DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ONCOLOGIC DRUG ADVISORY COMMITTEE
Donna Przepiorka, M.D., Ph.D., Chair
Johanna M. Clifford, M.S., RN,
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.
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)
Richard Pazdur, M.D.
Grant Williams, M.D.
Robert Temple, M.D.
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
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
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
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
Clinical Review, Kevin Ridenhour, M.D. 254
Statistical Review, Rajeshwari
Sridhara, Ph.D. 265
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
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
is in that capacity that I speak to you today,
1 but it is also in my capacity as an individual who
2 has been personally affected by the specter of
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
that the school that they go to and, in fact, the
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
What does this mean? That this
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
New England Journal of Medicine proving the
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.
Bernstein is a fourth grade teacher from a small
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
obligations in my district require me to actually
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
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
six-year battle with cancer.
However, due to
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
that achieved the most dramatic overall response.
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
Genasense and other new drug applications that can
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
Evaluation and Research present no potential for a
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
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
investigator-initiated study of a competing
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
other products or firms not already on the
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
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,
Director, Division of Oncology Drugs.
1 DR. FARRELL: Ann Farrell, clinical team
2 leader for Genasense.
3 DR. KANE: Robert Kane, medical reviewer.
4 DR. YANG: Peiling Yang, statistical
6 DR. BUKOWSKI: Ron Bukowski, medical
7 oncologist, Cleveland.
8 DR. BISHOP: Michael Bishop, Experimental
9 Transplantation, Immunology Branch, National Cancer
11 DR. HWU: Wen-Jen Hwu, medical oncologist
12 at the Memorial Sloan-Kettering.
13 DR. TAYLOR: Sarah Taylor, University of
15 DR. REAMAN: Gregory Reaman, George
16 Washington University and Children's National
17 Medical Center.
18 DR. REDMAN: Bruce Redman, University of
20 MS. CLIFFORD: Johanna Clifford, FDA,
21 executive secretary for this meeting.
DR. PRZEPIORKA: Donna Przepiorka,
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
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
20 MR. MCDONOUGH: Ken McDonough, patient
DR. GRILLO-LOPEZ: Antonio
1 Neoplastic and Autoimmune Diseases Research
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
phone calls, and advice on some of the most
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
demonstration of an improved survival as the gold
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
rates. Please member that since
this drug is added
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,
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
PFS progression-free survival requires rigor.
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
clinical relevance of the effect? This
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
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
Genasense in combination with dacarbazine for the
1 treatment of patients with advanced malignant
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.
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.
20 In addition to our distinguished speakers,
21 we are fortunate to have with us today a number of
experts in the field of melanoma,
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
review of radiographic studies. I
1 would like to now invite Dr. John Kirkwood to the
3 Melanoma Overview
4 DR. KIRKWOOD: Thank you, Loretta.
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.
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.
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
been used for the study to be discussed today.
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.
IL-2 responses were noted in 16 percent of
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.
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
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.
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
equivalent to dacarbazine. The
committee did not
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
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.
I would conclude that metastatic melanoma,
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.
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.
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
resulted in approximately 70 percent reduction in
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.
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
20 Patients received either DTIC at the
21 standard dose of 1000 mg/m
2 or the same dose of
DTIC preceded by a 5-day continuous infusion of
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
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
best interest of the patient, in consultation
1 with the treating physician.
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.
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.
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.
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.
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
reduction of DTIC.
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
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
survival; baseline differences in prognostic
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
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
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
historically reduced response rates in other
1 studies by 25-50 percent when compared to
2 investigator determinations.
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
with the site measurements. These
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.
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.
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.
In the next case, which demonstrates how
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
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
treatment. The FDA did not review
any of these
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
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
evaluations of this nature. Two
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.
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
included assessments which occurred in the
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.
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
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
been documented by duplicate CT scans using the
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.
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
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.
20 The evolution of the complete responders
21 on this study is shown in this slide. The two
responding DTIC patients are shown in yellow for
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
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
first quartile. As you can see,
the medians are
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
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.
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
died without documented disease progression
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.
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.
20 FDA has performed four analyses using
21 interval censoring techniques. Hazard ratios are
reported for this method. Approach number
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.
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.
In order to address FDA concerns about
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.
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.
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.
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
Safety data were
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.
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.
20 Neutropenia exhibited a similar pattern as
21 thrombocytopenia. The incidence of grade 3-4 and
serious events was increased in the Genasense arm.
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.
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
related to the overdose. Both
patients went on to
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.
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.
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
results; and demonstrated compelling clinical
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
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.
16 Clinical Benefit Summary
17 DR. HALUSKA: Thank you, Dr. Itri.
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
overview and some context for the clinical trial.
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
randomized, prospective trial, albeit with
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.
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
rate. The overall response rate
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
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
to their oncologist without having been told
1 that their disease is progressing. This, to my
2 mind, is clinical benefit.
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.
To summarize that, patients value
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
that Carey Kilbridge and my colleagues have
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.
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.
Finally, Genasense is still better
1 tolerated than other alternatives for melanoma
2 patients and, again, I think a review of the
3 literature is germane here.
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.
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
takes into account our genetic understanding of
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.
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
a dispassionate expert, scientifically objective
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.
21 Good morning. My name is Robert Kane. I
the medical reviewer for this NDA and I will be
1 presenting the FDA review along with Dr. Peiling
2 Yang, our statistical reviewer.
4 I would like to recognize our primary
5 review team members for this NDA.
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.
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
well-controlled investigations, generally
1 understood to mean at least two such studies for
2 new drug approval.
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.
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
Here are the currently approved drugs for
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.
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.
21 This NDA contained one main open-label
study, the primary endpoint of which was survival
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.
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
19 Temozolomide was not approved. The study
20 failed to demonstrate the primary endpoint of
21 survival benefit. Progression-free survival, a
secondary endpoint, was of small magnitude at best.
1 No symptomatic benefit was observed and a proposed
2 post hoc 6-month survival analysis was not
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
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
ambulatory infusion pump was required.
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.
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.
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
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
12 Statistical Review
13 DR. YANG: Thank you, Dr. Kane.
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,
secondary endpoint, progression-free survival,
1 was evaluated and the important question is
2 regarding progression-free survival.
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.
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
used by this applicant to represent the
1 assessment date in that cycle.
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.
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?
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.
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
could be caused by differences in the time of
1 lesion assessments.
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.
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
obtained for each treatment arm.
They were 48
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
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
proportion of patients who had the first
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.
6 Similar patterns were observed in the time
7 to the second assessment curves.
9 And to the third assessment curves.
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.
19 This slide illustrates the first impact.
20 A hypothetical example is given here to illustrate
21 how imbalance may be introduced in estimating
progression-free survival. In
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.
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
chance of falsely concluding treatment effect can
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.
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.
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
imbalance in assessment times between treatment
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.
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
progression-free survival because of systematic
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.
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
what is the clinical relevance.
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.
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
radiographs, as well as photographs of cutaneous
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.
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
independent review. For 49
percent there was full
1 concordance for the response category between Genta
2 and the independent review.
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.
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
20 For durable response rate Genta has
21 provided this analysis. This was a prespecified
secondary endpoint. The
difference was not
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.
8 For tumor-related symptoms, there were no
9 differences in symptoms observed between study arms
10 during the treatment.
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.
This represents the hematologic toxicity
1 which you have already heard. There was more grade
2 3-4 neutropenia and thrombocytopenia on the
3 combination arm.
5 For non-hematologic toxicity, all adverse
6 events were more frequent on the combination arm
7 with the addition of Genasense.
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.
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.
20 Looking again at the secondary endpoints,
21 these are usually considered to be exploratory and
progression-free survival there is no precedent
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.
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.
20 For performance status no benefit was
21 observed from the addition of Genasense to DTIC
over DTIC alone. Symptomatic
benefit was no
1 different. There is greater toxicity with the
2 Genasense combination than for DTIC alone. Thank
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
bias that can come from interval censoring and
1 from missing data we knew about and, in fact,
2 looked at--I need the slide, yes, that is the one.
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.
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
certainly is a differential time to measurement in
1 the two groups but analyses that adjust for that
2 time still show a statistically significant
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?
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
chipped, if you look at what that does, it is the
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
20 The other thing to remember is that from
21 the point of view of complete responses there is no
issue at all about either interval censoring or
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
values that you get from some of the other things
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
interpretation--just to reinforce what you just
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.
The regimen used in that trial was very,
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
company provided a pharmacokinetic study that, yes,
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
Genasense at that time and also looked at a
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
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
Bcl-2 at the protein level.
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?
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
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.
So a couple of things, one is we use
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
long is the effect once the infusion is
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
open and that is a common thing to do, to have a
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
21 The use of RadPharm--and I think it is
important to note that it was only responding
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
it is sort of troublesome. For example,
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
alive, most importantly. So, we
would welcome a
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?
DR. ITRI: It might be too early
to see it
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
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
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.
DR. TEMPLE: They are censored
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
deemed to be responders by the independent
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
more about that patient, that is, had the
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
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
setting the investigator-determined response was
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
tumors were screened for expression of Bcl-2 or if
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?
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
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?
DR. HWU: I agree that choosing melanoma
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
mind that it is a Phase 1 study.
That patient got
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
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.
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
used in this study for the Phase 3 study was
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
effective concentration. In
almost all of the
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
drop it below some threshold and that threshold is
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
21 DR. HALUSKA: I think that is a reasonable
proposition. I think that the
context of this
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
hard to view the future when those new therapies
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
research endeavors strictly. I
mean, their job is,
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.
DR. PRZEPIORKA: Other questions
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
we actually had many individuals who wanted to
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