefit.
11 In some cases where leukemia CRs
were of
12 uncertain duration, CR was considered a
surrogate
13 reasonably likely to predict clinical
benefit.
14 [Slide.]
15 Here are some examples. As first-line
16 indications for acute myeloid leukemia
--AML--both
17 idarubicin and daunorubicin were regular
approvals
18 based on demonstration of durable remissions
in
19 randomized trials. In addition, idarubicin also
20 demonstrated a survival advantage in two
21 comparative studies.
22 In the case of gemtuzumab,
accelerated
72
1 approval was granted for patients aged 60 or
older
2 with CD-33 positive disease who are not
candidates
3 for second-line cytotoxic chemotherapy. Approval
4 was based on a pooled complete remission
rate from
5
three single-arm studies. Of 277 patients enrolled
6 into these three studies, 157 were 60 years
or
7 older.
Although relaxed free survival was
8 evaluated, the ratio of remission could not
be
9
reliably ascertained, as 45 percent of patients who
10 achieved remission also received additional
11 anti-leukemic therapy.
12 [Slide.]
13 Next, I will discuss the clinical
14 background for this NDA.
15 Patients with newly-diagnosed AML,
if not
16 treated, will progress rapidly to a fatal
outcome.
17 The standard induction therapy for newly
diagnosed
18 AML, such as 3+7 regimen of cytarabine and
19 daunorubicin can be expected to achieve 60
to 75
20 percent complete remission. And the
21 treatment-related death rate, less than 10
to 20
22 percent in adult AML patients younger than
age 60.
23 [Slide.]
24 One follow-up study indicated that
30 to
25 40 percent of patients in this age group will
73
1 survive three years or more. However, clinical
2 outcome would depend on multiple factors.
3 Unfavorable outcome is usually associated
with
4 multiple poor-risk factors, such as poor
5 performance status, organ dysfunction, or
6 significant co-morbidity, older age,
unfavorable
7 karyotype, prior MDS, disease resistance
8 or patient intolerance to cytotoxic therapy.
9 Although the incidence of adult
AML
10 increases with age, the chance for patients
to
11 receive treatment decreases.
12 [Slide.]
13 Menzin, et al., analyzed a data
base of
14 over 2,600 AML patients aged 65 or older,
15 identified by Medicare claims. Overall, only 30
16
percent of those patients received some form of
17 chemotherapy. Asa shown here, the percentage of
18 patients receiving chemotherapy decreased
19 drastically with increasing age.
20 [Slide.]
21 Menzin, et al., also estimated
survival
22 for these patients. As indicated by the curve with
23 diamond points, the median survival for all
24 identified patients was two months, with a
two-year
25 survival of 6 percent.
74
1 [Slide.]
2 Compared to younger adults,
elderly AML
3 patients usually present with other risk
factors,
4 such as poor performance status, organ
dysfunction,
5 co-morbidity, unfavorable karyotype, prior
MDS, and
6 drug resistant disease, as mentioned
before. The
7 less tolerant to standard induction therapy
the
8 elderly poor-risk AML patients are, the more
likely
9 they are to be a therapeutic challenge.
10
[Slide.]
11 One review pointed out that
12 treatment-related mortality in elderly
patients
13 with poor-risk AML may be as high as 25
percent,
14 and the complete remission rate may be less
than 50
15 percent.
16 In a study of AML patients at
least 80
75
1 years of age, the mortality rate at one
month as 48
2 percent, and the complete remission rate was
less
3 than 30 percent.
4 Few elderly AML patients are
expected to
5 live free of disease after standard
cytotoxic
6 chemotherapy.
7 [Slide.]
8 Next, I will discuss the clinical
program.
9 Zarnestra is a farnesyl
transferase
10 inhibitor.
It is formulated in film coat 100 mg
11 tablets.
In the CTEP-20 study, Zarnestra was
12 tested as first-line AML induction
therapy. It was
13 administered hourly with food, at a dose of
600 mg
14
twice daily for 21 days, followed by a rest period
15 of seven to 42 days.
16 [Slide.]
17 Zarnestra is being proposed for
the
18 treatment of elderly patients with newly
diagnosed
19 poor-risk acute myeloid leukemia.
20 [Slide.]
21 Eleven studies relevant to safety
and dose
22 findings have been submitted in this
NDA. Among
76
1 those, the studies relevant to efficacy and
safety
2 in AML are summarized here. The most relevant
3 population for the proposed indication is a
4 subgroup of subjects in Study CTEP-20,
accounting
5 of 79 percent of CTEP-20 enrollment.
6 The studies INT-17 and CTEP-1 are
less
7 relevant to the proposed indication. Therefore we
8 will focus our discussion on CTEP 20.
9 I will now go over the CTEP-20
study
10 design in the next few slides.
11 [Slide.]
12 This open-label, single-arm,
multicenter
13 study which opened on October 10, 2001, was
14 originally designed to assess the efficacy
and
15 safety of Zarnestra in subjects with
previously
16
untreated, poor-risk hematologic malignancies.
17 After enrolling 110 patients, Amendment 6
was
18 implemented on September 16, 2003. The target
19 population as redefined as subjects either
75 years
20 or older with newly diagnosed AML, or 65 to
74
21 years of age with AML arising from prior
22 myelodysplastic syndrome.
23 [Slide.]
24 The original primary objective was
to
25 determine response rate, which included CR
and PR.
77
1 As mentioned, after the 6th Amendment, the
primary
2 objective changed to
determining the complete
3 remission rate in elderly subjects with
previously
4 untreated, poor-risk acute myeloid leukemia.
5 Secondary objectives were to determine
the
6 progression-free survival, overall survival,
7 duration of response, and safety profile.
8 [Slide.]
9 After Amendment 6, the major
inclusion
10
criteria can be described as follows: untreated
11 newly diagnosed AML patients, 75 years or
older, or
12 65 to 74 years of age with prior MDS.
13 Our eligible subjects should have
14
pathologic confirmation of AML showing equal or
15 more than 20 percent marrow or peripheral
blasts.
16 Patients must have an ECOG performance score
of
17 zero or one-- which was changed from the original
18 zero to two--with adequate renal and liver
19 function.
20 Patients with the following
conditions
21 were excluded: hypoleukocytosis despite
22 leukopheresis or hydroxyurea; acute
promyelocytic
23 leukemia; previous anti-leukemic
chemotherapy other
24 than hydroxyurea; disseminated intravascular
25 coagulation, or leukemia involvement of the
central
78
1 nervous system.
2 [Slide.]
3 Leukemia assessments were
conducted at
4 baseline and the end of each cycle, ranging
from 29
5 to 64 days.
This included medical history,
6 physical examination, bone marrow aspiration
and
7 biopsy, CBC and chemistry.
8 The criteria for response
assessment were
9 based on NCI-sponsored workshop on
definition of
10 diagnosis and response in acute myeloid
leukemia.
11 Per protocol, CR is defined as
marrow
12 showing less than 5 percent myeloblasts,
with
13 normal maturation of all cell lines; an ANC
of at
14 least 1,000 per micro liter; a platelet
count of
15 100,000 per micro liter; absence of blasts
in
16
peripheral blood; absence of identifiable leukemic
79
1 in the bone marrow; clearance of
disease-associated
2 cytogenetic abnormalities; and clearance of
any
3 previously existing extramedullary disease.
4 In addition, CR must be confirmed
four to
5 six weeks after initial documentation; at
least one
6 bone marrow biopsy should be performed to
confirm
7 CR.
8 Subjects who achieved a complete
remission
9 could receive additional Zarnestra treatment
until
10 disease progression, or receive up to three
11 additional cycles and stop.
12 Re-treatment with Zarnestra was
allowed.
13 Subjects with progressive disease at any
time
14 during the Zarnestra administration were
withdrawn
15 from the study. The first follow-up occurred 30
16 days after treatment termination for
subjects who
17 did not have a documented progression, or
had not
18 started subsequent therapy; every 90 days
after
19 documentation of progressive disease or
start of
20 subsequent therapy.
21 In the next few slides, I will
discuss the
22 CTEP-20 patient population efficacy data.
23 [Slide.]
24 Of the total 171 patients enrolled
in
25 CTEP-20, 158 of them had AML. At the time of
80
1 clinical cutoff, 157 AML subjects were
treated with
2 at least one cycle of Zarnestra. Of those, 136
3 were elderly subjects with poor-risk AML,
and are
4 most relevant to the proposed indication.
5 Please note that one of the
elderly
6 subjects with poor-risk AML was excluded
from FDA's
7 efficacy analysis, but not safety
analysis. The
8 reason for this exclusion was that this
patient's
9 baseline blast count was less than 20,000
per cubic
10 milliliter, as assessed by both the
investigator
11 and the sponsor's central review. This patient did
12 not respond to Zarnestra treatment.
13 This resulted in 156 evaluable
patients in
14 the all-treated AML population, and 135
patients in
15 the elderly poor-risk AML population.
16 Two thirds of subjects had a
performance
17 status of one, and a quarter of them had a
18 performance status of zero. There were
19 approximately 10 percent of patients who were
81
1 enrolled before Amendment 6, with a
performance
2 status of two. As per investigators, all 136
3 patients were ineligible for standard
chemotherapy
4 for at least one reason.
5 Of patients aged 75 or older, 96
percent
6 were considered ineligible due to age,
whereas in
7 the 65 to 74-year-old group, approximately
50
8 percent of patients had age or other risk
factors
9 as a reason for ineligibility.
10 [Slide.]
11 Based on the sponsor-provided
data, risk
12 factors in the CTEP-20 elderly poor-risk AML
13 population are summarized by category and
number.
14 Eighty-two percent of patients had
prior
15 MDS; more than half of the patients were
older than
16 75 years, or with poor organ function as
defined by
17 the sponsor; and two-thirds of patients had
18 unfavorable karyotypes; 44 percent and 35
percent
19 of patients had at least two or three of
these risk
20 factors, respectively. About 10 percent of
21 patients had either one or four risk
factors.
22 Complete responders were initially
82
1 assessed by the site investigators. The
sponsor
2 appointed an independent reviewer to
reassess the
3 complete remissions. FDA requested all available
4 bone marrow slides of CRs from the sponsor,
and
5 reviewed them with an FDA-appointed
hematology
6 consultant.
7 [Slide.]
8 The assessment of CR by the study
9 investigator, the independent reviewer, and
FDA are
10 summarized here. Of the three unconfirmed CRs, the
11 FDA and independent reviewer agreed with the
12 investigator that two could not be confirmed
due to
13 death and disease progression. FDA also agrees
14 with the independent reviewer that on CR by
15 investigator assessment was unconfirmed due
to
16 insufficient data. In addition, slides of two
17 subjects were not available for response
assessment
18 by the sponsor's independent reviewer or FDA
19 consultant.
20 [Slide.]
21 FDA agrees with the
sponsor-appointed
22 independent reviewer's assessment of
complete
83
1 remission; that is, 15 subjects were
confirmed
2 complete remission from the FDA-identified
elderly
3 poor-risk AML patient subgroup.
4 FDA assessment of the confirmed
complete
5 remission rate is 11.1 percent, with a 95
percent
6 confidence interval of 6.6 to 18 percent.
7 [Slide.]
8 Based on FDA exploratory subgroup
9 analysis, patients older than age 74 have a
lower
10 tendency to achieve complete remission than
do
11 patients age 65 to 74, with a rate of 6.7
percent
12 versus 16.4 percent, respectively.
13 In addition, of the 25 patients
older than
14 74 years with de novo AML who enrolled in
CTEP-20,
15 only one patient achieved complete remission
with
16 confirmation.
17 Less responders were seen in
subjects with
18 unfavorable karyotypes.
19 [Slide.]
20 The FDA has explored the duration
of
21 confirmed CR as a secondary endpoint of
study
22 CTEP-20.
Per protocol, no anti-leukemic therapy
84
1 other than Zarnestra was given to patients
who
2 achieved a response until after disease
progression
3
and removal from the study.
4 At the time of cut-off,
progression of
5 disease or death occurred in seven of 15
patients,
6 giving a median remission duration of 275
days,
7
with 95 percent confidence interval of 127 to 376
8 days.
9 Next, I will discuss the CTEP-20
safety
10 data.
11 [Slide.]
12 In CTEP-20, all of the elderly
poor-risk
13 AML patients received at least Zarnestra
during
14 first cycle; 47 percent of them were treated
for a
15 second cycle, and 20 percent received a
third
16 cycle.
17 The median duration of these
cycles was 36
18 to 38 days.
The mean intensity for the first cycle
19 was 749.4 mg per day, which is approximately
63
20 percent of the planned 1,200 mg per day
dose.
21 The calculated dose intensity may
not
22 reflect true drug exposure, since the
Zarnestra
85
1
exposure measurements were primarily based on the
2 pharmacy dispensation record. A patient medication
3 diary was not planned for CTEP-20.
4 [Slide.]
5 Ninety-eight percent of CTEP-20
subjects
6 experienced adverse events. The most frequently
7 reported non-hematological adverse events
were
8 diarrhea, fatigue, nausea, skin rash, fever,
9 anorexia, constipation, vomiting and
dyspnea.
10 Dizziness, and ataxia or abnormal gait were the
11 most frequently seen nervous system adverse
events.
12 In addition, confusion was the most commonly
seen
13
psychiatric adverse event. This
may be related to
14 age and hospitalization.
15 The most common dermatological and
16 infection-related adverse event were
neutropenia,
17
with or without fever; purpurea, thrombocytopenia,
18 anemia, bacterial infection, candida and
other
19 fungal infections.
20 The most frequent metabolic
disturbances
21 were increased creatinine, hypokalemia, and
22 hyponatremia.
23 Of 136 subjects, 21, 47 and 56
subjects
24 had at least one adverse event leading to
treatment
25 termination, dose reduction, and temporary
86
1 interruption of Zarnestra,
respectively. The top
2 three adverse events leading to changing
treatment
3
were neutropenia, increased creatinine and rash.
4 FDA agrees with the sponsor that
113
5 subjects, or 83 percent of the elderly
poor-risk
6 AML group, experienced Grade 3 or 4 adverse
events.
7 The most frequent treatment-emergent Grade 3
or 4
8 adverse events were secondary to
myelosuppression,
9 including neutropenia, with or without
fever,
10 infection, thrombocytopenia, and anemia.
11 Other frequent severe adverse
events were
12 fatigue, rash, dyspnea, confusion, diarrhea,
and
13 hypokalemia.
14 [Slide.]
15 Thirty-one of the 136 elderly
poor-risk
16 AML subjects in CTEP-20 died, either within
30 days
17 of treatment termination, or within 30 days
of
18 receiving the first dose of medication. The death
19
rate within 30 days of the first dose was 12
87
1 percent. Based on the sponsor-provided data,
we
2 verified the sponsor's summary and agree
that 19 of
3 31 deaths were due to disease progression,
and nine
4 of them were due to adverse events. The deaths due
5 to adverse events were 7 percent with causes
such
6 as cardiac failure and various infections.
7 One death due to adverse event was
thought
8 to be drug-related by the investigator. This was a
9 patient who had a neutropenic fever, fungal
10
infection, and renal dysfunction.
11 There were three of 31 deaths
attributed
12 to adverse events or progression of disease
on
13 subsequent treatment, after patients
progressed
14
from Zarnestra, which the sponsor categorized as
15 "other" cause of death.
16 [Slide.]
17 Eighty-one subjects, or 60 percent
of the
18 total 136 patients, were hospitalized during
the
19 study.
Fourteen percent of the subjects received
20 Zarnestra treatment in the outpatient
setting
21 completely.
22 The median total duration of
88
1 hospitalization was 15 days. Ten subjects required
2 at least three hospitalizations during the
study
3 period.
4 [Slide.]
5 In summary, durable complete
remission has
6 been accepted as an endpoint supportive of
regular
7 approval in AML. Zarnestra efficacy findings
8 should be considered in the context of a
poor-risk
9 AML population and the toxicity profile
observed.
10 Although the remission rate does not compare
11 favorably with that reported with cytotoxic
12
therapy, the one-month's mortality and treatment
13 related date rate of 12 percent and 7
percent,
14 respectively, compare favorably with the
greater
15 than 25 percent treatment-related death rate
16 reported in the literature for patients age
60 or
17 older, with or without other risk factors,
who had
18 adequate organ function to receive
chemotherapy.
19 We will have one question for the
20 committee to discuss: does the risk-benefit
21 analysis support regular approval of
Zarnestra for
22 the treatment of elderly patients with AML?
23 Thank you very much for your
attention.
24 DR. MARTINO: Thank you, Dr. Ryan.
25 At this point, ladies and
gentlemen, we
89
1
have one additional speaker, and that is Dr. Fred
2 Appelbaum, who will present via
videoconference at
3 a quarter to the hour.
4 So, at this point, I'm going to
give you
5 about 15, 20 minutes of a break, and we'll be
back
6 here at 10:45 for his video
presentation. We will
7 take questions subsequently.
8 [Off the record.]
9 DR. MARTINO: Back on the record.
10 The next presentation is Dr. Fred
11 Appelbaum.
He's going to speak to us via
12 videoconference. He is the Director of Clinical
13 Research at Fred Hutchinson Cancer
Center. And I
14 don't know if we are actually ready to go.
15 Ms. Clifford? Are we ready to go with Dr.
16 Appelbaum?
17 MS. CLIFFORD: I think so.
18 DR. MARTINO: I someone going to
clue him
19 in?
Or shall Dr. Martino simply say: "Action."
20 AML in Older Individuals
21 [Via videoconferencing]
22 DR. APPELBAUM: I couldn't hear
anything
23 you were saying. Can you see my slides?
24 VOICE: [Off mike.] [Inaudible.]
25 You won't be able to follow the
pointer,
90
1 is that right?
2 Well, thank you for inviting me to
say a
3 few words about AML in older
individuals. I was
4 asked by the FDA just to provide a general
5 background.
I am not speaking particularly about
6 this product or any of the information that
was
7 presented about the product, but rather just
a
8 global picture of AML in the elderly. Some of this
9 was probably already gone over this morning,
so I
10 will be relatively brief.
11 [Slide.]
12 The problem of AML
in the elderly is a
13 substantial one because the disease, as you
can see
14 from the first slide, in terms of incidence,
goes
15 up quite rapidly once patients are in their
sixth
16 decade.
Before that, it is relatively uncommon.
91
1 But once patients pass the age of 50, the
incidence
2
of AML goes up quite markedly.
3 The problem of AML in the
elderly--or the
4 older individual--is different than AML in
the
5 younger individual for two primary
reasons. First,
6
the patients are different and, secondly, the
7 disease is different.
8 In terms of patients being
9 different--well, older patients are
older. And,
10 with that comes an increased incidence
11 co-morbidities and decreased performance
status.
12 [Slide.]
13 This next slide shows you a
typical
14 picture of patients that were entered onto a
15 protocol for patients with AML above age 55,
using
16 a standard induction regimen of daunomycin
and
17 Ara-C.
18 As you can see from the
performance status
19 and the age, patients under age 60, a
relatively
20 small proportion of them--about 8
percent--will
21 have a very poor performance status of 3 or
22 greater; whereas once patients are over age
75,
92
1 that incidence at least doubles.
2 Yet, even on those over age 75, at
least
3 60 percent--on this Southwest Oncology Group
Study,
4 which was the last one performed--had a
performance
5 status of zero or one, indicating relatively
good
6 performance.
7 These statistics almost certainly
8
understate the problem of decreased performance
9 status in the elderly, because these are
patients
10 that the doctors chose to enter onto the
trial.
11 And it may be that, particularly among the
elderly,
12 there's a substantial proportion who were
not
13 entered onto the trial because of decreased
14 performance status.
15 I know of no easy--or no way, in
fact, at
16 all--that we can get data which truly
reflects the
17 performance status on a population basis of
the
18 elderly patients with AML. This is almost
19 certainly an underestimate of the difficulty.
20 [Slide.]
21 The next slide shows, I think, a
very
22 important principle that hasn't been talked
93
1 about--or it hasn't been published, to my
2 knowledge, quite in this way--and that is
the very
3 great interaction between performance status
and
4 age.
So that this looks at patients, again,
5 treated with a standard induct of
Daunomycin-45 x 3
6 and Ara-C, and a chance of dying within the
first
7 month of being entered onto study, based on
the
8 performance status and age.
9 So that older patients--that is,
those
10 that are over age 70, have a relatively low
chance
11 of dying within the first 30 days if they
have a
12 good performance status--only 9 percent,
which is
13 not substantially different than what you'd
see in
14 patients even under age 50.
15 Yet once patients get older, and
their
16 performance status goes done, then you see a
marked
17 interaction.
So that if you're both over age 70
18 and have a performance status of 3, the
chance of
19 dying within the first 30 days is 62
percent, which
20 is very, obviously, substantial. So there's this
21 interaction which is--both of performance
status,
22 because the younger patients don't have that
high
94
1 chance of dying, even with a poor
performance
2 standard.
That's only 17 percent. So you
can see
3 there's this interaction with both age and
4 performance status, which are cumulative.
5 [Slide.]
6 This, of course, reflects what
would
7 happen with the overall complete response
rate--I'm
8 sorry, this slide simply shows what I just
told
9 you, but in a different graphic form. That is
10 performance status and age being cumulative
in
11 terms of the chance of early death, with 62
12 percent--that's in the back right, versus a
very
13 low chance, in the front left, if you are
young and
14 have a good performance status.
15 [Slide.]
16 This clearly reflects--on complete
17
response rates, which are shown in the next slide,
18 so that if you're over age 70 treated with
standard
19 chemotherapy and have a good performance
status,
20 you have a relatively good chance--50 percent
or
21 greater--of getting a complete
response. But if
22 you're older and have a poor performance
status, it
95
1 deteriorates to, in this study, 29 percent.
2 Whereas if you're younger and have a poor
3 performance status, the interaction doesn't
seem to
4 be as great.
The numbers in these individual cells
5
get fairly small with a total n of 500.
6 So, the first way that AML in the
elderly
7 or the older patient differs is that the
patients
8 are older, they tend to have a poor
performance
9 status, and a poor performance status is a
clear
10 bad prognostic factor for getting a CR and
for
11 early death.
12 The second way that AML in the
older
13 patient differs is that is biologically is
14 different from AML in the younger
patient--in
15 general; not in each specific case, but as a
16 population it differs.
17 AML in the older patient is more
often
18 preceded by myelodysplasia. It is a less
19 proliferative disease. It's more frequently
20 associated with unfavorable cytogenetics,
and it
21 more often expresses multidrug resistence.
22 And I'll show you data about each
of
96
1 these.
2 First, as far as "preceded by
3 myelodysplasia"--and here one has to be
careful
4 about the definitions. If one takes a strict
5 definition of having a documented
hematologic
6 disorder preceding the diagnosis of AML by
at least
7 three months, generally this is seen in
about 15 to
8 18 percent of patients who are over age 55,
and
9 seen in about half that number in patients
who are
10 less than age 55.
11 [Slide.]
12 As far as "less
proliferative" is
13 concerned, that's shown on the slide you now
have
14 in front of you. And this is a large number of
15
patients--about 900 patients on three sequential
16 studies--and it just shows that the white
count, at
17 diagnosis for AML, in patients who were less
than
18 age 55 is about 17,000, but it goes down to
about
19 12,000 when you're over age 75. And the percent
20 blasts if you're less than age 55 tends to
be
21 higher, at 39 percent; but if you're over
age 75 it
22 drops to about 26 percent--not marked
differences,
97
1 but there is a biologic difference here
which
2 suggests that AML in the very old patient
tends to
3
be a less highly proliferative disease.
4 [Slide.]
5 The next slide shows the marked
difference
6 in cytogenetics as patients age in AML.
7 The blue bars at the very top are
the
8 percent of AML patients with unfavorable
9 cytogenetics, according to age. So that if you're
10 less than age 55, about 21 percent of
patients will
11 have unfavorable cytogenetics, using the
SWOG--or
12 Southwest Oncology Group--criteria for
cytogenetic
13 risk group--which is very similar, but not
quite
14 identical, to the MRC's definition.
15
If patients are over age 75, the incidence
16 of unfavorable cytogenetics increases
markedly from
17 21 percent to 52 percent; and, conversely,
the dark
18 bar at the bottom, the percent with
favorable
19 cytogenetics--that's 8;21, inversion 16, or
15, 17,
20 then that drops from 20 percent in patients
who are
21 less than age 56, to only 4 percent if
you're over
22 age 75.
23 The particular cytogenetic
abnormalities
24 which are seen more frequently as one ages
are
25 shown on the next slide.
98
1 [Slide.]
2 And they are of marked increase in
the
3 incidence in the loss of -5, or part -5, on
the
4 long arm, or loss of -7 or part of 7 on the
long
5
arm, where either one of these was seen in either 6
6 to 8 percent in patients age less than 56,
but if
7 you're over age 75, you see this in a three
or
8 four-fold higher incidence, with 26 or 22
percent,
9 respectively.
10 Similarly, a loss of the short arm
of 17
11 is seen in only 2 percent less than age 56,
and
12 greater than 11 percent in those age greater
than
13
75. And all those p-values you
can see are .0001.
14 Conversely, as I've already
mentioned,
15 inversion 16, and 8;21s drop as you get
older,
16 among the favorable cytogenetic risk group.
17 It is, I think, just
intellectually
18 interesting to speculate why we see this
particular
19 differences with age. We don't, in fact, know the
99
1 answer.
2 Some have argued that AML in the
elderly
3 is more the result of multiple cytogenetic
or
4 mutational [technical difficulty] a
myelodysplasia
5 with a subsequent alternations.
6 An alternative hypothesis is that
our stem
7 cells get older, and getting a leukemia stem
cell
8 is a bad thing to do and the disease,
therefore
9 behaves differently in the elderly. And there is
10 some data for each of those arguments.
11 [Slide.]
12 MRK is one way of measuring
multidrug
13 resistance.
It may not be the best. It's a
14 simple, reproducible one. But whether one uses MRK
15 staining, or one uses actual drug efflux,
which is
16 cyclosporin inhibitable, in either way that
you
17 measure it, you will find that, as patients
age,
18 there is a higher incidence of multidrug
19 resistance.
20 In this--which included about 600
21 patients--if you were less than age 56,
about 33
22 percent would have a bright MRK
staining. If you
100
1 were over age 75, it's about twice that
number.
2 [Slide.]
3 Now, if you take all of these
possible
4 changes, and you look at the likelihood of
getting
5 a complete response, in univariate analysis--this
6 is a study that we did in the Southwest
Oncology
7 Group--in univariate analysis you can see
that
8 these make a big difference in outcome. AML, if
9 you have a secondary AML--that is, secondary
to
10 primary myelodysplasia; this isn't treatment
11 related, which is another kind of secondary
AML.
12 But this is secondary to primary
13 myelodysplasia--the CR rates are half as
much as if
14 you have a de novo disease, if you are CD34
15 positive in some, but not all studies, in
this one,
16 that seemed to give a lower incidence of
complete
17 response rates.
18 As I obviously mentioned, MRK
staining--if
19 you have a bright, you have half as much
chance of
20 getting a CR as if you're negative.
21 Unfavorable cytogenetics--again,
about
22 half as much a chance of getting CRs as if
you have
101
1 intermediate or favorable. And functional drug
2 efflux, like MRK staining, also predicts for
CR
3 rates.
4 [Slide.]
5 Now, this is in univariate
analysis. When
6 we looked in multivariate analysis, we found
three
7 factors-- and that's shown on the next slide
that
8 predicted for complete response rate: and
that is
9 whether you had secondary AML; if you had
10 unfavorable cytogenetics, and then if you
had MDR1
11 expression--either by functional drug efflux
or MRK
12 staining.
And each one of these were independently
13 significant in this multivariate analysis.
14 And if you had all three factors
present,
15 you had almost no chance of getting a CR;
that is,
16 if you had secondary AML, with unfavorable
17 cytogenetics and MDR1 expression, the chance
of CR
18
was 11 percent. But even if you're over age 65, if
19 you had none of the three factors, you'd
have an 81
20 percent chance of getting a complete
response--much
21 like you would expect in a younger patient
with
22 AML.
23 [Slide.]
24 Now, we're not the only ones that
have
25 seen this.
This has been seen by others. One
of
102
1 the largest studies of treatment of AML was
the MRC
2 AML 11 Study. It looked at three different
3 preparative regimens: a classic
daunomycin-Ara-C
4 and 6TG regimen, versus the daunomycin-Ara-C
VP-16
5 regimen, versus a mitoxantrone-Ara-C
regimen--and
6 then also randomized to giving G-CSF after
7 induction.
And they also had a randomization and
8 consolidation of two, versus
six, cycles.
9 The study itself isn't what
I"ll be
10 talking very much about, since none of these
11 factors had a major impact on outcome. But I
12 would--just to look at this
study-- which was
13 published in Blood in 2001--for the general
14 principles of treatment of AML. And, as I said,
15 this was a large study--it will show on the
next
16 slide--with over 1,300 patients. And they had ages
17 between 56 and up to above 90 years old.
18 [Slide.]
19 As I said, in the Southwest
Oncology
103
1 Group, we see about a 15 to 18 percent
incidence of
2 secondary AML, which is exactly what the MRC
study
3 saw.
And they had a 4 percent incidence of
4 treatment-related disease. Ours was a bit higher
5 in SWOG--about 6 percent. But these are very
6 typical numbers for AML in the older
individual.
7 [Slide.]
8 In their study, they had a 62
percent
9 complete response rate. They had a 7 percent death
10 in incomplete response. They had a relapse rate of
11 78 percent, and they had disease-free
survival at
12 five years of 15 percent.
13 These results are fairly typical
of most
14 studies of chemotherapy for patients over
age 55.
15 As I have tried to make the
point--and
16 will make it again--
17 [Slide.]
18 --oh, this shows you the outcome
by
19 treatment group. And, as you can see, there is
20 essentially no difference among the three
groups,
21 with a median survival that is between nine
and 11
22 months, and a five-year survival which is
down
104
1 around 15 percent on these studies.
2 Now, the point I've tried to make
3 repetitively is that AML in older patients
is a
4 very heterogeneous disease.
5 [Slide.]
6 And this shows you--the next slide
shows
7 you--what the MRC found. And they found
8 essentially the same thing that we had
previously
9 reported in SWOG--and other have reported,
as
10 well--and that is that cytogenetics, age,
whether
11 you have primary or secondary disease,
performance
12 status and--in their hands--also white count
at
13
diagnosis were powerful predictors.
And you can
14 see, with a large study of over 1,300
patients, how
15 powerful these are. Those p-values are 10-14 or
16 10-6, or 10-7--so that's a lot zeros, suggesting
17 that these are very powerful
predictors. So that
18 unfavorable cytogenetics--both for complete
19 response rate and overall survival--is a bad
fact;
20 having a high white count likewise gives you
a low
21 chance of CR or overall survival. As you age,
22 things get worse. If you have secondary disease
105
1
and if you have a poor performance status--the same
2 things that we had previously reported.
3 [Slide.]
4 So, in summary then, using
conventional
5 chemotherapy, if you take a large cohort of
6 patients that are over age 60--or 55,
depending on
7 the particular study--complete response
rates of 50
8 to 60 percent can be expected; a median
survival of
9
9 months can be also expected in this cohort of
10 patients; and perhaps 10 to 15 percent may
continue
11 to be alive after four to five years.
12 However--and this is the most
important
13 point--the patient and disease-related
factors very
14 greatly, among this population, and heavily
15 influence treatment outcome. In my mind,
16 particularly important in considering any
patient
17 group are age, performance status, primary
versus
18 secondary presentation, cytogenetics and the
MDR
19 status.
20 And these facts have been
relatively
21 unchanged over the last several decades
because our
22 therapies for AML in the elderly haven't
changed
106
1 very much over the last several
decades. And there
2 clearly is a need for new and effective
agents for
3 this patient population.
4 I'd be happy to answer any
questions about
5 this relatively brief and perhaps
superficial
6 presentation.
7 Thank you.
8 DR. MARTINO: Fred, Thank you. And ladies
9 and gentlemen, it is my understanding that
we are
10 able to handle some questions to Dr.
11 Appelbaum--from a technical
perspective. So, if
12 there are questions to him directly, this
would be
13 your opportunity.
14 Dr. Mortimer?
15 DR. MORTIMER: Yes,
Fred--this is Joan
16 Mortimer.
I wonder if you could just make a
17 comment on the role of growth factors. I presume
18 that since you didn't talk about it in the
MRC
19 trial that there is no advantage or
disadvantage to
20 the use of growth factors?
21 DR. APPELBAUM: In the MRC trial
there was
22 no advantage or disadvantage for the use of
growth
107
1 factors.
There have been--as you know, probably
2 better than anyone on the planet, Joan--I
think at
3 least a dozen studies of the use of growth
factors
4 after chemotherapy for AML in older
individuals.
5 And the vast majority of those
studies
6 show that the use of growth factors shorten
the
7
duration of neutropenia quite consistently by five
8 to seven days. They are more variable in whether
9 that shortening of neutropenia changes the
risk of
10 significant infection; and only, as I'm
aware, two
11 studies showed a change in survival or
complete
12 response rate. The majority of them showed no
13 effect on CR rates or survival, but did show
an
14 important shortening of the period of
15 pancytopenia--that's after induction. And then
16 after consolidation, the results are a
little more
17 consistent that you shorten neutropenia and
18 decrease the incidence of infections--again,
with
19 no change in survival.
20 DR. MARTINO: Dr. Brawley, you're
next.
21 DR. BRAWLEY: Yes, Otis Brawley
here.
22 Dr. Appelbaum, in the studies that
you
108
1 presented, and all the data that we've
reviewed, it
2 seems like the goal is always to get a
complete
3
remission, as if the complete remission is a
4 surrogate for patient benefit in terms of
increased
5 survival.
6 Has anyone ever tried any studies
that
7 look at the possibility of a drug that might
sort
8 of suppress a smoldering factor, where the
goal is
9 not complete remission but suppression of
the
10 leukemia, and perhaps try to determine of
that
11 actually increases survival--especially in
an
12 older, sickly population?
13 DR. APPELBAUM: That's an excellent
14 question, Dr. Brawley. And the lessons that had
15 been learned in acute leukemia in younger
patients,
16 where it's a much more proliferative
disease, have
17 sort of given the indication that you really
have
18 to get a complete response if patients are
going to
19 survive for any length of
time, because the disease
20 is so very proliferative.
21 Now, on the other hand, if you
take the
22 totally other tack of looking at
myelodysplasia as
109
1 being a sort of symbol for a less aggressive
2 disease--we now have data that a drug which
doesn't
3 get complete response rates, so that it
4 phibezacytadine by perhaps a slowing--some
people
5 can argue why phibezacytadine works. Some people
6 believe it's a differentiation factor. Other
7 people believe that it actually is working
as a
8 cytotoxic.
But, without getting complete
9 responses, it appears that it may prolong
survival.
10 Years ago, the way that many
11 patients--very old patients with AML--were
treated
12 was with much less aggressive therapy using
oral
13 6MP, or using daily or weekly VP16, trying
to keep
14 the cap on things. And I believe that there were
15
some suggestions--not proven in randomized trials
16 ever, but suggestions that there was
improvement in
17 survival.
18 You are, I thin, correct that it
is
19 possible that there will be drugs--maybe
many
20 drugs--that could cause differentiation,
slowing
21 down the proliferation, and be of some
benefit to
22 the patient without getting a complete
response.
23 But the lessons from the more
aggressive
24 disease is that generally those effects are
25 temporary and not as lasting as physicians
would
110
1 like.
2 I'm not sure if that answers the
question
3 adequately.