1
DEPARTMENT OF HEALTH AND HUMAN
SERVICES
FOOD AND DRUG
ADMINISTRATION
CENTER FOR DRUG EVALUATION AND
RESEARCH
ONCOLOGIC DRUG ADVISORY
COMMITTEE
Hilton
2
PARTICIPANTS
Donna Przepiorka, M.D., Ph.D., Chair
Johanna M. Clifford, M.S., RN,
Executive Secretary
MEMBERS:
John T. Carpenter, Jr., M.D.
Bruce D. Cheson, M.D.
James H. Doroshow, M.D.
Stephen L. George, Ph.D.
Antonio J. Grillo-Lopez,
M.D.
Pamela
J. Haylock, RN
Silvana Martino, D.O.
Gregory
H. Reaman, M.D.
Bruce G. Redman, D.O.
Maria Rodriguez, M.D.
Sarah A. Taylor, M.D.
CONSULTANTS (VOTING):
Michael Bishop, M.D.
Ronald Bukowski, M.D.
Ralph D'Agostino, Ph.D.
Maha Hussain, M.D.
Jan Buckner, M.D.
Wen-Jen Hwu, M.D.
Joanne Mortimer, M.D.
Michael Perry, M.D.
PATIENT REPRESENTATIVES (VOTING):
Kenneth McDonough (for Genasense)
Natalie Compagni-Portis
(for RSR 13 Injection)
FDA STAFF:
Richard Pazdur, M.D.
Grant Williams, M.D.
Robert Temple, M.D.
3
C O N T E N T S
Opening Remarks, Donna Przepiorka, M.D., Ph.D. 5
Comments by Congressman Peter
Deutsch 5
Comments by Alex Delpizo 11
Conflict of Interest Statement,
Johanna M. Clifford, M.S., RN 14
Opening Remarks, Richard Pazdur,
M.D. 20
Genta Presentation:
Introduction, Loretta M. Itri,
M.D. 26
Melanoma Overview, John Kirkwood,
M.D. 29
Study GM301, Loretta M. Itri,
M.D. 36
Clinical Benefit Summary,
Frank Haluksa, M.D., Ph.D. 60
FDA Presentation:
Medical Review, Robert Kane, M.D. 69
Statistical Review, Peiling Yang,
Ph.D. 76
Clinical Relevance, Robert Kane,
M.D. 86
Questions from the Committee 93
Open Public Hearing 125
Committee Discussion 152
Allos Presentation:
Introduction, Pablo J. Cagnoni,
M.D. 206
Brain Metastases, John H. Suh,
M.D. 209
The Science of RSR13, Biran D.
Kavanaugh,
M.D., MPH 216
Clinical Efficacy Results,
Pablo
J. Cagnoni, M.D.
225
Conclusions, Paul A.
Bunn, Jr., M.D. 251
FDA Presentation:
Clinical Review, Kevin Ridenhour,
M.D. 254
Statistical Review, Rajeshwari
Sridhara, Ph.D. 265
4
C O N T E N T S
Questions to the FDA and the Sponsor 278
Open Public Hearing 309
Subgroup Analysis in Clinical Trials,
Stephen George, Ph.D. 314
Committee Discussion 333
5
1 P R O C E E D I N G S
2 Opening Remarks
3 DR. PRZEPIORKA: Good morning to all and
4
welcome to the Food and Drug Administration's
5
Advisory Committee for Oncologic Drugs.
My name is
6
Donna Przepiorka. I will be
chairing the
7
committee. I just wanted to
remind everyone in the
8
audience that the purpose of the individuals on
9
this panel is to serve as independent consultants
10 to
the FDA. We do not work for the
FDA. We are
11
also not anyone who makes any decisions; we only
12
provide advice.
13
Our first item on the agenda--we are going
14 to
go a little bit out of order. We want to
hear
15
first from Congressman Deutsch who has a few words
16 to
say.
17
CONGRESSMAN DEUTSCH: Thank you
very much.
18 I
appreciate the opportunity to be here.
My name
19 is
Congressman Peter Deutsch, and I recognize that
20 it
is not at every meeting of this committee that
21 you
are addressed by a member of Congress.
Largely
22 it
is in that capacity that I speak to you today,
6
1 but
it is also in my capacity as an individual who
2 has
been personally affected by the specter of
3
melanoma.
4
On several occasions I have had basal
5
cells removed from my body.
Thankfully, they were
6 not
malignant but their existence renders me high
7
risk. My dermatologist now
evaluates me on a
8
quarterly basis for melanoma and guides me on how
9 to
reduce my risk profile. I pray that this
risk
10
never materializes but, if it does, I need to know
11
that my physician and I have access to every
12
therapeutic treatment available for this horrible
13
disease. As someone who actually
hears people
14
testify in many settings, I am trying to get your
15
attention so actually I have pictures of my kids
16 who
both have red hair so, obviously, they are high
17
risk for skin cancer as well especially as having a
18
parent who has been diagnosed with basal cells.
19
They also happen to live in Florida.
20
Again, most of the people in this room
21
don't live in Florida and I am not exaggerating
22
that the school that they go to and, in fact, the
7
1
schools they have gone to since pre-K, do not have
2
hallways. It is one of the unique
things about
3
Florida, south Florida in particular so they are
4
literally outside all the time.
For anyone who has
5
kids, especially in a setting like south Florida,
6
think about the summer when you try to get your
7
kids to wear suntan lotion. It is
not an easy
8
thing to do. So, this is a very
real thing. I
9
mean, I have fights with my kids, especially as
10
they have gotten older, about putting suntan lotion
11 on,
on a continuous basis.
12
But it is not just for my kids; it is not
13 for
myself that I am here today. It is for
all the
14
constituents I represent and all the citizens
15
around the nation. So, it is on
their behalf as
16
well that I stand before you today, not to advocate
17 for
the approval of this drug but to advocate that
18 the
mind set from which you consider this
19
application be your own mind set--clinical
20
physicians dedicated to the welfare of their
21
patients.
22
What does this mean? That this
8
1
application be a referendum on whether you would
2
want this drug available to your patients if they
3
were diagnosed with metastatic melanoma.
That is
4 the
standard we owe cancer patients and that is the
5
standard government is obligated to uphold.
6
I did not come here to preach to this
7
committee to the extent me and Congress have had
8
frustration with over-regulation by the FDA. It is
9 not
of your doing; quite the opposite. It is
10
people like yourselves who give up your time to
11
guide the FDA. I cannot
over-emphasize the
12
importance of your role. You
provide the FDA a
13
window that they otherwise do not have, a window
14
into the real world, if you will, a world in which
15
dying cancer patients are desperate for and must be
16
given access to every reasonable treatment that
17
might save their lives.
18
As you may know, there were two relevant
19
newspaper articles last week that got some
20
attention in Congress. One was an
article in The
21 New
York Times about a Japanese study published in
22 The
New England Journal of Medicine proving the
9
1
effectiveness of a drug called UFT in treating a
2
form of lung cancer. What was
staggering about the
3
article was that this same technology was rejected
4 in
this country by the FDA. In other words,
5
thousands of cancer patients in this country could
6 be
dying because the government failed them.
7
What I later learned was that the FDA
8
rejected this drug even though this very advisory
9
committee composed of your predecessors voted
10
unanimously to approve it and, because the FDA did
11 not
accept the recommendations of clinicians,
12
countless Americans lack access to that drug today.
13
That is inexcusable.
14
In the other article, the Wall Street
15
Journal related to this committee's hearings. It
16
offered no views on whether this drug should be
17
approved but, instead, noted the absence of
18
treatments for metastatic melanoma and a couple of
19
vignettes about the people who took the drug. One
20 of
those was an individual names David Bernstein
21 who
is scheduled to join us here today. Mr.
22
Bernstein is a fourth grade teacher from a small
10
1
town in New Jersey. The article
said that Mr.
2
Bernstein's cancer went away and he is alive today,
3
teaching his students in his fourth grade classroom
4
because of the drug before you today.
5 I am not a physician nor a scientist
and I
6
have not studied the clinical data regarding this
7
drug, but I do know this, if you find that this
8
drug is as safe and effective as other available
9
treatments, if it reasonably presents another
10
possible course of treatment, by what right can
11
government deny cancer patients an avenue to save
12
their lives? This is not about a
passing illness
13 for
which there are other treatments. This
is
14
about cancer, an absolutely devastating disease
15
that has in some ways affected nearly every single
16
American. This is about cancer
patients who are
17
dying and desperate for a chance to live longer.
18 It
is in their interest that we must be foremost in
19
today's hearing.
20
I flew back to Washington last night to
21
speak to you this morning, however, prior
22
obligations in my district require me to actually
11
1
literally turn around right now and return to
2
Florida this morning. I regret
that I can't stay
3
here to listen to all of the testimony but I wish
4 to
thank this committee for its time, and it has
5
been an honor and pleasure to speak with you this
6
morning.
7
DR. PRZEPIORKA: Thank you,
Congressman
8
Deutsch. Any questions for the
Congressman?
9
[No response]
10
Thank you, sir.
11
CONGRESSMAN DEUTSCH: Thank you.
12
DR. PRZEPIORKA: Next we will hear
from a
13
representative from Congressman Ferguson's office.
14
MR. DELPIZO: My name is Alex
Delpizo. I
15 am
here representing Congressman Mike Ferguson of
16 New
Jersey who, unfortunately, is in New Jersey and
17
couldn't be here with us today.
18
I am not a scientist or a clinician or a
19
chemist but everyone knows a person whose life has
20
been taken by cancer. For me,
that person was my
21
mother. She fought and eventually
lost her
22
six-year battle with cancer.
However, due to
12
1
miracle life-extending drugs she saw two of her
2
children get married and met her three
3
grandchildren. My mother was
fortunate enough to
4
experience all of the wonderful things that mothers
5 and
grandmothers experience later in life.
6
As you know, Genasense us used to treat
7
stage 4 metastatic melanoma.
Metastatic melanoma
8 is
currently a death sentence. When two
available
9
therapies treat the disease and the last
10
chemotherapy therapy treatment was approved in
11
1975, yours is an awesome responsibility. The FDA
12
works every day to ensure that Americans and their
13
food and drug supply are safe.
Your decisions on
14
which drugs are approved are based on numbers, and
15
numbers are very important, however, we would never
16 want to approve a placebo. However, an
17
over-emphasis on statistics at the expense of
18
patient needs does a life-threatening disservice.
19 The
failure to appreciate mean or median
20
statistical analyses in any size sampling also
21
fails to take into account a patient population
22
that achieved the most dramatic overall response.
13
1
Given the devastating nature of this
2
disease and the relatively few treatments
3
available, even marginal increases in life
4
expectancy can clearly be the difference between
5
rapid death and years of life extension for those
6
patients that will see a benefit from this and
7
other drugs.
8
In closing, I would like to highlight the
9
experience of one of my constituents in Montgomery
10
Township in New Jersey. David
Bernstein was
11
diagnosed with skin cancer and prescribed
12
chemotherapy to remove a grape-sized tumor on his
13
chest. Mr. Bernstein opted to
supplement the
14
chemotherapy by joining a clinical trial of an
15
experimental drug. Six weeks
after his first dose
16 he
received the news that his tumor had essentially
17 disappeared.
This was two years ago. That
18
experimental drug was Genasense.
19
For my mother, David Bernstein and for all
20 of
those who have been diagnosed with cancer, I
21
respectfully request that you look favorably on
22
Genasense and other new drug applications that can
14
1
provide hope for those for whom hope is all they
2
have. Thank you very much.
3
DR. PRZEPIORKA: Thank you. Again, I
4
would like to ask the folks who are standing along
5
that far wall by the doors to please step outside
6
into the hall, or take a seat, or take a stand at
7 the
back wall only, please. You are going to
need
8 to
vacate that area immediately, please.
9
We would like to now move on to the first
10
item on the agenda and Johanna Clifford will read
11 the
conflict of interest statement. Thank
you.
12 Conflict of Interest Statement
13
MS. CLIFFORD: Thank you. The following
14
announcement addresses the issue of conflict of
15
interest with respect to this meeting and is made a
16
part of the record to preclude even the appearance
17 of
such at this meeting.
18
Based on the submitted agenda and
19
information provided by the participants, the
20
agency has determined that all reported interests
21 in
firms regulated by the Center for Drug
22
Evaluation and Research present no potential for a
15
1
conflict of interest at this meeting, with the
2
following exceptions:
3
In accordance with 18 USC Section
4
208(b)(3), Dr. Ronald Bukowski has been granted a
5
waiver for serving on a competitor's advisory board
6 on
an unrelated matter for which he receives less
7
than $10,000 a year; consulting with the sponsor of
8
dacarbazine on an unrelated matter for which he
9
receives less than $10,000 a year; and, finally,
10 for
consulting with a competitor on an unrelated
11
matter for which he receives less than $10,000 a
12
year.
13
Dr. Maha Hussain has been granted waivers
14
under 18 USC 208(b)(3) and 21 USC 505(n) for
15
unrelated consulting for the co-developed of
16
Genasense for which she receives less than $10,000
17 a
year; and owning stock in the co-developer of
18
Genasense, valued from $25,001 to $50,000.
19
Dr. Wen-Jen Hwu has been granted a limited
20
waiver under 18 USC 208(b)(3) for her employer's
21
contract with a competitor for an
22
investigator-initiated study of a competing
16
1
product. The contrast is less
than $100,000 a
2
year. Under the terms of the
waiver, Dr. Hwu will
3 be
permitted to participate in the committee's
4
discussions of Genasense. She
will not, however,
5 be
able to vote.
6
A copy of these waiver statements may be
7
obtained by submitting a written request to the
8
agency's Freedom of Information Office, Room 12A-30
9 of
the Parklawn Building.
10
We would also like to disclose that Dr.
11
Silvana Martino has been recused from participating
12 in
all matters concerning Genta's Genasense.
13
Lastly, we would like to note for the
14
record that Dr. Antonio Grillo-Lopez, Chairman,
15
Neoplastic and Autoimmune Diseases Research
16
Institute, is participating in this meeting as in
17
industry representative, acting on behalf of
18
regulated industry. He would like
to disclose that
19 he
is a scientific advisor to Chiron and receives
20
speakers fees from Roche.
21
In the event that the discussions involve
22 any
other products or firms not already on the
17
1
agenda for which FDA participants have a financial
2
interest, the participants are aware of the need to
3
exclude themselves from such involvement and their
4
exclusion will be noted for the record.
5
With respect to all other participants, we
6 ask
in the interest of fairness that they address
7 any
current or previous financial involvement with
8 any
firm whose product they may wish to comment
9
upon.
10
DR. PRZEPIORKA: Thank you. Once again,
11
there are still some folks registered for the open
12
public hearing who have not signed in.
I just want
13 to
remind you that if you do wish to speak at the
14
open public hearing you will need to sign in at the
15
table outside.
16
Next, I would like the members of the
17
committee and the other participants to introduce
18
themselves and we will start with Dr. Pazdur.
19
DR. PAZDUR: Richard Pazdur,
Director of
20 the
Division of Oncology Drug Products, FDA.
21 DR. WILLIAMS: Grant Williams, FDA,
22
Director, Division of Oncology Drugs.
18
1
DR. FARRELL: Ann Farrell,
clinical team
2
leader for Genasense.
3 DR. KANE: Robert Kane, medical reviewer.
4
DR. YANG: Peiling Yang,
statistical
5
reviewer.
6
DR. BUKOWSKI: Ron Bukowski,
medical
7
oncologist, Cleveland.
8
DR. BISHOP: Michael Bishop, Experimental
9
Transplantation, Immunology Branch, National Cancer
10
Institute.
11
DR. HWU: Wen-Jen Hwu, medical
oncologist
12 at
the Memorial Sloan-Kettering.
13
DR. TAYLOR: Sarah Taylor,
University of
14
Kansas.
15
DR. REAMAN: Gregory Reaman,
George
16
Washington University and Children's National
17
Medical Center.
18
DR. REDMAN: Bruce Redman,
University of
19
Michigan.
20
MS. CLIFFORD: Johanna Clifford, FDA,
21
executive secretary for this meeting.
22
DR. PRZEPIORKA: Donna Przepiorka,
19
1
University of Tennessee, Memphis.
2
DR. RODRIGUEZ: Maria Rodriguez,
medical
3
oncologist, M.D. Anderson Cancer Center.
4
DR. DOROSHOW: Jim Doroshow,
Division of
5
Cancer Treatment and Diagnosis, NCI.
6
DR. CHESON: Bruce Cheson,
Georgetown
7
University Lombardi Comprehensive Cancer Center.
8
DR. GEORGE: Stephen George, Duke
9
University.
10
MS. HAYLOCK: Pamela Haylock. I am a
11
nurse and I am at the University of Texas.
12
DR. CARPENTER: John Carpenter,
University
13 of
Alabama at Birmingham.
14
DR. D'AGOSTINO: Ralph D'Agostino,
Boston
15
University biostatistician.
16
DR. MORTIMER: Joanne Mortimer,
medical
17
oncology Eastern Virginia Medical School.
18
DR. HUSSAIN: Maha Hussain,
University of
19
Michigan.
20
MR. MCDONOUGH: Ken McDonough,
patient
21
representative.
22
DR. GRILLO-LOPEZ: Antonio
Grillo-Lopez,
20
1
Neoplastic and Autoimmune Diseases Research
2
Institute.
3
DR. PRZEPIORKA: Thank you to
all. I
4
think Dr. Pazdur will open with some remarks.
5 Opening Remarks
6
DR. PAZDUR: Thank you very much,
Donna.
7
First, I would like to recognize the contributions
8 of
four ODAC members who will be leaving the
9
committee after this meeting.
These members
10
include our chairman, Donna Przepiorka, John
11
Carpenter, Sarah Taylor and Bruce Redman. We, at
12 the
FDA, recognize their efforts at providing us
13
advice at these public meetings and, in addition,
14 we
appreciate their valuable assistance throughout
15 the
years in providing us with their insights at
16
other FDA meetings and in reviewing and assessing
17
protocols. Our work and the
welfare of the
18
American public is greatly facilitated by their
19
hours of work and their talents devoted to these
20
tasks. Again, Donna, John, Sarah
and Bruce, we
21
thank you for your efforts, your patience with our
22
phone calls, and advice on some of the most
21
1
perplexing issues of drug development.
Let me say
2
this, this is not "adios" but "hasta la vista" and
3 it
is not "hasta la vista, baby."
We will be
4
calling you; we will be in touch; this will be a
5
continuous process that we will be dealing with you
6
over the years, but we do appreciate your kindness
7 and
your efforts at helping us with some of the
8
problems that we have at hand.
9
Let's turn to the issues at hand.
This
10
morning's meeting focuses on a drug for the
11
treatment of patients with advanced melanoma who
12
have not received prior chemotherapy.
I would like
13 to
spend some time addressing issues for you to
14
consider during the presentations provided by the
15
sponsor and the FDA staff. These
issues are
16
important to this application but also this
17
afternoon's application and in drug development in
18
general, especially as we have continuing, ongoing
19
discussions and dialogue with the committee on
20
endpoints for drug development.
21
The FDA has long considered the
22
demonstration of an improved survival as the gold
22
1
standard for drug approval. An
improvement in
2
survival associated with an acceptable safety
3
profile is of unquestionable clinical benefit. It
4 is
assessed daily and is unambiguous. When
we, at
5 the
FDA, began our discussions with the committee
6 on
drug approval we realized that there may be some
7
disadvantages to requiring survival improvement for
8
drug approval. These
disadvantages include the
9
confounding of survival analysis by crossover with
10
frequently large patient numbers required to be
11
enrolled on trials for survival, and the long
12
follow-up that may be required in selected
13
oncological diseases.
14
This trial at hand this morning was
15
originally discussed with the agency to be a trial
16
with a primary endpoint of survival improvement.
17 The
trial did not demonstrate an improvement in
18
overall survival. We are asked to
evaluate this
19
drug for approval on the basis of secondary
20
endpoints of claimed improvements in
21
progression-free survival or PFS and response
22
rates. Please member that since
this drug is added
23
1 to
a standard therapy we must assess the drug's
2
contribution to that standard therapy and any
3
claimed response rates or claims for PFS advantages
4
represent a combination of the investigational
5
agent and the standard therapy.
Hence, we must
6
isolate the efficacy of the drug in assessing the
7
drug's efficacy.
8
Let's turn our attention to the
9
measurement and assessment of PFS which will be
10
discussed during this meeting on multiple
11
occasions. The assessment of PFS
may be difficult
12 and
uncertain in unblinded trials with a small
13
effect on this endpoint and where there is a lack
14 of
attention to clinical trial issues that are
15
important in measuring and comparing PFS data
16
between treatment arms. These
issues include a
17
prospectively defined methodology for assessing,
18
measuring and analyzing PFS.
These need to be
19
detailed in the protocol and in the statistical
20
plan. Tumor progression should be
carefully
21
defined in the protocol. The FDA
and the sponsor
22 should agree prospectively on the protocol,
the
24
1
case report forms and the statistical analysis plan
2 for
PFS. There should be a prespecified
analysis
3
plan for handling missing data, especially missed
4
assessment visits. Censoring
methods and
5
assessment of progression in non-measurable lesions
6
must be prospectively outlined and agreed upon.
7
Most importantly, visits and radiological
8 assessments
should be symmetrical on the study arms
9 to
prevent systematic bias. When possible,
studies
10
should be blinded. This is
especially important
11
when the patient or investigator assessments are
12
included as components of the progression endpoint.
13 If
progression is assessed by both the treating
14
physician and an external review panel or an
15
external radiology committee, the protocol should
16
prospectively stipulate whose assessment will be
17 used
in defining PFS. This cannot occur after
the
18
study data has been examined.
19
Hence, from a practical perspective, PFS
20 as
a primary endpoint for drug approval takes
21
meticulous, prospective planning.
The measurement
22 of
PFS progression-free survival requires rigor.
25
1
This planning is frequently lacking in clinical
2
trials that relegate PFS to a secondary endpoint.
3
Some practical problems outlined above in
4
accurately characterizing the treatment of PFS will
5 be
discussed by the FDA reviewers.
6
Provided an acceptable safety profile, one
7 has
to answer the following question, what is the
8 magnitude
of the drug's effect on PFS that would be
9
considered clinically relevant? A
very small
10
effect may raise questions about the very existence
11 of
this effect, especially when the study is
12
unblinded and attention to the symmetry of
13
assessments and handling of missing assessments is
14 not
evident.
15
In answering whether marketing approval
16
should be granted to an agent, two important
17
questions need to be answered.
First, does the
18 drug have a convincing effect that can be
19
adequately characterized?
Secondly, and this
20
question can only be addressed if the first
21
question is answered in the affirmative, what is
22 the
clinical relevance of the effect? This
26
1
obviously must take into account a risk-benefit
2
analysis. However, benefit can
only be assessed in
3
this equation if it convincingly exists and also
4 can
be adequately characterized.
5
I hope these comments will provide a
6
catalyst for your considerations this morning, this
7
afternoon and tomorrow as we discuss endpoints of
8
drug approval. Donna, I turn the
program over to
9 you and I will answer questions after the FDA
10
presentations. Thank you.
11
DR. PRZEPIORKA: Thank you, Dr.
Pazdur.
12
Let's go ahead and begin with the sponsor
13
presentation, with an introduction by Dr. Itri.
14
Sponsor Presentation
15 Introduction
16
[Slide]
17
DR. ITRI: Dr. Przepiorka, members
of the
18
Oncology Drug Advisory Committee, ladies and
19
gentlemen, it is my pleasure, on behalf of Genta,
20 to
introduce the agenda and the participants for
21 the
presentation of the new drug application for
22
Genasense in combination with dacarbazine for the
27
1 treatment of patients with advanced
malignant
2
melanoma.
3
Following my introductory remarks, Dr.
4
John Kirkwood will give an overview of malignant
5
melanoma and available treatments.
After Dr.
6
Kirkwood's presentation I will return to the podium
7 and
discuss the results of GM301 in detail.
At
8
that point, Dr. Frank Haluska will summarize the
9
risks and benefits in the context of the disease we
10 are
treating.
11
[Slide]
12
By way of introducing our speakers, Dr.
13
Frank Haluska is from Harvard University and Mass.
14
General Hospital. He is chairman
of the CALGB
15
melanoma committee. Dr. John
Kirkwood is professor
16 and
vice chairman of Medicine at the University of
17
Pittsburgh and is also chairman of the ECOG
18
melanoma committee.
19
[Slide]
20
In addition to our distinguished speakers,
21 we
are fortunate to have with us today a number of
22 clinical
experts in the field of melanoma,
28
1
including Dr. Sanjiv Agarwala from the University
2 of
Pittsburgh Cancer Center, Dr. Agop Bedikian from
3
M.D. Anderson Cancer Center, Dr. Paul Chapman from
4 the
Memorial Sloan-Kettering Cancer Center, Dr.
5
Robert Conry from the University of Alabama, Dr.
6
Peter Hersey from the University of Newcastle, all
7 the
way from Australia, and Dr. Evan Hersh from the
8
University of Arizona Cancer Center.
9
Drs. Bedikian, Conry, Hersey and Hersh
10
were principal investigators in our study and
11
together are responsible for managing approximately
12 20
percent of patients who are on our trial.
They
13 are
available to address any issues you may have
14
regarding patient management in the study. Dr.
15
Janet Wittes, formerly head of statistics at the
16
National Heart, Lung and Blood Institute and
17
currently president of Statistics Collaborative, is
18
available to provide expert biostatistical
19
consultation. Dr. Robert Ford,
chief medical
20
officer and founder of RadPharm, is with us to
21
address the intricacies related to the blinded
22 independent
review of radiographic studies. I
29
1
would like to now invite Dr. John Kirkwood to the
2
podium.
3 Melanoma Overview
4
DR. KIRKWOOD: Thank you, Loretta.
5
[Slide]
6
Dr. Pazdur, Dr. Przepiorka, members of
7
ODAC and the FDA, I am delighted to speak with you
8
today about a disease that many of us here have
9
spent all of our lives working on.
10
[Slide]
11
This is a disease that has risen in
12
epidemic proportions and is 4 percent of new
13
cancers, rising at 5 percent per year.
The
14
mortality from this cancer is also rising and most
15 notably
for men over 50 for whom there is a 157
16
percent increase in mortality in just the last
17
decade. The societal impact of
this cancer is even
18
more because of its median age of incidence in the
19
late 40s, and it takes a toll in terms of
20
productive life years that exceeds many more
21
frequent cancers, even including prostate cancer.
22
[Slide]
30
1
In the past 37 years only three agents
2
have been approved for the treatment of this
3
disease in the advanced setting.
Not one of these
4
agents was approved on the basis of randomized,
5
controlled Phase 3 trials prior to their approval.
6
None of these agents has ever shown a survival
7
benefit. Approval of these agents
was based solely
8 on
response rate.
9
Hydroxyurea, approved in 1967 with a 10
10
percent response rate, has not been used in the
11
clinical community for 20 years or more.
12
Dacarbazine, approved in 1975 with a
13
response rate of 23-25 percent, has more recently
14
been summarized in an article to appear next month
15 in
the European Journal of Cancer. The
response
16 rates that range between 7-13 percent I think
are
17 far
more accurate assessments of the true response
18
rate to this agent. Most of these
were done
19
pre-RECIST criteria and we don't know really what
20 the
objective response rate will be in larger
21
trials using the newer RECIST criteria that have
22
been used for the study to be discussed today.
31
1
[Slide]
2
Turning to IL-2, the most recent agent
3
approved for the treatment of metastatic melanoma,
4 the
IL-2 NDA pooled 8 Phase 2 small studies.
The
5
regimen was not compared in these to any other
6
therapy. The approval was based
upon quality of
7
response, durable responses and, given the
8
significant toxicity of this agent, the population
9
that was treated was highly atypical of the general
10
community of patients that we have to deal with in
11 the
country at large. The median age was 42
years.
12 The
patients had in general no co-morbidity in
13
terms of cardiac or pulmonary disease.
Most of the
14
patients who had responses had disease confined to
15
skin, lymph nodes and lung. The
toxicity of this
16
regimen is so regularly, predictably severe that,
17 in
fact, specialized units are required for the
18
administration of this agent. Its
administration
19 is
confined to specialized centers in general
20
across the country.
21
[Slide]
22
IL-2 responses were noted in 16 percent of
32
1
patients treated, about one-third of whom had
2
surgery to maintain this complete response, and 10
3 percent
partial responses, defined using pre-RECIST
4
criteria. The most salient aspect
of the IL-2
5
benefit in these patients has been the long
6
duration of response observed in some patients.
7
While the median duration of patients treated at
8
large was 9 months, the median duration for
9
patients who achieved complete responses was
10
greater than 5 years.
Unfortunately, the number of
11
those complete responses alive is rather small.
12 The
drug-related mortality with this treatment in
13
this series was 2 percent, further compromising
14
this relative benefit.
15
[Slide]
16
Over the years there have been many
17
attempts to improve upon the therapeutic benefit of
18 dacarbazine.
The largest of the trials conducted
19 in
the last five years are summarized in this
20
slide, beginning with the IL-2 experience which was
21
Phase 2 and, therefore, for which no comparator
22
exists.
33
1
These include the Dartmouth regimen,
2
adding tamoxafin to BCNU, cisplatin and
3
dacarbazine; two regimens of biochemotherapy
4
including one that the Eastern Cooperative Oncology
5
Group and the Intergroup presented to the ASCO
6
meetings just a year ago, now enrolling 416
7
patients; and a similarly large study from the
8
EORTC that has not yet been published; as well as a
9
publication just recently in JCO from the French
10
group with a total number of more than 1000
11
patients in which overall there has been no
12
combination that has shown a statistically
13
significant difference in overall response rate, in
14
complete response rate, in durable response rate or
15 in
progression-free survival.
16
[Slide]
17
I appeared last before this committee in
18
1999 in relationship to metastatic melanoma. In
19
that setting, it was to introduce the application
20 for
temozolomide. This is an oral equivalent
of
21
dacarbazine that I think no one questions was
22
equivalent to dacarbazine. The
committee did not
34
1 vote
to approve that agent which achieved
2
equivalency in a trial that had been targeted upon
3
superiority. But since that time
I think it has to
4 be
admitted that temozolomide has been the most
5
widely used drug in the community across the
6
country. The FDA briefing that
you have before you
7
suggests that Genasense is, in fact, comparable to
8
temozolomide. I would argue that
it is not.
9
The overall response rate for the
10
temozolomide application was not significantly
11
different. The complete
responses, identical; the
12
durable responses, not detailed; and the
13
differences in progression-free survival with an
14
asymmetrical interval of assessment for the two
15
arms, as Dr. Pazdur has just spoken about,
16
significant but 11 days.
17
The other major difference about
18
temozolomide is that this agent was already going
19 to
be available to the community at large for trial
20
exploration, and the agent that we are going to
21
discuss today will not be available if it is not
22
approved today.
35
1
[Slide]
2
In summary, despite more than 25 years of
3
work and low response rates with the single agent
4
dacarbazine, this agent remains the reference
5
standard for the field. No single
cytotoxic drug
6 nor
any biological agent or combination has been
7
shown to be superior to single agent dacarbazine in
8
relation to survival.
9
Relative to dacarbazine, no large
10
randomized, multicenter comparative study has ever
11
shown a statistically significant benefit in
12
overall response rate, in complete response rate or
13 in
progression-free.
14
High-dose IL-2 is a useful agent that many
15 of
us use for selected patients who lack
16
significant co-morbidity and who are willing to
17
accept its side effects. This
drug is not suitable
18 for
the majority of patients who present to us with
19
metastatic melanoma and is particularly unsuited
20 for
patients who are elderly.
21
[Slide]
22
I would conclude that metastatic melanoma,
36
1
upon which I have focused the last 33 years of my
2
work, is a drug-refractory neoplasm.
We need new
3
agents desperately. Thank you.
4 Study GM301
5
DR. ITRI: Thank you, Dr.
Kirkwood.
6
[Slide]
7
Genasense is an example of a new class of
8
drugs called antisense. Antisense
is fundamentally
9 a
protein knockout strategy. Genasense
inhibits
10
Bcl-2 production. Bcl-2 is a
protein and is
11
believed to be an important mediator of cancer cell
12
resistance to chemotherapy.
Genasense is
13
administered for 5 days before chemotherapy,
14
reduces Bcl-2 production and renders the cancer
15
cell more susceptible to chemotherapy.
In this
16
way, Genasense is postulated to enhance the
17
efficacy of chemotherapy.
18
[Slide]
19
Bcl-2 is ubiquitously expressed by
20
melanoma cells. Five days of
continuous IV therapy
21
with Genasense prior to the administration of DTIC
22
resulted in approximately 70 percent reduction in
37
1
Bcl-2 levels in melanoma cells taken from patients
2
before and after Genasense treatment.
These
3
results provided the rationale for a Phase 3 study
4 in
patients with advanced malignant melanoma.
5
[Slide]
6
This study is the largest randomized trial
7
ever conducted in patients with advanced malignant
8
melanoma. It was an open-label,
multicenter trial
9
involving 139 investigational sites in 9 countries
10
around the world.
11
The primary endpoint was overall survival
12 and
the secondary endpoints included
13
progression-free survival, antitumor responses
14
using computer calculated RECIST based on
15
evaluations of site tumor measurements; durable
16
responses which were defined as responses lasting
17
longer than 6 months; and, of course, safety in all
18
patients.
19
[Slide]
20
Patients received either DTIC at the
21
standard dose of 1000 mg/m
2 or the same dose of
22
DTIC preceded by a 5-day continuous infusion of
38
1
Genasense at a dose of 7 mg/kg/day.
Patients were
2
stratified according to the three major prognostic
3
factors for melanoma, ECOG performance status 0 or
4
1-2; the presence or absence of liver metastases;
5 and
normal or elevated LDH levels. Patients
could
6
receive up to 8 cycles during a treatment phase
7
which were administered every 21 days.
Restarting
8
evaluations were performed at the end of every two
9
cycles.
10
It is important to note that the timing of
11
interval measurements were fixed and similar in
12
both arms, and they were prospectively defined with
13 FDA
agreement, with the temozolomide review issues
14
clearly in mind. Crossover was
not permitted from
15 the
DTIC arm into the Genasense arm, and follow-up
16 was
continued for 2 years in both arms of the
17
study. Patients on the Genasense
arm only could
18
receive up to an additional 8 cycles of the
19
combination therapy in extension protocol GM214 if
20
they achieved at least stable disease by the end of
21 the
treatment phase and it was considered to be in
22 the
best interest of the patient, in consultation
39
1
with the treating physician.
2
[Slide]
3 The statistical assumptions for this
study
4
were based on an overall median survival for DTIC
5 of
6 months which was derived from published
6
reviews. Genasense was postulated
to add an
7
additional 2 months, for total a median survival of
8 8
months; 750 patients would provide 90 percent
9
power to see a difference between groups, with an
10
alpha level of 0.05. It was
assumed that accrual
11
would be constant at 30 patients per month. In
12
agreement with FDA, an analysis was planned when at
13
least 508 deaths had occurred on the study.
14
[Slide]
15
The two groups were balanced for age and
16
gender. The median age of
patients in this study
17 was
60 years but patients ranged in age from 16 to
18
93. Approximately 40 percent of
our patients in
19
this study were greater than 65 years of age and,
20
remarkably, more than 10 percent were more than 75
21
years of age.
22
[Slide]
40
1
The two groups were equally balanced with
2
regard to baseline performance status and
3
approximately half of all patients were symptomatic
4 at
baseline.
5
[Slide]
6
Similarly, the two groups were balanced
7
with respect to the major prognostic indicators
8
including time from initial diagnosis, LDH/disease
9
site distribution and prior immunotherapy which
10 consisted
primarily of alpha interferon
11
administered as an adjuvant therapy in both groups.
12
[Slide]
13
Forty patients who were randomized into
14 the
study did not receive treatment. The
primary
15
reason for this is that in the DTIC arm some
16
patients, later being randomized to the standard of
17
care, were unwilling to travel or withdrew consent
18
once they learned they would not be receiving
19
experimental therapy. The amount
of DTIC delivered
20 to
both groups was equivalent. Overall, the
21
addition of Genasense did not require dose
22
reduction of DTIC.
41
1
[Slide]
2
This is a summary of the efficacy
3
parameters which, taken together, provide evidence
4 for
the benefit of combining Genasense with DTIC.
5 I
will discuss each of these in more detail in
6
following slides.
7
Although not statistically significant,
8
improvement in overall survival was noted for the
9
Genasense group. Statistically
significant
10
improvement was noted in both progression-free
11
survival and response rates, and I will shortly be
12
showing you some interesting updated results
13
regarding complete responses in this study. We
14
also saw a positive trend in patients with durable
15
responses.
16
[Slide]
17
The FDA has raised a number of
18
considerations for the committee's review. These
19
include response rate concordance; the impact of
20
interval assessments on progression-free survival;
21 the
impact of missing data on progression-free
22
survival; baseline differences in prognostic
42
1
factors; and the influence of non-U.S. sites on
2
response rate. I will address
each of these issues
3
separately in the appropriate sections of my
4
presentation.
5
[Slide]
6
This Kaplan-Meier plot of overall survival
7
shows that both arms outperformed expectations.
8
DTIC was associated with a 7.9 month median
9
survival as opposed to the expected 6 months, and
10
Genasense treatment resulted in a 9.1 month median
11
survival. These differences were
not statistically
12
significant. Please note that the
overall survival
13
curves begin to separate at 6 months and the median
14
follow-up at the time of database lock was 7
15
months.
16
[Slide]
17
The addition of Genasense was associated
18
with an overall response rate of 11.7 percent as
19
compared to 6.8 percent for DTIC alone.
This
20
difference is significant, with a p value of 0.019.
21 Use
of the stringent RECIST measurement system has
22
historically reduced response rates in other
43
1
studies by 25-50 percent when compared to
2
investigator determinations.
3
[Slide]
4
It is appropriate at this point to discuss
5 how
responses were calculated in this study.
The
6
investigators did not determine response.
7
Investigators measured lesions and entered these
8
data onto an electronic case report form. The
9
computer then calculated whether the response met
10
criteria for RECIST. RadPharm was
only contracted
11 to
review responding patients. The sponsor
was
12
provided with measurements of target lesions and
13
evaluations of non-target lesions by RadPharm.
14
These measurements were also assessed by the same
15
computer algorithm using RECIST criteria. RadPharm
16
reviewers were blinded as to the treatment arm and
17 all
clinical information in which tumors had been
18
selected by the sites as target lesions.
All marks
19
made by the sites on x-rays were removed.
20
There are three major reasons why RadPharm
21
readings might not have been strictly concordant
22
with the site measurements. These
include the
44
1
evaluation of different target lesions with
2
different measurements, the absence of important
3
clinical information regarding preexisting lesions
4 and
controversy regarding the reporting of normal
5 or
residual lymph node tissue.
6
[Slide]
7
The patient on this slide had extensive
8
liver metastasis at baseline which resolved
9
completely during treatment. This
patient has
10
remained in complete clinical
remission for
11
approximately three years.
12
[Slide]
13
Due to the presence of a persisting liver
14
lesion in the same patient, RadPharm was unable to
15
confirm a complete response. By
procedure,
16
RadPharm was unaware that this was a documented
17
preexisting cystic lesion that was benign. This
18 patient is being cared for by Dr. Hersey who
is
19
here with us today and can answer any questions you
20
might have regarding her treatment course.
21
[Slide]
22
In the next case, which demonstrates how
45
1 the
absence of medical history can confound
2
concordance, a biopsy-proven metastatic lesion of
3 the
frontal sinus was read by RadPharm as
4
incidental sinusitis. Because
this patient had
5
undergone a Caldwell Luck enterotomy with removal
6 of
the inferior turbinate due to metastatic
7
melanoma, RadPharm reasonably assumed that this was
8 an
infectious process and did not confirm the
9
response.
10 [Slide]
11
Because RECIST criteria do not provide
12
guidance for the interpretation of normal lymph
13
nodal architecture at the site of previous disease,
14
RadPharm could not confirm complete response in the
15 next
case and several others like it. Despite
16
complete regression of the tumor next to the blood
17
vessel, here, RadPharm could only assign partial
18
response due to the presence of small residua.
19
The PET scan results for this same patient
20
confirmed complete clinical response and shows no
21
residual evidence of a viable signal post
22
treatment. The FDA did not review
any of these
46
1 x-rays
and based their concordance judgments solely
2 on
raw measurements in percent reductions provided
3 by
the sponsor at their request. I urge the
4
committee to address questions regarding
5
radiographic reviews to Dr. Robert Ford, who is
6
here with us today as an expert consultant in
7
radiology and who personally reviewed all of these
8
films.
9
[Slide]
10
Seventy-one responding patients were
11
evaluated by RadPharm and 60 of these were
12
considered to be evaluable; 11 patients were not
13
evaluable due to the poor quality of photographs or
14
films or the absence of lesions which could be
15
considered measurable by RadPharm.
Five of these
16
cases occurred in the Genasense arm and 6 occurred
17 in
the DTIC arm.
18
Point-to-point concordance for two time
19
point evaluations were available for 38 patients
20 and
give the concordant rate of 63 percent which is
21
consistent with literature citations for
22
evaluations of this nature. Two
additional
47
1
responding patients were confirmed to be responses
2 but
were assessed differently by the site and by
3
RadPharm. Eight cases were
consistent at a single
4
evaluation and were within 10 percent of response
5 at
the second evaluation. Four patients,
such as
6 the
ones I have previously described to you, were
7
easily explained by the absence of appropriate
8
medical history. If we include
only the 40
9
responders confirmed by RadPharm and agreed to by
10 the
FDA on treatment comparison, Genasense is
11
completely consistent to DTIC as demonstrated by
12
odds ratios. If only those 40
responses considered
13 to
be confirmed by both RadPharm and the FDA are
14
included, odds ratios reveal a 91 percent
15
improvement in response rate by RadPharm compared
16 to
an 82 Percent improvement in response for
17
Genasense as reported in the NDA.
18
[Slide]
19
These cases were randomly selected by FDA
20 and
included 40 cases in each arm of the study.
21
X-rays were collected from around the world and
22
included assessments which occurred in the
48
1
follow-up period after NDA cutoff.
As a
2
consequence of this unplanned review of cases,
3
RadPharm was able to identify additional responses
4
which occurred in the follow-up period after NDA
5
cutoff. These important clinical
findings prompted
6
Genta to evaluate all patients in follow-up who met
7
RECIST criteria for response during at least one
8
time point during the treatment phase and all
9
patients who ended the treatment phase without
10
disease progression and who had received no
11
intervening therapy.
12
[Slide]
13
As with response, we observed good
14 concordance
regarding the conclusions about time to
15
progression between the investigational site
16
assessments and RadPharm determinations.
When the
17
site assessments and RadPharm determinations for
18
time to progression are compared, both showed a
19
benefit for the Genasense group.
RadPharm
20
assessments of time to progression in the Genasense
21
group were generally longer than the site
22
assessments.
49
1
[Slide]
2
Six additional responses have been
3
identified which occurred in the follow-up period
4
after the NDA submission and all were in the
5
Genasense group. Only complete
responses are
6
reported since they are the ones most unequivocally
7
associated with clinical benefit and constitute a
8
result not commonly observed with single-agent
9
DTIC. Three of these complete
responses were
10
upgraded from the partial response category and 3
11
were patients with long-standing stable disease.
12
Information regarding these additional responding
13
patients was submitted to the FDA on April 9th of
14
this year.
15
It is important to note that the submitted
16
database has not been updated or altered in any
17
way, nor are we attempting to change the data
18
provided in our NDA. We wish
simply to inform you
19 of
important and frankly unanticipated clinical
20
findings. These responses all
occurred in the
21
absence of other intervening therapies and have
22
been documented by duplicate CT scans using the
50
1
same RECIST criteria as specified in the protocol.
2 The
physicians caring for several of these patients
3 are
here with us today and are able to answer any
4
questions you may have directly.
5
[Slide]
6
Complete responses were evenly distributed
7 by
gender and generally exhibited the same
8
demographic pattern as the overall population.
9
Importantly, one-third of the responses occurred in
10
patients with elevated LDH and half were observed
11 in
the worst AJCC prognostic categories, M1b and
12
M1c.
13
[Slide]
14
Survival for the complete responders
15
ranges from 15 months to more than 3 years on the
16
Genasense arm, and 19 to 21 months on the DTIC arm.
17 The
plus signs denote ongoing responses. Two
18
patients have died, one on each arm of the study.
19
[Slide]
20
The evolution of the complete responders
21 on
this study is shown in this slide. The
two
22
responding DTIC patients are shown in yellow for
51
1
comparison. The solid bar denotes
the database
2
cutoff of August 1, 2003 and is the information
3
contained in the NDA. The dotted
line denotes the
4 date
of the FDA inquiry that precipitated review in
5 the
follow-up period after database cutoff.
6
As you can see, partial responses tend to
7
occur later in the Genasense arm and evolved over
8
time into complete responses. Three
of the
9
Genasense responses, similar to what has been
10
described for IL-2, have been surgically
11
maintained. Once again, all
responses were based
12 on
strict RECIST criteria with duplicate
13
measurements and no patient received intervening
14
therapy.
15
[Slide]
16
Returning now to the data previously
17
reported in the NDA database, the duration of
18
response is presented using a box-and-whisker plot
19 on
this slide. The red line denotes the
median.
20 The
top of the box is the boundary of the third
21
quartile and the bottom is the boundary of the
22
first quartile. As you can see,
the medians are
52
1
similar but an important difference is observed in
2 the
third quartile, resulting in a longer mean
3
duration of response in patients who received
4
Genasense.
5
[Slide]
6
Durable responses, defined as responses
7
lasting at least 6 months, were more than doubled
8 in
the Genasense group, as shown in this slide.
9
[Slide]
10
Median progression-free survival for the
11
Genasense group was 74 days as compared to 49 days
12 for
the DTIC group. The relative risk of
having
13
progressive disease or death was reduced by
14
approximately 27 percent in the Genasense arm.
15
These differences are highly significant, with a p
16
value of 0.0003.
17
Time to progression was performed as a
18
sensitivity analysis for progression-free survival.
19 The
results were very similar and showed
20
approximately a 27 percent reduction in the risk of
21
progressive disease. In this analysis,
11 patients
22 who
died without documented disease progression
53
1
were censored to the day of last lesion
2
measurement. These 11 patients
constitute the only
3
difference between progression-free survival and
4
time to progression in this study, and explain why
5 the
two curves are so similar.
6
[Slide]
7
Genta conducted multiple sensitivity
8
analyses to address possible biases in the
9
calculation of progression-free survival. In all
10
instances the hazard ratios remained stable and all
11
were statistically significant, attesting to the
12
robustness of the observation.
The most common
13 concerns
regarding progression-free survival
14
analyses include the impact of scheduled assessment
15 and
missing data which can potentially be a source
16 of
bias. Several of the methods used by
Genta
17
address these issues and all confirm the conclusion
18
derived from the original planned analysis.
19
[Slide]
20
FDA has performed four analyses using
21
interval censoring techniques.
Hazard ratios are
22 not
reported for this method. Approach number
one
54
1
specifically addresses the issue of assessment
2
schedule bias and remains statistically significant
3 in
favor of Genasense. Approaches two,
three and
4 four
address both assessment schedule and missing
5
data biases taken together.
Approaches two and
6
three remain statistically significant in favor of
7
Genasense. Only approach four,
which represents a
8
rather extreme case assumption, and I will show you
9 an
example of this on the next slide, resulted in
10 an
insignificant p value and would have resulted in
11 the
deletion of almost half of the data.
12
[Slide]
13
Using this example of patient data by
14
interval censoring technique number four all of the
15
data in yellow would have been thrown out because
16 the
investigator failed to repeatedly record the
17
absence of brain metastases. I
would encourage
18
committee members to address any questions you
19
might have for the sponsor regarding this analysis
20
technique to Dr. Janet Wittes.
21
[Slide]
22
In order to address FDA concerns about
55
1
potential differences for baseline variables to
2
affect efficacy endpoints, progression-free
3
survival results and response rates were adjusted
4 for
the variables of age, gender and AJCC LDH
5
disease site criteria. Results
show that both
6
hazard ratios and odds ratios remain stable and all
7
results remain statistically significant. Thus,
8
there was no apparent impact of potential baseline
9
imbalances on results.
10
[Slide]
11
An additional concern has been raised
12
regarding benefit for patients in the United States
13
when response rates are examined by country. This
14
tree plot shows that confidence limits overlap and
15
point estimates are similar for the United States
16 and
non-United States. There is, of course,
17
expected variability in some countries with small
18
sample sizes but no evidence exists that the
19
beneficial effect of the Genasense combination is
20
different in the United States than it is outside
21 the
United States.
22
[Slide]
56
1
In summary, we have demonstrated
2
radiographic concordance and superiority of
3
Genasense regardless of who reviews the x-rays.
4
Progression-free survival was not biased by missing
5
data or interval assessment irregularities. No
6
effect on endpoints was observed related to
7 baseline
demographic variables and similar benefit
8 was
observed for both U.S. and non-U.S. patients on
9 the
study.
10
[Slide]
11
Turning now to safety, adverse events were
12
generally increased in the Genasense arm, as can be
13
expected with add-on therapy. The
committee is
14
referred to the briefing document provided by the
15
sponsor for details of adverse events.
16
Importantly, no new or unexpected adverse events
17
were observed in the study which have not been seen
18
with DTIC alone. We did see an
increase in the
19
incidence of fever, which is a well-known effect
20
related to Genasense as a single agent, as well as
21 an
increase in neutropenia, thrombocytopenia and
22
catheter-related complications.
Safety data were
57
1
regularly and carefully monitored by an independent
2
drug safety monitoring board who at no point
3
identified any safety concerns in the study.
4
[Slide]
5
There is an increased incidence of grade
6
3-4, as well as serious events of thrombocytopenia
7 in
the Genasense arm. The word
"serious" in this
8
context is defined in its regulatory context and
9
generally means the need for hospitalization or the
10
prolongation of hospitalization.
However,
11
bleeding, which is the major clinical consequence
12 of
this laboratory abnormality with grade 3-4
13
bleeding, serious bleeding--serious bleeding
14
related to thrombocytopenia, shows no difference
15
between the arms. Similarly, the
number of
16
patients who required platelet transfusions with
17 the
absolute number of units transfused were no
18
different between the two treatment arms.
19
[Slide]
20
Neutropenia exhibited a similar pattern as
21
thrombocytopenia. The incidence
of grade 3-4 and
22
serious events was increased in the Genasense arm.
58
1
Although higher in the Genasense arm and largely
2
related to the presence of a central line, the
3
incidence of grade 3-4 and serious neutropenic
4
infections was generally low in both groups.
5
[Slide]
6
Not surprisingly, catheter-related
7
complications occurred almost solely in the
8
Genasense arm and the incidence was consistent to
9
that reported in the literature for central venous
10
catheters. Injection site
infections occurred in
11
approximately 4 percent of patients and thrombotic
12
events occurred in approximately 2 percent of
13
patients receiving Genasense, whereas injection
14
site reactions occurred only in the DTIC group
15
where peripheral lines are generally used for DTIC
16
administration. Two patients in
the Genasense arm
17
received their 5-day Genasense dose in 5 hours due
18 to
a mis-programming of the pump. Both of
these
19
patients experienced nausea, fever and
20
thrombocytopenia. Both patients
recovered
21
completely within 48 hours and had no sequelae
22
related to the overdose. Both
patients went on to
59
1
receive the additional cycles of therapy and one of
2
these patients has achieved a PR after 7 additional
3
cycles of treatment. We are
hopeful that
4
subcutaneous and other alternative dosing methods
5 in
development will mitigate the need for a central
6
line and its attendant complications.
7
[Slide]
8
Adverse events leading to discontinuation
9
were increased in the Genasense arm.
However, the
10
majority of events in both arms were related to
11
disease progression. In this
study disease
12
progression could be reported as an adverse event.
13
Importantly, adverse events resulting in death and
14
deaths which occurred within 30 days of the last
15
dose of study drug were no different between the
16 two
treatment arms.
17
[Slide]
18
In summary, this study was the largest
19
randomized trial ever completed in patients with
20
advanced malignant melanoma. The
study was
21
carefully conducted; showed internally consistent
22
results; and demonstrated compelling clinical
60
1
benefit.
2
We believe that we have addressed all of
3 the
study questions given to ODAC for
4
consideration. Finally, we
believe that the study
5
shows consistent clinical benefit, which will be
6
summarized by Dr. Frank Haluska in his closing
7
remarks.
8
In closing, I would like to thank the
9
patients and their families, the physicians, the
10
nurses and the site coordinators who made the study
11
possible. I would also like to
thank the dedicated
12 and
professional employees of Genta who worked
13
tirelessly to contribute to the treatment of cancer
14
patients. Thank you for your
attention. Dr.
15
Haluska?
16 Clinical Benefit Summary
17
DR. HALUSKA: Thank you, Dr. Itri.
18
[Slide]
19
My task today is to provide you with a
20
summary of the data that you have just seen, that I
21
think have been so clearly presented, as well as an
22
overview and some context for the clinical trial.
61
1
[Slide]
2
I think the best way to do this is to in
3 our
minds assume the role of ODAC and if I were a
4
member of ODAC right now I would have two major
5
questions. The first of these is
that the sponsor
6
here has failed to meet the primary endpoint of the
7
study, which is survival--can I still approve this
8
drug? I think the answer to that
question is an
9 emphatic
yes. Dr. Pazdur has already commented
10
that although meeting a survival endpoint is
11
desirable and is the gold standard, the failure to
12 do
so does not preclude approval, and I think that
13 is
germane here.
14
I addition, I think it is important to
15
consider the recent regulatory history of the
16
melanoma field, specifically with regard to IL-2
17 and
temozolomide. IL-2, as you know, was
approved
18
several years ago based on the rate, the quality
19 and
the duration of the responses, data that we are
20
presenting here, and I think these data are
21
stronger because they are the result of a
22
randomized, prospective trial, albeit with
62
1
secondary endpoints.
2
The other drug that I think is relevant is
3
temozolomide and, as Dr. Kirkwood has already
4
explained, the data are better for Genta than for
5 the
temozolomide submission as well. So, I
think
6
that this drug is approvable despite the failure to
7
meet the primary endpoint.
8
The second question that must be on your
9
mind is do the secondary endpoints confer or
10
support the conferral of clinical benefit? Are
11
they strong enough to support approval of this
12
drug? I do think that significant
clinical benefit
13 is
strongly suggested by these data. So,
let's
14
consider that.
15
[Slide]
16
These are I think the most
important
17
endpoints of this study. Again, I
want to stress
18
that they were prospectively identified as opposed
19 to,
for instance, IL-2s which were the result of
20
Phase 2 data.
21
The first of them is the overall response
22
rate. The overall response rate
approaches 12
63
1
percent versus 6.8 percent in the DTIC arm. This
2 is
an improvement. In this field, no
improvement
3
with statistical significance has ever been
4
demonstrated in response rate for advanced
5
melanoma.
6
We have demonstrated improvement in
7
complete responses, 11 versus 2.
This is
8
significant as well and, again, this has not been
9
demonstrated in a reaction study.
I think the IL-2
10
experience is relevant to both of these.
As I
11
said, IL-2 was approved on the basis of the rate,
12 the
quality and the duration of survival. We
have,
13 in
this trial, 9 patients that are alive, an
14
increment that is not seen in the DTIC trial, and I
15
want to point out that IL-2 was approved on the
16
basis of 10. So, this is
certainly in keeping with
17
previous decisions that have been made.
18
The final issue is progression-free
19
survival, 74 versus 49 days, nearly an additional
20
month for patients who are presenting to their
21
oncologist. That is an extra
visit a patient can
22 come
to their oncologist without having been told
64
1
that their disease is progressing.
This, to my
2
mind, is clinical benefit.
3
[Slide]
4
What is the context of these findings?
5
These are the data from the five largest randomized
6
trials that have been conducted in melanoma and the
7
trial in front of you today is the largest. There
8 are
2019 patients that have been treated on these
9
trials and until today there has never been a
10
significant clinical improvement for any of the
11
measures that we are discussing today.
Response
12
rate has not been shown to be improved and it is
13
shown to be improved here.
Complete responses have
14
never been documented in a randomized study to be
15
improved and they are improved here.
And,
16
progression-free survival has never been shown to
17 be
improved and it is improved here. I
think this
18
trial sets itself apart from the progress in the
19
field in the last few years and I think that is why
20 it
requires your careful consideration today.
21
[Slide]
22
To summarize that, patients value
65
1
responses and value complete responses.
The FDA in
2 the
past has made it clear that these are important
3
criteria to consider and, in fact, there are no
4
melanoma drugs approved that have been approved on
5 any
other criteria.
6
You might ask is a 10 percent response
7
rate, or the order of magnitude of 10 percent,
8
important to patients and I think it is with, I
9
think, the recent approval history and data on
10
responses in other malignancies, particularly in
11
lung cancer. The IRESSA
experience that has
12
recently been clarified with data published last
13
week suggests that a 10 percent response rate is
14
clinically important. We
understand the biological
15
basis of some of these responses and a 10 percent
16
response rate can certainly change the field; it
17 can
certainly change a patient's life. So, I
do
18 not
think that a 10 percent response rate in and of
19
itself argues against approval.
20
What about the magnitude of time to
21
progression? A month, I think, is
important. Data
22
that Carey Kilbridge and my colleagues have
66
1
examined with regard to how melanoma patients view
2
their experience strongly suggest that any
3
additional time without being told their disease is
4
progressing or without the presence of disease is
5
important to them. In my opinion,
what the
6
sponsors have shown today constitutes clinical
7
benefit for the melanoma patient.
8
[Slide]
9
What about safety? When we
research a
10
treatment for our patients we do it based on an
11
evaluation of risk versus benefit.
What are the
12
risks of this therapy? The
sponsor has shown that
13
there are no new or unexpected adverse events
14
concomitant to treatment with DTIC and Genasense.
15
There is no difference in the treatment-related
16
deaths between the two arms.
There is an increase
17 in
fever, neutropenia and thrombocytopenia.
Some
18 of
this is likely due to catheter-related
19
complications and this is certainly not the only
20
agent on the market or potentially on the market
21
that would be administered with a pump.
22
Finally, Genasense is still better
67
1
tolerated than other alternatives for melanoma
2
patients and, again, I think a review of the
3
literature is germane here.
4
[Slide]
5
These are three of the trials for which we
6
have good safety data in comparison to the trial in
7
front of you today. They
demonstrate that the rate
8 of
complications for the DTIC arm is certainly
9
similar to what was seen in other studies with
10
regard to grade 3 or 4 neutropenia and grade 3 and
11 4
thrombocytopenia, and certainly the rates of
12
complications that can be attributed to the
13
combination of Genasense and DTIC are less than
14
what we see with other alternatives for melanoma
15
patients. I think that argues
that this is a safe
16
combination and the risk-benefit analysis is
17
completely reasonable to be attributed to therapy.
18
[Slide]
19
Conclusions--I think this is a novel drug.
20 It
is the first of a class of agents that has been
21
shown to be efficacious by several measures. It
22
takes into account our genetic understanding of
68
1
this disease. It is in keeping
with the movement
2 in
the field broadly for targeted therapy and I
3
think that should be taken into consideration.
4
It confers a clinical benefit with DTIC by
5
multiple measures that I think have been reliably
6
demonstrated in this large clinical trial that
7
include response rate, complete responses and
8
progression-free survival. And,
it has a
9
predictable and manageable safety profile.
10
[Slide]
11
Melanoma is refractory to current
12
front-line therapy. You have
heard and I think you
13
will hear further today that we need new agents.
14
This product is safe; it is effective when combined
15
with DTIC to treat stage 4 melanoma.
In other
16
words, this drug works. I think
it is up to you to
17
define today what "works" means but I don't think
18 we
can discard the randomized trial demonstrated
19
improvement in response rate, in progression-free
20
survival and in complete response rate.
21
A final comment--I am supposed to be here
22 as
a dispassionate expert, scientifically objective
69
1 and
clinically removed but I don't think I can
2
completely play that role because I do take care of
3
melanoma patients. The melanoma
field has been
4
criticized for trying to consistently hit the
5
clinical home run. But this
represents progress.
6 It
is incremental progress. It is not a
clinical
7
home run but it is incremental progress, and if we
8 are
ultimately going to make real progress in this
9
disease to cure it, it will require the
10
accumulation of incremental progress.
Allow us to
11
make incremental progress; make this drug available
12 to
our patients. Thank you.
13
DR. PRZEPIORKA: We are going to
hold
14
questions for the first presentation until the FDA
15
presentation has been completed.
Dr. Kane, if you
16
could begin? Thank you.
17
FDA Presentation
18 Medical Review
19
DR. KANE: Thank you.
20
[Slide]
21
Good morning. My name is Robert
Kane. I
22 am
the medical reviewer for this NDA and I will be
70
1
presenting the FDA review along with Dr. Peiling
2
Yang, our statistical reviewer.
3
[Slide]
4
I would like to recognize our primary
5 review
team members for this NDA.
6
[Slide]
7
Randomized, controlled trials
8
prospectively designed with clear, quantitative
9
endpoints statistically analyzed provide the basis
10 to
assess the merits of new drugs. Clinical
11
judgment translates these findings for best patient
12
care. Our presentation today will
include
13
requirements for new drug approval based on federal
14 law
and regulations; aspects of ODAC review of
15
temozolomide which are relevant to today; the FDA
16
examination of the Genasense, oblimersen, NDA; and
17
concluding remarks.
18
[Slide]
19
In the FD&C Act of 1962 substantial
20
evidence of effectiveness was required by Congress.
21
This was defined as evidence from adequate and
22
well-controlled investigations, generally
71
1
understood to mean at least two such studies for
2 new
drug approval.
3
[Slide]
4
The FDAMA legislation in 1997 indicated
5
that one trial may suffice for approval with
6
confirmatory evidence. The
guidance document on
7
effectiveness in 1998 indicated that for a single
8 trial
to suffice it should be of excellent design,
9
internally consistent with highly reliable and
10
statistically strong evidence of an important
11
clinical benefit, such as an effect on survival,
12 and
a confirmatory study might be difficult to do
13 for
ethical reasons.
14
[Slide]
15
New drug approval can take two forms.
For
16
regular approval a sponsor needs to show clinical
17
benefit. Accelerated approval
uses a surrogate
18
endpoint reasonably likely to predict clinical
19
benefit and requires subsequent confirmation of the
20
benefit.
21
[Slide]
22
Here are the currently approved drugs for
72
1
metastatic melanoma. In the past
response rate was
2 the
primary basis, as you have seen and as you have
3
already heard, for hydroxyurea and for dacarbazine.
4
Survival times were, and continue to remain, in the
5
range of 5 to 9 months. More
recently,
6
improvements in the quantity or the quality of
7
survival have served as the basis for approval.
8
Also as you have heard, the aldesleukin,
9
interleukin-2, approval was heavily related to the
10 very long complete responders, some in excess
of 5
11
years. Complete responses will be
abbreviated as
12 CRs
on this slide.
13
[Slide]
14
I would like to remind the committee that
15 the
evidence for interferon supported approval for
16 its
adjuvant use although it is often used in the
17
treatment for metastatic disease.
The temozolomide
18
evaluation by ODAC in 1999 is relevant and
19
instructive for today's review.
20
[Slide]
21
This NDA contained one main open-label
22
study, the primary endpoint of which was survival
73
1
time. It was designed to show a
3-month survival
2
benefit for temozolomide alone over DTIC alone.
3
Secondary endpoints were progression-free survival,
4
abbreviated here as PFS, and response rate, RR.
5
[Slide]
6
The results of this study showed no
7
survival benefit for temozolomide over DTIC.
8
Median survivals were 7.7 versus 6.4 months. For
9
progression-free survival the difference was found
10 to
be highly statistically significant with a
11
log-rank p value of 0.002.
However, the median
12 progression-free
survival difference was only 11
13
days. When an ample size is
chosen for a survival
14
endpoint the statistical significance of small
15
differences in early endpoints can appear
16
magnified. Response rates were
not significantly
17
different.
18
[Slide]
19
Temozolomide was not approved.
The study
20
failed to demonstrate the primary endpoint of
21
survival benefit.
Progression-free survival, a
22
secondary endpoint, was of small magnitude at best.
74
1 No
symptomatic benefit was observed and a proposed
2
post hoc 6-month survival analysis was not
3
convincing.
4
[Slide]
5
For Genta's NDA, here are the
important
6
study dates. The Phase 3 protocol
began in July,
7
2000. The data cutoff date was
August 1, 2003, and
8
this represents excellent accrual to the study. On
9
December 8, 2003 the NDA was submitted for FDA
10
review.
11
[Slide]
12
Genta has just presented their trial
13
design. I would like to emphasize
a couple of
14
points. This was a very large,
multicenter,
15
multinational, unblinded study. This was an add-on
16 of
Genasense to DTIC. Prolonged central
venous
17
access is required for the 5-day infusions of
18
Genasense. Genasense may be
abbreviated as G or
19
G3139 on our slides. The protocol
specified an
20
independent review, a blinded group, to assess
21
responders. Also, the ability to
deal with an
22
ambulatory infusion pump was required.
75
1
[Slide]
2
The primary endpoint was survival.
The
3
design was to detect a superiority in survival.
4 The
protocol included seven secondary endpoints,
5
listed here.
6
[Slide]
7
The trial design was to identify a 2-month
8 median
improvement in survival time from 6 months
9
with DTIC alone to 8 months for the addition of
10
Genasense to DTIC. The primary
analysis for the
11
trial was to be the unadjusted log-rank analysis
12 for
the intent-to-treat population.
13
[Slide]
14
The study disposition of patients showed
15
that less than half the patients were still on
16
therapy after the first assessment about day 42.
17
Most patients went off study because of progressive
18
disease; 44 percent remained on study after the
19
first assessment. As I mentioned,
the data cutoff
20
date was August 1 and analysis occurred at 535
21
deaths.
22
[Slide]
76
1
In the primary endpoint analysis, using
2 the
protocol-specified analysis with the
3
intent-to-treat population, no survival benefit was
4
demonstrated by adding Genasense to DTIC treatment
5
versus DTIC alone. These are the
actual survival
6
results. As you have already
seen, the hazard
7
ratio was 0.89 and the log rang p value for the
8
survival difference was 0.18.
9
Dr. Peiling Yang will now provide a more
10 detailed
examination of the progression-free
11
survival.
12 Statistical Review
13
DR. YANG: Thank you, Dr. Kane.
14
[Slide]
15
As seen in Dr. Kane's presentation, the
16
study failed to demonstrate efficacy in the primary
17
endpoint of overall survival at a two-sided alpha
18
level of 0.05. From a statistical
perspective, an
19
efficacy demonstration based on any other endpoint,
20
such as progression-free survival, would only infer
21 a
false-positive error rate. Despite this
concern,
22 the
secondary endpoint, progression-free survival,
77
1 was
evaluated and the important question is
2
regarding progression-free survival.
3
[Slide]
4
We have doubt regarding the applicant's
5
findings and, second, as Dr. Kane will be
6
discussing, there are questions regarding its
7
clinical significance. This will
be summarized in
8
this presentation.
9
[Slide]
10
My review of the progression-free survival
11 is
as follows, review of applicant's analyses and
12
results; then the major FDA concern about
13 assessment
times; then additional FDA concerns.
14
Let's first review the applicant's
15
analysis and results.
Progression-free survival
16 was
defined as time from the data of randomization
17 to
the date of disease progression or death.
The
18
data of disease progression was recorded as the
19
assessment date when disease progression was
20
documented. If the assessment was
on different
21
days, then the latest date among all assessments
22 was
used by this applicant to represent the
78
1
assessment date in that cycle.
2
[Slide]
3
This slide summarizes the applicant's
4
results. The protocol specified as
secondary
5
efficacy analysis or progression-free survival was
6 the
log-rank test with the missing data imputed by
7 the
last observation carried forward method.
The p
8
value based on this approach was very small.
9
However, in a large trial a small p value can be
10
observed even if the treatment effect is small.
11
During the review process FDA requested the
12
applicant to analyze the data using a different
13
approach by censoring patients at the last
14 assessment date when at least 50 percent of
target
15
lesions were measured if the disease had not
16
progressed yet. The p value based
on this approach
17 was
also very small. However, when analyzed
by
18
this approach the observed median progression-free
19
survival in the combination therapy dropped by 13
20
days and in the control arm dropped by only 1 day,
21 as
presented in this table.
22
[Slide]
79
1
An important question is raised while
2
interpreting the results of the analysis of
3
progression-free survival. Is the
applicant's
4
finding a true finding?
5
[Slide]
6
FDA has a major concern in evaluation of
7
progression-free survival, that is, imbalance in
8
observed lesion assessment times between treatment
9
arms. The next few slides address
this concern.
10
[Slide]
11
Lesions were to be measured every 6 weeks
12
during the treatment phase. In
practice, this did
13 not
always occur. Even when they were
assessing
14 the
planned cycles there were still differences in
15
timing between the two arms.
Because this is a
16
very large open-label trial involving two different
17
regimens, one administered on 6 days and the other
18
only 1 day and because the claimed difference was
19
very small, FDA was concerned that the observed
20
differences in progression-free survival might be
21
affected by systematic bias. One
potential bias
22
could be caused by differences in the time of
80
1
lesion assessments.
2
[Slide]
3
We must remember a critical difference
4
between the analysis of survival and of lesion
5
progression. The date of death,
represented by the
6
star, will not change regardless of the evaluation
7
schedule. With progression
measurement, however,
8 the
date we assign for progression is usually the
9
date of a scheduled visit occurring sometime after
10 the
actual progression date. It should not
be
11
surprising that assessing progression at longer
12
intervals leads to a longer time to progression.
13
[Slide]
14
To address this concern FDA summarized the
15
time from the date of randomization to each of the
16
first 3 observed assessments in this pivotal trial.
17
Included in this summary are those assessments
18
which occurred by the time of disease progression
19 or
death and where there was at least one target
20
lesion measurement. The observed
median times from
21
randomization to each of these assessments were
22
obtained for each treatment arm.
They were 48
81
1
versus 43 days to the first assessment; 94 versus
2 87
days to the second assessment; and 137 versus
3 129
days to the third assessment. The p
values for
4 the
log-rank test comparing the entire curves were
5
also obtained for each assessment.
Note that the
6
difference in timing of lesion assessments shows
7
striking statistical significance, with p values of
8 the
same order of magnitude as the claimed
9
difference in progression-free survival.
This
10
finding raises a concern that all or some of the
11
observed progression-free survival difference were
12
caused by this systematic bias in lesion assessment
13
times.
14
[Slide]
15
These are the times to the first
16
assessment curves. Please note
that these are not
17
time to disease progression curves.
The blue curve
18
represents the combination therapy and the red one
19
represents DTIC alone. On the
horizontal axis we
20
have the time from randomization to the first
21
assessment in days. On the
vertical axis we have
22 the
proportion of patients who had the first
82
1
assessment later at a given time.
As seen here,
2 the
blue curve stayed above the red curve all
3
along, suggesting a systematic delay in the first
4
assessment time in the combination treatment arm.
5
[Slide]
6
Similar patterns were observed in the time
7 to
the second assessment curves.
8
[Slide]
9
And to the third assessment curves.
10
[Slide]
11
Imbalance in assessment times may have
12
impact in several ways on the analysis of
13
progression-free survival. The
first impact is
14
that bias may be introduced in estimating
15 progression-free
survival. Second, with a large
16
trial even a small imbalance between treatment arms
17 may
lead to incorrect conclusions.
18
[Slide]
19
This slide illustrates the first impact.
20 A
hypothetical example is given here to illustrate
21 how
imbalance may be introduced in estimating
22
progression-free survival. In
this example,
83
1
suppose that the actual day of disease progression
2 was
day 35 post randomization for both patients,
3 one
in the control arm and the other in the
4
experimental arm. However, the
first assessment
5 for
the patient in the control arm was on day 42
6 and
for the patient in the experimental arm it was
7 on
day 48. The recorded days of
disease-free
8
progression will be on days 42 and 48 respectively.
9
These recorded days, not day 35, will be the
10
observations used in the analysis.
11
[Slide]
12
This slide illustrates the impact of
13
systematic bias by a simulation study.
In the
14
simulation study progression-free survival was
15
generated from identical distribution in both arms
16
with a median of 50 days and 300 subjects in each
17
arm. However, a systematic
increase by 2 days in
18
assessment times in one arm was introduced. In 98
19
percent of the 5000 simulations p values were less
20
than 0.05. This illustrates that
even with a small
21
imbalance in assessment times between two arms the
22
chance of falsely concluding treatment effect can
84
1 be
very high when, in fact, there is no treatment
2 effect
at all, also the chance of incorrectly
3
concluding increases as the sample size increases.
4
[Slide]
5
An additional FDA concern is about missing
6
data. Missing data was observed
in both treatment
7
arms, especially for non-target lesions which also
8 had
an influence on the determination of disease
9
progression. In this study lesion
assessments were
10 not
always performed in planned cycles.
Also,
11
lesions were assessed at baseline or assessed post
12
baseline. In the presence of
missing data bias
13
could be introduced in estimating treatment
14
effects, especially in an open-label study as this
15
is. This is a common problem in
assessing
16
progression in most of the studies.
17
[Slide]
18
This slide summarizes the progression-free
19
survival findings. The claimed
progression-free
20
survival benefit in the combination therapy over
21
DTIC alone may not be a true finding because of
22
imbalance in assessment times between treatment
85
1
arms. The true progression-free
survival benefit
2 of
the combination therapy over DTIC therapy alone
3 was confounded by imbalance in assessment
times
4
between treatment arms. Thus,
true treatment
5
effect with respect to progression-free survival
6
cannot be isolated. The chance of
falsely
7
inferring progression-free survival benefit could
8 be
high. Even if there was, indeed, no
benefit, it
9
will be magnified by increasing the sample size.
10
Missing data is always a concern in oncology
11
studies evaluating progression as an endpoint. The
12
confidence in the amount of difference in
13
progression-free survival is diminished in the
14
presence of missing data and may allow introduction
15 of
bias, especially in an open-label study.
16
[Slide]
17
Finally from a statistical perspective,
18
this large randomized, open-label study failed to
19
demonstrate the protocol specified primary efficacy
20
based on the overall survival benefit with respect
21 to
the secondary efficacy analysis of
22
progression-free survival because of systematic
86
1
bias in ascertainment. It is not
clear whether the
2
benefit of progression-free survival in the
3
combination therapy over DTIC alone exists. If it
4
exists, the magnitude is uncertain.
Also, there
5 are
multiplicity issues with analyses conducted to
6
support the efficacy. Dr. Kane
will address the
7
clinical relevance.
8 Clinical Relevance
9
DR. KANE: Dr. Yang has provided a
10
detailed assessment of some of the concerns related
11 to
progression-free survival.
12
[Slide]
13
To summarize these concerns, assessments
14 in
this study were done at 6-week intervals.
The
15
progression-free survival difference, however, was
16
only in the range of 2-3 weeks.
The
17
progression-free survival difference is highly
18
statistically significant but may be fully
19 accounted
for by asymmetry in the timing of
20
assessments between the two arms.
The magnitude of
21 the
effect size is uncertain. The real
problem is
22
what is the clinical relevance.
87
1
[Slide]
2
The Division examined all of the secondary
3
endpoints of the protocol for the possibility of
4
patient benefit, given the fact that the overall
5
survival analysis failed.
6
[Slide]
7
We will next look at the response rates
8
among the secondary endpoints.
The data submitted
9 at
the time of the original NDA submission and
10
analysis, as has been presented here, indicated
11
that the Genta investigator-determined responses
12
were derived from an algorithm using tumor
13
measurements from the case report forms.
In that
14
examination, 11.7 percent of patients were reported
15 as
responders to the combination versus 6.8 percent
16
with DTIC alone. The p value for
this difference
17 was
0.018 and the actual difference was just under
18 5
percent.
19
The study protocol also called for a
20
blinded independent review and confirmation for all
21 responders.
The protocol stated that all
22
radiographs, as well as photographs of cutaneous
88
1
lesions, were to be provided to this review group.
2 The
blinded independent reviewers, as you have
3
heard, reported different response rates, 6.7
4
percent response for the combination versus 3.6
5
percent for DTIC alone, a difference of 3.1 percent
6 and
of borderline significance. Ordinarily,
7
adjudication by an independent review is considered
8 to
be the definitive response rate.
9
[Slide]
10
Some of this discordance may be due to
11
technical difficulties, such as providing the
12
independent review group with the appropriate
13
images. However, we must point
out that 5 complete
14
responses, which constituted all of the responses
15 in
the initial NDA submission identified by the
16
Genta site investigators--there were 3 in the
17 combination
arm and 2 in the DTIC alone arm. None
18 was
adjudicated as complete responses by the
19
independent review. Forty-four
percent of the
20
responders by the Genta site investigators were
21
determined as not assessable or unconfirmed by the
22
independent review. For 49
percent there was full
89
1
concordance for the response category between Genta
2 and
the independent review.
3
[Slide]
4
You have also heard that on April 9th--a
5
couple of weeks ago--Genta provided new data on
6
responders. This new data is
being examined.
7
There are problems with data that is developed
8
outside of the study protocol.
There can be
9
ascertainment bias between arms when an analysis is
10 not
prospectively planned. Subsequent
therapies,
11
such as surgery not being part of the protocol
12
treatment, may not be applied symmetrically.
13
[Slide]
14
Turning to duration of response, another
15
secondary endpoint, this is Genta's analysis. This
16
data is skewed data and, therefore, we refer to the
17
median to describe it and the medians are quite
18
similar.
19
[Slide]
20
For durable response rate Genta has
21
provided this analysis. This was
a prespecified
22
secondary endpoint. The
difference was not
90
1
significant.
2
[Slide]
3
Performance status is a measure of
4
functional capacity. There were
no differences in
5
performance status observed between study arms to
6
suggest a benefit for adding Genasense to the DTIC.
7
[Slide]
8
For tumor-related symptoms, there were no
9
differences in symptoms observed between study arms
10
during the treatment.
11
[Slide]
12
This slide introduces the adverse events
13
which represent the toxicity safety endpoint for
14 the
study. You have heard from Dr. Itri that
the
15
grade 3-4 adverse events, the serious adverse
16
events, and the adverse events leading to
17
discontinuation all were increased with the
18
addition of Genasense to DTIC.
Since the DTIC
19
doses were the same, the increased toxicity is
20
likely due to the Genasense.
21
[Slide]
22
This represents the hematologic toxicity
91
1
which you have already heard.
There was more grade
2 3-4
neutropenia and thrombocytopenia on the
3
combination arm.
4
[Slide]
5
For non-hematologic toxicity, all adverse
6
events were more frequent on the combination arm
7
with the addition of Genasense.
8
[Slide]
9
In total, there were 18 patients with
10
upper extremity thrombosis on the combination arm
11
compared to 3 on the DTIC alone arm.
12
[Slide]
13
In summary, the Genasense trial failed to
14
achieve its primary protocol-specified endpoint.
15 No
survival benefit was demonstrated with the
16
addition of Genasense to DTIC compared to DTIC
17
alone. The efficacy of the
control arm, DTIC
18
alone, is consistent with that of other studies.
19
[Slide]
20
Looking again at the secondary endpoints,
21
these are usually considered to be exploratory and
22 for
progression-free survival there is no precedent
92
1 for
progression-free survival as evidence of
2
clinical benefit for metastatic melanoma. This may
3 not
be a true finding. The progression-free
4
survival difference between the two arms may be 13
5 or
25 days depending on which censoring technique
6 is
chosen for missing data. The clinical
relevance
7 is
uncertain.
8
[Slide]
9
For response rate, the difference from
10
DTIC alone may be in the range of 3-5 percent. No
11
complete responses in the original NDA submission
12
were confirmed by the independent blinded review
13
committee. The clinical relevance
of this result
14 is
uncertain. Thus far, response rates in
these
15
ranges have not conferred survival benefits for
16
metastatic melanoma. For the
durable response
17
rate, no significant difference.
Response
18
durations were practically identical.
19
[Slide]
20
For performance status no benefit was
21
observed from the addition of Genasense to DTIC
22
over DTIC alone. Symptomatic
benefit was no
93
1
different. There is greater
toxicity with the
2
Genasense combination than for DTIC alone. Thank
3
you.
4 Questions from the Committee
5
DR. PRZEPIORKA: Thank you for the review.
6 We
are now going to open the session for questions
7 to
either the sponsor or to the FDA. Dr.
Cheson?
8
DR. CHESON: I am sure the 11 or
so
9
patients out there still in remission will be
10
disturbed to know that modeling suggests that they
11
shouldn't be there. We have heard
some difficult,
12
complicated analyses of modeling suggesting that
13
what we heard from the elegant presentation from
14 Dr.
Itri and her co-workers might not be as
15
clinically relevant. So, we have
one side
16
suggesting one set of outcomes showing clinical
17
benefit, then the computer modeling and the FDA
18
suggesting perhaps that these are not reliable. I
19 would like to hear from the company, from Dr.
20
Wittes, their side of this spin.
21
DR. WITTES: The issue about the
potential
22 for
bias that can come from interval censoring and
94
1
from missing data we knew about and, in fact,
2
looked at--I need the slide, yes, that is the one.
3
[Slide]
4
In fact, that is why we did some of the
5
sensitivity analyses. These
sensitivity analyses
6
look at three different kinds of things, the
7
missing data and the interval censoring, and the
8
last three are the ones that look at interval
9
censoring, the by-cycle analysis, the assumed
10
progressive disease, back to the scheduled
11
visit--these are three different ways of trying to
12
adjust for the interval censoring.
What you see is
13
some changes in hazard ratio but quite similar to
14
what they were before and then statistically
15 significant
p values.
16
[Slide]
17
Next slide, CC49--the FDA's approach for
18
interval censoring, which is a method due to
19
Michael Fay, is a non-parametric approach. It is a
20
score statistic and, again, the p value remains
21
statistically significant. So,
yes, there
22
certainly is a differential time to measurement in
95
1 the
two groups but analyses that adjust for that
2 time
still show a statistically significant
3
benefit.
4
DR. PRZEPIORKA: Dr. D'Agostino?
5
DR. D'AGOSTINO: Janet, the
procedure the
6 FDA
used is not unreasonable. I am asking a
7
question but it is a set of assumptions that could,
8 in
fact, underlie some of the differences we see,
9 and
I guess the point that the FDA was making, I
10
thought, was that you could chip away at these
11
differences not only in statistical significance
12 but
magnitude of difference, clinical difference,
13 and
that I think should be taken into account with
14 the
interpretation of these techniques.
15
DR. WITTES: I agree, Ralph, but
can we go
16
back to that 49?
17
[Slide]
18
Here is the chipping away. I
mean, the
19
chipping away is to look at both the interval
20
censoring and the missing data. I
think if you
21
approach four, which is the one that is most
22
chipped, if you look at what that does, it is the
96
1
Michael Fay approach to interval censoring plus a
2
very conservative method for missing data, and let
3 me
describe that a little bit because I think it is
4
important to know what happens here.
5
There are basically three kinds of missing
6
data. There are those that Dr.
Itri showed where
7
there is an assessment, it is clear and then you
8
don't keep on looking at that--the no lesion. That
9 is
one source. There is another kind of
missing
10
data where you have an assessment.
At the next
11
assessment you don't measure that lesion and then
12
subsequent to that you do measure it and there is
13 no
progression. So, to me, that isn't
really
14
missing. If you take away those
two and leave the
15
missing data where you really can't know whether
16
there is an assessment or not, this method becomes
17 an
0-3 again. So, I think if you chip it
away you
18
still get evidence of benefit in progression-free
19
survival.
20
The other thing to remember is that from
21 the
point of view of complete responses there is no
22
issue at all about either interval censoring or
97
1
missing data.
2
DR. PRZEPIORKA: Dr. D'Agostino?
3
DR. D'AGOSTINO: But just again
though, we
4 are
left in the dilemma of how do you respond to
5 the
data as collected, as the assessments were made
6 and
so forth, and there is uncertainty in terms of
7 how
comfortable some of us are with the p values.
8 I
think also with a large study you can generate
9 very
large p values with small differences and
10
maybe some of that is here also.
Again, p values
11 are
important but there is clinical significance
12 the
way these numbers draw closer together by, I
13
think, relatively comfortable assumptions that is
14 of
concern I think.
15
DR. WITTES: I think someone else
should
16
address the clinical significance.
17
DR. PRZEPIORKA: Dr. Temple?
18
DR. TEMPLE: Janet, one of the
things
19
about 0.003 is that you don't worry about
20
adjustment for multiplicity and stuff like that.
21 It
kind of blows you away. But with the
smaller p
22
values that you get from some of the other things
98
1 you
did that might become an issue. Do you
have a
2
view as to how one should take into account the
3
fact that this is not the primary endpoint? It is
4 one
of at least several things one could have done.
5 What would you say the right kind of
adjustment
6
would be in a case like that, assuming that some of
7 the
closer to 0.05 p values were the ones that
8
might count?
9
DR. WITTES: Yes, I don't know the
answer
10 to
that. I mean, if the question is what is
the
11
type-1 error of this study, I think one can't
12
really answer that question. Of
course, one looks
13 at
consistency. One worries about the
potential
14 for
bias and, again, I feel that those complete
15
responses kind of avoid--they become a different
16
kind of criterion. But if you ask
me what is the
17
type-1 error rate, I don't know.
18
DR. PRZEPIORKA: Dr. D'Agostino?
19
DR. D'AGOSTINO: Just again, when
you look
20 at
the secondary endpoints after you have a failure
21 in
the primary endpoint, the whole
22
interpretation--just to reinforce what you just
99
1
said, no one around this table is going to be able
2 to
put a real p value on any of these things that
3 we
have given that the primary didn't turn out to
4 be
statistically significant.
5
DR. PRZEPIORKA: Any other
questions from
6 the
committee? Dr. Hwu?
7
DR. HWU: I have a question for
Dr. Itri
8
regarding the design of this trial, especially the
9
regimen used in this large trial for the
10
experimental arm. The initial
scientific
11
indication of this incremental improvement in the
12
treatment of melanoma was based on the Phase 1 and
13 2
trial, which was published in Lancet by Jansen
14 and
colleagues in 2000. The Phase 1 and 2
trial
15
design was extremely careful.
They screened the
16
patients who had shown in tissue increased
17
expression of Bcl-2. Also, the
pharmacokinetic
18
study was done very carefully and was a clinical
19
correlate of the tissues at the level of decrease
20 of
Bcl-2 expression. Also, there is
correlation
21
with responses.
22
The regimen used in that trial was very,
100
1
very reasonable in design. They
were giving
2
infusion on day 1 to day 14, continuous infusion.
3
Clearly by day 5 the Bcl-2 expression was maximally
4
down-regulated. DTIC was given
from day 5 to 9 in
5
divided doses of 200 mg/m
2 every day for 5 days.
6 In
other words, when DTIC is infused in patients,
7 the
G31 and 39 Genasense treatment also continues.
8
Now, the response was clearly shown in the
9 M1a
group, the patient with skin metastases or
10
lymph node metastases. No
response was noted in
11 the
lung or visceral organs. However, the
12
responses were impressive. Even
one patient who
13 had
prior DTIC had a partial response.
14
My question to Dr. Itri is why we changed
15 the
protocol which has clearly demonstrated
16
scientifically that it worked as a target therapy
17 and
now we have changed to 5-day infusion of
18
Genasense followed by 1 infusion of DTIC and even
19
forgot that DTIC is not an active chemotherapy
20
agent by itself; it requires hepatic activation to
21 its
active metabolite MTIC? We do know that
the
22
company provided a pharmacokinetic study that, yes,
101
1 the
continuous infusion of Genasense that achieved
2 the
maximal plateau level within 10 hours if you
3
were giving it at the 7 mg/kg/hour rate--I am
4
sorry, per kilogram--however, once the infusion
5
stopped, less than 10 hours later the level for the
6
Genasense clearly dropped to what we call the
7
biological active level of I think 1 mcg/L.
8
So, I would like to know before we launch
9
this large Phase 3 trial are there any other Phase
10 2
studies, other than the safety, well-tolerated
11
5-day infusion by 1 day of DTIC, that have shown
12
that there is tissue correlation and also efficacy
13 as
shown by the Phase 1 and 2 trial. Thank
you.
14
DR. WALL: I am Dr. Ray Wall, from
Genta.
15 Dr.
Hwu, I think I will take a whack at those
16
questions since I was around at the time the study
17 was
done and took it with Dr. Haluska down to FDA,
18 and
Dr. Itri was not.
19
The Genasense study was informative.
I
20
would point out to the committee it was a Phase 1
21
studies that looked at a couple of different doses
22 of
Genasense at that time and also looked at a
102
1
couple of different routes of administration, both
2
subcutaneous administration as well as continuous
3 IV
infusion. So, it was Phase 1 and it was
a total
4 of
12 patients. It was published in Lancet
in year
5
2000.
6
What we had found both in that study and
7
also in a variety of other studies, some of which
8 are
presented in your briefing book, are a couple
9 of
things with respect to the biological activity
10 of
the drug. The pharmacokinetics are very
well
11
described and I will skip them for the time being.
12
What we see in human tumor cells
13
subsequent to administration of Genasense is that
14 the
onset of the down-regulation of Bcl-2 at the
15
protein level, not the RNA level but of the protein
16
level seems to occur at least as early as day 3 and
17 is
maximal at day 5. The one other thing
that had
18
been a very, very important driver of our clinical
19
schedule is that the continued administration of
20
Genasense beyond day 5, if the dose is not changed
21 you
do not seem to get any further down-regulation
22 of
Bcl-2 at the protein level.
103
1 I didn't bring a lot of blots in
my back
2
pocket here but I think I can show you one from a
3
melanoma patient, if I can have MA-25, please?
4
[Slide]
5
This is a Phase 1 study looking at a very,
6
very low dose. This is a dose
that is about 20
7
percent of our Phase 3 doses, and this is from the
8
Jansen study looking at continuous infusion over a
9
14-day period. Again, you see
maximal
10
down-regulation by about day 5 and, despite the
11
fact that the infusion is continued, you don't see
12 any
further decrease in the down-regulation of
13
Bcl-2 protein effect. These are
human tumor cells,
14
serial biopsies of patients with malignant
15
melanoma.
16 So, from these data and from other
data
17
that have been obtained from a variety of other
18
patients and other cells, both malignant cells as
19
well as normal cells, that molecular information
20 has
been used to drive the clinical studies,
21
including the one that you have seen today.
22
So a couple of things, one is we use
104
1
rather short infusions to maximize the
2
down-regulation of Bcl-2 so that that effect is
3
maximal at the time that chemotherapy is
4
administered and we don't continue beyond. Dr.
5
Tony Tolcher, who actually is in the audience, has
6
done some of the best scheduling work but, again,
7
modeling preclinically, suggesting that when you
8
administer Genasense with chemotherapy the effect
9 is
maximized when you administer Genasense in
10
advance of chemotherapy. The
second thing that he
11 has
shown is that there seems to be no advantage to
12
overlapping Genasense with chemotherapy.
The final
13
observation from the Tolcher lab is that if you
14
reverse the sequence, if you give Genasense after
15
chemotherapy is administered, then you basically
16 eliminate the synergistic effect. So, the
17
constellation of these kinds of pharmacodynamic
18
events have driven the schedules that you have seen
19
here today in Phase 3.
20
DR. PRZEPIORKA: Before you leave
the
21
podium, just one more question to follow-up, how
22
long is the effect once the infusion is
105
1
discontinued?
2
DR. WALL: As was pointed out, the
3
half-life of this drug is around 3-4 hours and
4
fundamentally disappears probably by about 10-12
5
hours. The data are a little
fragmentary and
6
mostly derived from in vitro cell culture studies,
7 but
it does look like the half-life of Bcl-2
8 protein is in the order of 16 to about 22
hours.
9 So,
you would expect that if you get complete
10
shut-down of Bcl-2 production by knocking out the
11
messenger RNA, then pharmacokinetically within 5
12
half-lives or so you should have no protein within
13 the
cell, and recovery would be equally as rapid as
14
soon as it is shut back on.
15
DR. PRZEPIORKA: Dr. Temple?
16
DR. TEMPLE: Dr. Itri or others,
there was
17 a
lot of discussion about the responses.
You
18
clearly had two different ways of calculating
19
responses, one based on investigators and the other
20
based on RadPharm. My presumption
was that the
21
RadPharm analysis existed because the study was
22
open and that is a common thing to do, to have a
106
1
blinded analysis of the response rates.
In your
2
presentation though I gather you were disappointed
3
with what RadPharm produced and you considered it
4
inaccurate. Could you clarify the
intended role,
5
what happened and whether you think there ought to
6 be
a further blinded analysis, or what?
This is a
7
somewhat unusual situation and it wasn't clear what
8 the
original intent was. As Dr. Kane said,
usually
9
when you have a group like that, they are the
10
primary analysis. Was that not
true? Just what
11 was
the arrangement?
12
DR. ITRI: That was not true here.
13 DR. TEMPLE: Then why did you do it?
14
DR. ITRI: The response per
statistical
15
analysis plan was RECIST measurements based on
16
investigational site measurements that were then
17
calculated by computer to see whether or not they
18 met
criteria for a partial response or a complete
19
response. That is primary and
that is what is
20
reported.
21
The use of RadPharm--and I think it is
22
important to note that it was only responding
107
1
patients that they looked at so if we were going to
2
rely on RadPharm to actually give us a response
3
rate for the study they would have had to review
4
everyone. They were really used
by us for quality
5
control purposes. We wanted to
make sure that the
6
relative numbers we were seeing were consistent
7
with what has been reported in the literature; that
8 the
concordance rates weren't really out of whack.
9 I
think that the best person to speak about this is
10 Dr.
Ford because he can put this into real context
11 and
explain what the literature shows, and really
12 how
we stack up in terms of other studies that have
13
utilized a similar review. Is
that okay?
14
DR. TEMPLE: Anything is okay, but
you
15
have two somewhat separate, somewhat different
16
calculations based on the ones that went to them.
17
Usually that is distressing and I guess the further
18
question I have is do you have some way of
19
resolving this? Should this be
subjected to
20
another blinded review where people get the whole
21
files, or something? I mean, as
it is, you can see
22 why
it is sort of troublesome. For example,
all of
108
1 the
complete responses they didn't think were
2
complete responses although you feel that complete
3
responses are very important for the reasons Dr.
4
Cheson mentioned earlier. That is
troublesome, and
5 now
you have found more which we haven't had a
6
chance to review yet, but the same problem could
7
arise there too. So, it does seem
important to
8
figure out what it all means.
9
DR. ITRI: I really think you need
to talk
10 to
Dr. Ford about this.
11
DR. TEMPLE: Whatever you like.
12
DR. ITRI: But the other issue is
that,
13 you
know, if the agency would like us to submit
14
these x-rays for review and if that would make you
15
more comfortable, we would be totally willing to do
16
that. We believe that what is
being called lack of
17
concordance really relates to the fact that Dr.
18
Ford is going to elucidate now.
And, it would not
19 be
a problem; we would be so happy to sit with
20
anyone and give you the clinical data that supports
21
this because these are real and the patients are
22
alive, most importantly. So, we
would welcome a
109
1
chance to sit down and review these x-rays.
2
DR. TEMPLE: While you are at
that, that
3 is
the second question I was going to ask you and
4 maybe
you want to answer them both. The
survival
5
curves don't seem to have different tails on them.
6 So,
I am a little confused about where the
7
long-term survivors you are referring to come from
8 if
they are not in the survival curve, or maybe the
9
curve has been extended.
10
DR. ITRI: We provided update
survival
11
information to the agency--
12
DR. TEMPLE: I just need the one
you
13
showed though.
14
DR. ITRI: Well, that was an early
cutoff
15 so
we don't really know what the tail is doing.
16
That was the 7-month median.
17
DR. TEMPLE: It is really Dr.
Cheson's
18
question I am following up on, if there were a
19
small subset of people that got really important
20
responses, wouldn't you see a difference in where
21 the
tails end up?
22
DR. ITRI: It might be too early
to see it
110
1 on
that curve.
2 DR. TEMPLE: Well, that means they are in
3
both groups then. There are
long-term survivors in
4
both groups. Is that right?
5
DR. ITRI: There are some
long-term
6
survivors.
7
DR. WITTES: It depends on the
nature of
8 the
censoring, where the censoring is. So,
some of
9
that could be showing up before the edge of the
10
tail occurs because they haven't been followed long
11
enough. I mean, the fact that
they come together
12
doesn't eviscerate the point. You
have to look at
13
where the specific events occurred relative to
14
censoring.
15
DR. TEMPLE: That is fair
enough. There
16 was
reference to at least some people who were
17
getting really spectacular benefits and I would
18
have thought that would show up as curves where the
19
flat part is here on one and the flat part is below
20 on
the other.
21
DR. WITTES: They are censored.
22
DR. TEMPLE: They are censored
because
111
1
they haven't been on long enough--
2
DR. WITTES: It is like three
years.
3
DR. FORD: Well, thank you very
much for
4 the
opportunity to address the committee on this
5
topic, the topic at hand being how does an
6
investigator who sees the patient on a daily basis
7 or
a regular basis assess response compared to how
8 an
independent review facility would assess
9
response in the same patient in a remote location,
10 not
having access to the clinical information.
11
I think that there is little written in
12 the
medical literature about this topic, but there
13 are
two particular studies that I would like to
14
review kind of as a background for this discussion.
15 The
first was a study that was published in the
16
Annals of Oncology in 1997. The
author was a
17
radiologist and that was a review of a 100-patient
18
ovarian cancer trial. In that
review there were 24
19
claimed responders who were reviewed by an
20
independent review facility and in that instance
21
there were 14 patients who were concordant, that
22 is,
deemed to be responders by the independent
112
1
review facility and deemed to be concordant with
2 the
investigator.
3
There was a second study that was done,
4
also published in 1997 in the Journal of Clinical
5
Oncology. It was a review of a
renal cell trial
6
where there were 133 subjects who were reviewed.
7 In
that review an independent review facility
8
reviewed those studies and the responses were
9 concordant in 62 out of those reviews. In that
10
article you can see the concordance, that is, site
11
same PR to independent review facility saying PR
12 was
approximately 60 percent, and in the second
13
study it was lower, on the order of 48 percent.
14
Now, with that as a background, there is a
15
significant difference in the methodologies in
16
which those reviews were performed.
That is, in
17
those examples the investigators who enrolled the
18 patients
in the trial were actually part of the
19
review process. A radiologist sat
down with the
20
films, made the measurements and reviewed the
21
images in concert with the physicians who knew much
22
more about that patient, that is, had the
113
1
additional clinical history that the radiologists
2
would have at the time of the review.
3
Now, that as a background, discussing the
4
current study, the current study was a radiology
5
only review. When it was
performed there was no
6
clinical information provided. In
that instance,
7
even in that particular setting the concordance was
8 63
percent. So, 63 percent of the time that
the
9
investigators assessed the response on this trial,
10 the
independent review facility assessed the same
11
response.
12
DR. TEMPLE: When they are
different how
13 do
you know which one is right? When they
are
14
different, non-concordant, how do you decide which
15 one
is right? I am sure I understand that
16
different groups will reach different conclusions.
17
Sometimes these special committees have a
18
tie-breaker when they don't agree. But what is one
19
supposed to do that when they are non-concordant?
20 How
do you decide which is true?
21
DR. FORD: Well, in this
particular
22
setting the investigator-determined response was
114
1
chosen.
2
DR. TEMPLE: When? I mean, was this
3
prospectively defined in the protocol how any
4
discrepancies were going to be handed?
5
DR. ITRI: Yes, it was.
6 DR. TEMPLE: So, the protocol was clear
7
that the investigator-determined conclusion, or the
8
analysis based on the investigator--
9
DR. ITRI: The investigator
measurements
10
were fed into the computer and that is what was to
11 be
used for determination of response.
12
DR. PRZEPIORKA: Dr. Rodriguez?
13
DR. RODRIGUEZ: Yes, this is a
follow-up
14 to
the question by Dr. Hwu because I didn't hear
15 the
response to part of her question, that is, you
16
know, this is a biologically targeted agent and one
17
assumes that one is going to look for the
18
appropriate target or that one would select
19
patients who are appropriate to be treated with
20
this drug. I didn't hear whether
all patients
21
entering on the study were screened, if their
22
tumors were screened for expression of Bcl-2 or if
115
1
there had been an attempt to quantitate category of
2
patients because, obviously, some patients are
3
going to be appropriate for trial and others are
4
not. Was that done?
5
DR. WALL: That is a very good
question.
6 Can
I have slide MA-18, please?
7
[Slide]
8
The challenge with Bcl-2 is the ubiquity
9 of
Bcl-2 expression in melanoma. So, this
is not
10
comparable, for instance, with HER2 expression in
11
breast cancer in which the incidence of expression
12 in
advanced cases is on the order of 20, 25 percent
13 so
that you would not want to treat 100 percent of
14
women. You could theoretically
benefit 25 percent
15 so
the absolute response rate would be 5 percent of
16
your total. In general, we chose
melanoma because
17 of
the very, very high prevalence of expression
18
which in these studies, whether you look at
19
immunohistochemistry, which is the blue bars, or
20
RT-PCR of excised specimen, you are talking about
21 something in the range of 90, 95 percent
expression
22 of
tumors.
116
1
So, the kinds of correlations that you are
2
going to be able to make with respect to
3 over-expression
we thought, going into this study,
4
were going to be extremely limited due to the very
5
high prevalence of baseline expression.
Again, it
6
certainly influenced our choice of melanoma as one
7 of
the early targets for this particular disease.
8
After that it is not clear where you could go if
9 you
were going to look at percentage
10
down-regulation. That meant
serial biopsies of
11
fresh tissues from multiple sites, handled very,
12
very carefully, centrally managed, exponential
13
increases in cost and ability to manage--that
14
simply overwhelmed us as a small company. So, we
15
figured we would pick a big tumor in which would be
16 an
unquestioned level of very, very high expression
17 at
baseline but it did preclude the ability to make
18
subset selections based on--at least at the stage
19 we
were dealing with this in 2000--Bcl-2 expression
20 per
se.
21
DR. PRZEPIORKA: Dr. Hwu?
22
DR. HWU: I agree that choosing melanoma
117
1 as
this malignancy is very important based on what
2 we
know of Bcl-2 over-expression. My
question to
3 you
that you didn't answer is based on your current
4
regimen with some 300 patients.
Have you any data
5 to
show that it clearly reproduced your finding in
6 the
previous Phase 1 and 2 using completely
7
different regimens?
8
DR. WALL: Well, the Phase 1
study, as you
9
know, did not show correlations.
It really was not
10
appropriately powered to look for correlations
11
between baseline Bcl-2 expression and percentage of
12
down-regulation. That is very
difficult to model
13
even preclinically. I am not sure
I am answering
14
your question.
15
DR. HWU: I don't agree that that
is not
16 the
conclusion from the publication. Clearly
the
17 CR
person that has the highest incremental decrease
18 of
Bcl-2 is the percentage of decrease; it is not
19 the
total amount of expression. That is what
I
20
learned from the paper.
21
DR. WALL: I think you need to
keep in
22
mind that it is a Phase 1 study.
That patient got
118
1 a
rather low dose. The majority of
patients were
2
actually not serially sampled.
And, the ability to
3
make inferences with respect to those kinds of
4
correlations with a total N of 12 is I think very
5
problematic.
6
DR. HWU: To make a correction,
the
7
patient got the highest dose level of 6.5 and she
8 had
70 percent--
9
DR. WALL: And that blot was shown
to you,
10 by
the way.
11
DR. HWU: --and the patient had
never
12
received any chemotherapy prior either.
13
[Slide]
14
DR. WALL: Right, and here is the
blot
15
from that patient that Dr. Itri showed.
I think
16 the
major point, however, is with an N of 1 in a
17
sample size of 12 in a Phase 1 study we didn't feel
18
like we could make inferences. I
would say that
19 one
of the advantages of being an oncologist is
20
that you can fall back on issues related to
21
maximally tolerable dose and we felt that the dose
22
used in this study for the Phase 3 study was
119
1
comfortably above the threshold that we needed to
2
achieve down-regulation of Bcl-2, which is a dose
3
just above what this particular patient got. Did
4
that happen in 300 patient? We
don't have that
5
information. The willingness of
patients to be
6
serially sectioned for us to obtain this
7
information on a fresh basis is rather limited and
8 it
was simply not part of the study. It
9
overwhelmed our capabilities in year 2000 and was
10 not
done.
11
DR. PRZEPIORKA: If Dr. Tolcher is
here, I
12
have a question. In the in vitro
studies is there
13 a
threshold amount of Bcl-2 that needs to be
14
down-regulated to in order for the chemotherapy to
15
show synergy?
16
DR. TOLCHER: That is a very good
question
17 and
it is not well addressed. Most of the
models
18
are, you know, somewhat artificial and in vitro
19
versus in vivo really has no strict correlation.
20 We
functioned for a period of time with the
21
assumption that 1 mcg/mL is probably the minimum
22
effective concentration. In
almost all of the
120
1
studies published to date we have a steady state
2
concentration of 5 mcg/mL as an average.
So, based
3 on
the work that was done preclinically, published
4 by
Martin Gleave and others, we are well above what
5 we
would need in the in vitro setting but, again,
6 the
major caution always is that it is hard to
7
relate what are the necessary concentrations in
8
vitro to what are the necessary plasma
9
concentrations for maximal effect.
Does that
10
answer your question?
11
DR. PRZEPIORKA: I guess I was
asking what
12 is
the amount of Bcl-2 intracellularly that we need
13 to
get the level down to in order to see the
14
synergy with chemotherapy.
15
DR. TOLCHER: An excellent
question. You
16
know, the issue is that it is dynamic so one
17
doesn't know necessarily. You are
lowering it so
18
that you essentially are shifting the equilibrium
19 in
favor of apoptosis. You clearly do not
need to
20
extinguish all the Bcl-2 to have a pronounced
21
effect in vivo. In fact, you
probably only have to
22
drop it below some threshold and that threshold is
121
1
unknown. It gets more complex as
well in that
2
there is a diversity of Bcl-2 expression in
3
different tumors.
4
So, what I would say is that
it is not
5
necessarily a simple equation where you have to
6
drop it below X amount. It may be
very dependent
7 on
the chemotherapy that is given with it.
So, it
8 is
not clear. The certainty is that we do
know
9
that you do not have to extinguish all the Bcl-2 to
10
have a synergistic effect preclinically.
11
DR. PRZEPIORKA: Thank you. Dr. Bishop?
12
DR. BISHOP: I am relatively new
to all
13
this so I don't know if this question is
14
appropriate or not but I am going to turn it to Dr.
15
Kirkwood and Dr. Haluska. You
made passionate
16
pleas for the treatment of metastatic melanoma in
17
this randomized study. So, would
this treatment,
18
Genasense plus DTIC, become the standard of care in
19 the
control arm for future CALGB and ECOG studies
20
respectively?
21
DR. HALUSKA: I think that is a
reasonable
22
proposition. I think that the
context of this
122
1
trial's conduct is that we have never shown any of
2
these improvements and I think we shouldn't lose
3
site of the fact that we are chipping away, as has
4
been articulated, at numbers that have not been
5
able to be chipped at away before because they
6
haven't existed. So, I think that
that is a
7
decision to be made by the community, but an
8
improvement clinically like we have seen should be
9 the
standard against which other stage 4 therapies
10
will be compared. I think that is
reasonable.
11
DR. BISHOP: Let me make it more
specific
12
then. In your future randomized
trials will this
13
become the control arm? The data
with DTIC we know
14 is
not very impressive yet that is the community
15
standard outside of immunotherapy.
So, as you plan
16
your future trials, and you believe these results
17 are
impressive enough, will that become the control
18
with which new therapies will be developed and
19
compared to?
20
DR. HALUSKA: I wish we had new
therapies
21 to
compare to now. I would have to say that
it is
22
hard to view the future when those new therapies
123
1
become available. The landscape
for drug
2
development for melanoma right now includes other
3
targeted therapies. None of them
is at the stage
4
where we would choose a comparison arm like this
5 but
the short answer to your question is yes.
6
DR. PRZEPIORKA: Dr. Kirkwood?
7
DR. KIRKWOOD: I agree with
Frank's
8
conclusion so I think this is an incremental
9
advance. I think this is
something that we have
10
been trying to do in the studies that I reviewed
11 and
have not succeeded to do. Obviously, if
one
12
were going to take survival as an endpoint in a
13
future study it could still be dacarbazine but I
14
think that we are talking here about response rate
15 and
we don't have anything that has reliably before
16
shown response rates and complete response rates
17
incrementally advanced as this has, with the single
18
exception of high dose IL-2, which we have spoken
19
about previously.
20
DR. HALUSKA: Something else
occurs to me.
21 I
don't think it is the agency's job to support our
22
research endeavors strictly. I
mean, their job is,
124
1 as
I understand it, to make agents available for
2
public consumption. But, clearly,
these decisions
3 do
affect our research and we have, for reasons
4
that are not clear to any of us who work in
5
melanoma, been very unsuccessful in improving
6
overall survival. I don't believe
that as long as
7 we
hold that out as the only endpoint that we can
8
meet that we are going to meet it because it has
9
been such an impediment. But
there is nothing in
10 my
mind that prevents small improvements in these
11
sorts of endpoints from accumulating with addition
12 of
different agents and you can envision a variety
13 of
other things that you could add Genasense to
14
that might also prove additive to the responses and
15
progression-free survival we have seen today.
16
Ultimately, that is how I think we are going to
17
make real progress with the survival endpoint in
18
this field.
19 DR. PRZEPIORKA: Dr. Redman?
20
DR. REDMAN: Thank you but Dr.
Kirkwood
21
answered my question.
22
DR. PRZEPIORKA: Other questions
from the
125
1 committee?
Dr. Tolcher, could you please come back
2 to
the microphone? We need to have you
identify
3
your affiliation, please, for the record.
4
DR. TOLCHER: Sure. I came actually today
5
without personal compensation by Genta or any of
6 the
pharmaceutical sponsors, although my travel
7
arrangements have been paid for Genta.
I have been
8 the
principal investigator on three clinical
9
studies and have acted as an occasional advisor to
10 Genta
and Aventis and have been compensated with
11
honoraria for those less than $10,000.
12
DR. PRZEPIORKA: Thank you. Hearing no
13
other questions, we will break for ten minutes and
14
return at 10:40 to begin the open public hearing.
15 We
will need to begin the afternoon session on time
16 so
please be on time for the next part.
17
[Brief recess]
18 Open Public Hearing
19
DR. PRZEPIORKA: If we could have
the
20 doors
closed, please, we will begin the second half
21 of
this session. This is the open public
hearing
22 and
we actually had many individuals who wanted to
126
1
speak this morning and, in order to give everyone
2 who
is registered a chance to participate and to be
3
fair to all, we will be following some fairly
4
strict procedures. We have a
timer. Each speaker
5 has
been allotted two minutes and at the end of the
6 two
minutes we will ask that speaker to return to
7
their seat and the next speaker to immediately
8
begin. Due to considerations of
fairness and these
9
restrictions of time, only speakers who have
10
registered will be allowed to come to the podium.
11
Both the FDA and the public believe in a
12
transparent process for information gathering and
13