UNITED STATES OF AMERICA

FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

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ONCOLOGIC DRUGS ADVISORY COMMITTEE

73RD MEETING

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Tuesday,

December 17, 2002

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The above‑entitled meeting was convened in the Versailles Room of the
Holiday Inn Bethesda, 8170 Wisconsin Avenue, Bethesda, Maryland, at
12:30 p.m., Donna Przepiorka, Chair, presiding.

[MEMBERS PRESENT]{.underline}:

DONNA PRZEPIORKA, M.D., Ph.D. Chair

DOUGLAS W. BLAYNEY, M.D.

OTIS W. BRAWLEY, M.D.

JOHN T. CARPENTER, Jr., M.D.

STEPHEN L. GEORGE, Ph.D.

DAVID P. KELSEN, M.D.

SILVANA MARTINO, D.O.

JODY L. PELUSI, F.N.P., Ph.D. Consumer Representative

GREGORY H. REAMAN, M.D.

SARAH A. TAYLOR, M.D.

[ALSO PRESENT]{.underline}:

KAREN M. TEMPLETON‑SOMERS, Ph.D. Executive Secretary

JAMES DONALD BRIDGES, M.D. Bexxar Consultant

JAMES E. KROOK, M.D. Bexxar Consultant

SUSAN KRIVACIC Patient Representative

[ALSO PRESENT: (cont.)]{.underline}

GEORGE H. OHYE Industry Representative

SATISH MISRA FDA

STEPHEN LITWIN FDA

GEORGE MILLS FDA

PATRICIA KEEGAN FDA

JAY SIEGEL FDA

[I-N-D-E-X]{.underline}

[Agenda]{.underline} [Page]{.underline}

Call to Order and Opening Remarks 4

Donna Przepiorka, Chair

Introduction of Committee 5

Conflict of Interest Statement 7

Karen Templeton-Somers

Open Public Hearing 9

Introduction to Tositumomab Therapeutic

Regimen ‑‑ Terrye G. Zaremba 48

Sponsor Presentation

Introduction ‑‑ Cindy Jacobs 57

Disease Outcome and Therapy for 59

Low-Grade And Transformed NHL ‑‑

Richard Fisher

Efficacy and Safety Overview: Basis 69

for Approval ‑‑ Cindy Jacobs

Risk/Benefit Assessment ‑‑ James Armitage 94

Questions 107

FDA Presentation ‑‑ Stephen Litwin 140

Questions 167

Committee Discussion and Vote 175

P-R-O-C-E-E-D-I-N-G-S

12:38 p.m.

CHAIRPERSON PRZEPIORKA: Good afternoon. Welcome to the 73rd meeting of
the Oncology Drugs Advisory Committee. I just want to state for the
record and to clarify that this Committee is not a decision-making or a
policy-making body but rather we sit as consultants to the FDA, and we
will use the information presented here as well as our own individual
knowledge base to address questions asked specifically by the FDA
regarding the product being presented this afternoon to us.

The agenda has been handed out or is available at the tables outside. We
will start with a conflict of interest ‑‑ well, actually, we\'ll start
with the introduction of the Committee members, the conflict of interest
statement and open public hearing, the Sponsor presentation, the FDA
presentation, and for those folks who registered to present at the open
public hearing, if you so choose to actually hold your presentation
until after hearing the data presented, we will be very happy to
accommodate you at a second chance for an open public hearing later this
afternoon. Thereafter, we will have a discussion of the questions that
the FDA has submitted to the Committee and take votes, then adjourn.

I\'d like to start then by having introductions for the Committee
members, starting with Mr. Ohye.

MR. OHYE: I\'m George Ohye, industry representative.

DR. MARTINO: Silvana Martino, medical oncologist.

DR. PELUSI: Jody Pelusi, oncology Nurse Practitioner and consumer
representative.

DR. BRAWLEY: Otis Brawley, medical oncologist.

DR. TAYLOR: Sarah Taylor, Medical Oncology, Palliative Care.

DR. BRIDGES: James Bridges, Radiation Oncologist.

MS. KRIVACIC: Susan Krivacic, patient rep.

CHAIRPERSON PRZEPIORKA: Donna Przepiorka, Chief Hematology and
Transplantation, University of Tennessee Cancer Institute.

DR. TEMPLETON-SOMERS: DR. REAMAN: Karen Templeton-Somers, Executive
Secretary to the Committee, FDA.

DR. KELSEN: David Kelsen, Medical Oncology.

DR. CARPENTER: John Carpenter, Medical Oncology.

DR. KROOK: Jim Krook, Medical Oncology.

DR. GEORGE: Stephen George, Biostatistics, Duke University.

DR. BLAYNEY: Doug Blayney, Medical Oncology.

DR. MISRA: Satish Misra. FDA.

DR. LITWIN: Stephen Litwin, Medical Reviewer.

DR. MILLS: George Mills, FDA, Medical Reviewer.

DR. KEEGAN: Patricia Keegan, the Center for Biologics.

DR. SIEGEL: Jay Siegel, Office of Therapeutics, Center for Biologics,
FDA.

CHAIRPERSON PRZEPIORKA: Thank you to all, and our Executive Secretary,
Karen Templeton-Somers, will now read the conflict of interest
statement.

DR. TEMPLETON-SOMERS: The following announcement addresses the issue of
conflict of interest with regard to this meeting and is made a part of
the record to preclude even the appearance of such at the meeting. Based
on the submitted agenda for the meeting and all financial interests
reported by the Committee participants, it has been determined that all
interests in firms regulated by the Centers for Drug Evaluation and
Research and Biologics Evaluation and Research, which have been reported
by the participants, present no potential for an appearance of a
conflict of interest at this meeting with the following exceptions.

Dr. Bruce Cheson and Dr. Bruce Redman are excluded from participating in
today\'s discussion and vote concerning Bexxar.

Dr. Silvana Martino has been granted a waiver under 18 USC 208(b)(3) for
unrelated consulting for a competing firm on unrelated matters. She
received less \$10,001 a year. And for the review of a manuscript for a
competing firm, she received less than \$5,001 a year.

Dr. Douglas Blayney has been granted waivers under 18 USC 208(b)(3) and
21 USC 355(n)(4) Amendment of Section 505 of the Food and Drug
Administration Modernization Act for ownership of stock in competitors.
The first stock in a competitor is valued between \$25,001 and \$50,000.
The other stock holding is valued at less than \$5,001.

Dr. Sarah Taylor has been granted a waiver under 21 USC 355(n)(4)
Amendment of Section 505 of the Food and Drug Administration
Modernization Act for ownership of stock in a competitor valued at less
than \$5,001.

A copy of these waiver statements may be obtained by submitting a
written request to the Agency\'s Freedom of Information Office, Room
12A-30 of the Parklawn Building. We would also like to note for the
record that George Ohye is participating in this meeting as an industry
representative acting on behalf of regulated industry. Mr. Ohye has
reported that he owns stock in Eli Lilly, Schering Plough, Amgen and
Merck.

In the event that the discussions involve any other products or firms
not already on the agenda for which an FDA participant has a financial
interest, the participants are aware of the need to exclude themselves
from such involvement and their exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of
fairness that they address any current or previous financial involvement
with any firm whose products they may wish to comment upon. And I\'d
also like to announce that copies of the disclosure statements are
available for your viewing at the front desk if you\'re interested.
Thank you.

CHAIRPERSON PRZEPIORKA: Thank you and let us now proceed directly to the
open public hearing. We have a number of individuals who have registered
to make comments at this open public hearing. I would ask that they come
forward, beginning with Thom Jones from Pittsburgh, Pennsylvania, and I
would also ask that any of the speakers at the open public hearing also
provide their financial conflicts of interest if they have any. Mr.
Jones?

MR. JONES: Good afternoon. I have nothing new to say to you, no stories
of the drug, other than the fact of my own experience. The most
important thing I do for people, I believe, in this community and in my
hometown of Pittsburgh is simply show up every day. I am, for better or
worse, undeniable proof of the efficacy of Bexxar. It was four years ago
this past Thanksgiving that I was discharged from the University of
Pittsburgh Medical Center, and my doctor said, as I said, \"I\'ll see
you in three weeks,\" because my cancer was recycling every three weeks,
he said, \"Don\'t come back,\" and I said, \"Excuse me?\" He said,
\"Don\'t come back.\" He said, \"We can\'t do anything for you.\"

I was extremely fortunate. I had a great friend who heard a news
broadcast and called a friend of his, and I met Dr. Armitage when I was
looking into a bone marrow transplant at the University of Nebraska, and
I called him and he said, \"Yes, we\'re testing Bexxar and you\'re a
perfect candidate, Thom.\" When I said, \"I won\'t make the four weeks
for the study,\" he said, \"Yes, you will.\" I was privileged to get
Rituxan to buy me the four weeks, and I went to the University of
Nebraska on Christmas Eve, 1998, got my first dose of Bexxar.

I tell this story to a lot of people. I even had a gentleman fly me to
Denver on a plane just to kick my tires to make sure I was telling the
truth and so he could look in my eye when I tell him. Most people
who\'ve been through chemo and anyone ‑‑ I\'m sure most people in here
who\'s seen people go through chemo have seen the ravages. When I tell
them that I went out to Nebraska and that evening my sister and I went
out and celebrated together, although we had to stay at opposite ends of
the table because I was hot from Bexxar, we had a heck of a Christmas
Eve. Turned around and my therapeutic dose fell on New Year\'s Eve, so
we went out and partied again on New Year\'s Eve. This time we took a
table for six and sat far enough away so that we could keep partying. I
tell about that, that I did that the same night that I had the drug and
people don\'t believe me. I tell people all over that I took the drug
and it has had no worse side effect than a glass of water.

I show up in my community, I\'m a volunteer fire fighter, I\'m a
paramedic, I contribute to my community every way I can. I work with my
friends and neighbors and the greatest pleasure it gives me is simply to
show up and watch the look in their eyes when they try and compute this.
I look at people who call me all the time because the word gets out
about Bexxar, and they call and say, \"Can I get this drug,\" and I used
to say, \"It will be there in a minute.\" I don\'t say that anymore.

I don\'t know what has slowed it down. Every year when I go see Dr.
Armitage again, I walk in the door and I say, \"Well, how close is it,\"
and it\'s gotten non-verbal now. He just shrugs and we go on about the
business of getting me checked out. I don\'t know what I can do. I do
know what patients ‑‑ what we all do is we try and make it evident to
everyone else just how undeniable it is what the drug does. I could not
be here, I would not be here. I had three weeks to live and without pain
or suffering Bexxar brought me back. And everything I do for anyone or
with anyone is because of that drug. Thank you all who worked on Bexxar.
I appreciate your time.

CHAIRPERSON PRZEPIORKA: Thank you, Mr. Jones. Next is Erica Hertz from
the Wellness Community.

MS. HERTZ: Good afternoon. My name\'s Erica Hertz, and I\'m the Director
of Patient Education and Outreach for the Wellness Community. For the
record, the Wellness Community receives unrestricted educational funding
from GlaxoSmithKline; however, I receive no funding or compensation for
my presence here today.

By way of background, the Wellness Community is a national non-profit
organization, and we provide free services to people with cancer and
their loves ones by way of support, education and hope. Our programs
include professionally facilitated support groups, educational seminars,
nutritional workshops, exercise, mind-body programs and many others. Our
aim is to help people with cancer and their loved ones regain a sense of
control over their lives, feel less isolated and restore their sense of
hope in the future regardless of the stage of their disease, and we\'ve
worked with over 25,000 people last year alone.

At the Wellness Community, we see a wide range of diagnoses and provide
direct services to thousands of people with lymphoma. We\'ve learned a
great deal from these patients and believe in the importance and value
of an educated and empowered patient. People with cancer often feel
stigmatized, alone and overwhelmed with grief. They feel stronger and
more hopeful when they have more options available to them for the
treatment of their disease. With more than 56,000 individuals diagnosed
with non-Hodgkin\'s lymphoma each year in the U.S., we\'re in great need
of improved treatment options and better access to those treatments. We
have the opportunity to expand the chances that these families have for
a better life with new treatment options, and we feel very strongly
about supporting that opportunity, especially when treatment promises
limited side effects, has potentially long-term efficacy leading to
remission, improved quality of life and other positive outcomes.

I ask today that you carefully consider the plight of patients with
lymphoma and endeavor to understand the psychological and physiological
issues that they face daily. So please take a leadership in approving a
broader range of treatments and then encourage patients to be informed,
empowered and optimistic about the possibility of longer, healthier
lives. Thank you.

CHAIRPERSON PRZEPIORKA: Thank you, Ms. Hertz. We appreciate you being
here today. Next, Patricia and Joseph Bashaw from Brookfield, Wisconsin.

MS. BASHAW: First of all, neither of us have received any reimbursement
or compensation for being here. I entitle this, \"One Bexxar Patient\'s
Perspective.\"

Thank you for giving me the opportunity to speak to you. The reason why
I\'m here is that I was treated with Bexxar in a phase two clinical
trial and went into complete response. I have relapsed, and I have been
told that I cannot have Bexxar again unless the FDA approves it. I will
soon need retreatment and I beg you to recommend Bexxar\'s approval so
that it will be available for me and others.

I retired from the federal government in January 1996 after 28 years of
service. I have four children, two are to be married in the next two
years. I hope and pray that I will live long enough to see and enjoy my
grandchildren. I do live in Wisconsin near Milwaukee. I have no medical
background. Whatever I have learned about lymphoma comes from dealing
with the disease. Obviously, I\'m not an expert in disease; however,
with respect to Bexxar, I consider myself pretty knowledgeable in that I
am only one of a few people in this room who have actually had Bexxar
coursing through their bodies.

In October 1995, I had a mammogram which showed enlarged bilateral lymph
nodes. After appropriate testing, I was diagnosed with stage IV,
low-grade B-cell follicular non-Hodgkin\'s lymphoma. The first and only
treatment I have received is Bexxar in February 1999 as part of a phase
2 clinical trial of previously untreated patients. Bexxar put me into
complete response for two years. I am HAMA-negative, I went from
PCR-positive to PCR-negative. Unfortunately, I went out of remission,
but it has been approximately four years since the treatment, and I\'ve
remained stable.

I know what it is like to have Bexxar. I have experienced being hooked
up to an IV and having the tracer dose enter my bloodstream. Through
scans I saw how the antibodies were initially aimless, and then I saw
how they began to target my lymphoma. I took the treatment dose. I
experienced the restrictions that were in place during the treatment
phase and a few days following treatment. I took precautions at home as
I was instructed. These were not burdensome. I had weekly blood tests, I
saw the counts drop off and then return to normal. I experienced some
fatigue, and this was not a problem. My recovery was uneventful and very
tolerable.

Before my treatment, I spoke with a fellow lymphoma patient who had
numerous chemotherapies and then Bexxar. He told me that if I have
Bexxar without having had chemo, I would not have had any real cancer
treatment experience. He was right. During the entire treatment period,
which was two infusions a week apart and recovery, I would never have
known I had been treated for widespread cancer.

With respect to Bexxar\'s possible thyroid toxicities, I\'ve already
been taking thyroid replacement hormones since the 1970s. This has not
been a problem. For patients who require thyroid replacement because of
Bexxar, a one-a-day tablet is easy to handle. Taking a pill a day is a
lot better than death.

As you know, the nature of this disease is that it is progressive and
terminal. Without proper treatment, I will die. There is no cookie
cutter recipe in the treatment of lymphoma. Lymphoma responds to
treatment such as chemotherapy, how eventually the lymphoma cells learn
to reject, eject treatment poisons from the tumor cells. Eventually,
treatments become ineffective, the tumor cells grow uncontrollably and
the patient dies. Chemotherapy drugs wreak havoc on healthy cells, and
they create long-term disabilities and problems. Because of its
toxicities, I would like to stay away from chemotherapy drugs as long as
I can.

We need more treatment options now, not years from now. It is very
important that treatments be given in a proper sequence and timing so
that bridges are not burned and opportunities lost. This must be
individualized. Until the molecular differences between low-grade
lymphomas and differences in immune systems are identified, this will
remain the case. People search for a perfect cure. This is great, but as
far as I\'m concerned, if I were kept stable for the rest of my life, I
would consider myself cured. I assume all lymphoma patients share this
sentiment. Stable does not kill.

During the clinical trial, I faithfully followed the instructions I was
given and had what I thought an excellent result. I consider Bexxar to
be an ace in the hole in fighting this disease. I was shocked to find
out that even though I tolerated Bexxar so well and had excellent
results that I could not be retreated with the drug because it was not
approved. I cannot have Bexxar even though it is my choice of
retreatment and that of my oncologist.

It makes absolutely no sense to me that I may be forced to take a
probably more toxic therapy or therapies for which I have no experience,
but I cannot take the drug that I have already had and which gave me
good results. I feel like I have been used to help provide an answer in
a Phase 2 trial and then summarily abandoned and discarded when no
longer useful. How is it right that I am prohibited from taking a drug
that is effective? A two-year remission is not nothing.

It is now almost four years since my Bexxar treatment. These past four
years have been wonderful. I\'ve been able to see all of my children
graduate from college and be successful in their careers. From my
patient perspective, Bexxar is non-toxic, and, I may say, a breeze to
take. I know it can work.

Since I was treated with Bexxar, I am no longer an untreated patient,
and therefore I do not qualify for many of the other treatment
possibilities, the promising drug trials going on now. I understand that
the FDA may have certain questions they would like answered, possibly
through Phase 3 trials. I would also like questions answered but at what
expense? Am I to die sooner and thousands of others while waiting for
the answers? We need options now. It\'s bad enough coping with this
disease but worse knowing that there is an effective treatment that I
cannot have. I need this drug. Please do not fail me and thousands like
me.

From my perspective as a lymphoma patient, Phase 3 clinical trials with
their randomization take advantage of desperately ill people fighting to
stay alive. They make patients succumb to treatment protocols that they
may not want only to be given the possibility of getting a desired drug.
They may wind up burning bridges. The randomization means that patients
wanting a certain drug which is shown to be effective may not even get
the drug after all after going through the whole protocol. Why is it
necessary to randomize double-blinded studies in non-Hodgkin\'s lymphoma
since the results of the treatment can be objectively found on CT scans,
bone marrow biopsies and blood tests?

I believe that at some point, even before all questions are answered
concerning an effective drug, the drug should be available for use. I do
not believe that oncologists and their patients are stupid and unable to
make reasonable choices regarding treatments for their terminal illness.
Please don\'t kill me and thousands of others of us while the research
community is getting questions answered.

I think that the whole study of lymphoma would benefit from a lymphoma
registry similar to that of bone marrow and children\'s cancer
registries. Oncologists could enter data on their patients\' diseases,
treatments used and results so that researchers can study the data and
make recommendations on the overall effectiveness of treatments.

When I was first diagnosed with cancer I did not know if I had months or
years to live. I promised my family, as upset as they were, that I would
do whatever was humanly possible to stay alive and be with them. I want
to keep this promise. Please recommend that Bexxar be approved so that I
and countless others can benefit from this effective drug. We need more
treatments to fight the disease now.

MR. BASHAW: Good afternoon. Thank you very much for the opportunity to
speak to you. You just heard my wife tell you about her fight with
lymphoma and her personal experience with Bexxar. She was diagnosed
seven years ago. I have accompanied my wife to all of her doctor visits,
tests and treatment visits as well as to a large number of conferences
conducted by lymphoma specialists. Two years ago something changed. I
was diagnosed with low-grade lymphoma. I became a lymphoma patient also.

I was with my wife throughout her Bexxar treatment and recuperation. I
saw the good results from Bexxar and felt confident that if the disease
came back she would be able to be retreated. Because of these good
results, she had four excellent years. We were told that some patients
who were treated with Bexxar and then relapsed had been retreated with
Bexxar with excellent results. My wife will need treatment soon, but she
has been told she cannot get Bexxar because it is not FDA- approved,
even though the drug worked well for her. All drugs do not work the same
on all people.

After I was diagnosed with lymphoma, I had radiation treatments because
I was stage II. Most oncologists and radiologists tell me that it may be
only a matter of time before my lymphoma comes back and I will need
treatment. I had thought Bexxar would be an excellent choice for me
because of what I observed for what it did for my wife. Now I cannot get
Bexxar.

As you know, low-grade lymphoma is unique. First of all, it is terminal.
Life expectancy is about eight years from diagnosis, on average. These
statistics have changed little, if any, in the past 30 years. Every
low-grade patient tries the same treatment options, because there are
only so many, and each time one is treated the remission is for a
shorter period. We are just trying to stay alive. Bexxar may keep us
alive a few extra years. Two to three years may not seem like much to
some people, but when one has an average of an eight-year life
expectancy, two to three extra years is huge.

I am 62 years old, and I have had a good life. I have seen my four
children grow up. As bad as the disease is for wife and me, it is much
worse for many young people who have it. We were recently at a lymphoma
conference in Los Angeles, and we met several people with lymphoma who
were in their 30\'s, 40\'s and even in their 20\'s. They have new
spouses, young children and in some cases just starting careers. They
all talked about their treatment options so they can stay alive. Bexxar
might give them another option.

The lymphoma specialists who have spoken at conferences we have attended
have usually spoken about Bexxar as though they expected that the drug
would soon be available. I have never heard a negative word from any of
these physicians about Bexxar. We have asked several of them why they
thought Bexxar had not been approved, and they all said they did not
know. None of them spoke of any negative side effects or any other
reasons they knew why Bexxar had not been approved.

Please recommend that Bexxar be approved. We need it now, not several
years down the road when many of us are dead. It may help thousands of
patients stay alive longer and if we are real lucky help us stay around
until a cure is found. Thank you again for me giving me, a patient, an
opportunity to speak to you.

CHAIRPERSON PRZEPIORKA: Are there any questions?

(Applause.)

CHAIRPERSON PRZEPIORKA: Thank you, Mr. and Mrs. Bashaw. Next is Kent
Halbach from White Bear Lake, Minnesota.

MR. HALBACH: Hello. First of all, I\'d like to thank the Committee for
the service that they perform and for giving me a chance to talk about
my experience with Bexxar. My name is Kent Halbach, and along with my
wife and two teenage daughters, I live in White Bear Lake, Minnesota.
I\'m here on my own behalf. I do not represent any company or
organization. I have no financial stake in any product of company
related to this discussion. I\'ve paid all my own expenses.

When I was diagnosed a little over six years ago with low-grade
lymphoma, I was told that my disease was chronic, incurable and
uniformly fatal. It took a little while before the reality of that
statement sunk in. I was 41 years old, and I was going to die. That
reality permanently changed my decision-making process, and primary
among those decisions would be what treatment to seek. I was told that
regardless of which treatment I selected my life expectancy was likely
to be short. With longevity not attainable, quality of life became a top
priority. So I began my search with that in mind.

After spending countless hours studying clinical trial abstracts and
other data, I decided that Bexxar had the capability to provide what I
was looking for: a treatment that wasn\'t worse than the disease itself.
In March of 1998, my turn came to participate in a clinical trial at the
University of Michigan. By that time, without a CT scan, I could count
well over a dozen tumors in my neck, armpits and groin. Several tumors
in my neck were approximately the size of a half an orange. In addition,
my spleen was heavily involved and had become very enlarged.

The treatment was so simple I could hardly believe it. A tracer dose one
week, some gamma scans on ensuing days to track the antibodies?
migration path and absorption rate, a personally tailored therapeutic
dose the next week, a couple days watching TV and then go home and back
to work. I didn\'t lose any hair, I didn\'t throw up.

Two weeks after the therapeutic dose my platelet count began a one-month
process of dipping down and then going back to normal. A week following
the platelets, the white blood cells did the same thing. These lowered
counts did not result in any infections, illnesses, transfusions or any
other complications. I haven\'t experienced any thyroid problems or any
other long-term side effects so far. My tumors shrank slowly over a
period of a few months, and my spleen returned to normal. A complete
remission was the result.

The before and after CT scans paint a truly remarkable contrast. I set
out to find a treatment that would allow me to maintain a high quality
of life and with Bexxar I achieved that. I have been able to serve as a
volunteer coach for both my daughters\' basketball teams. I have been
able to enjoy a quality of life that I didn\'t think was possible when I
was diagnosed with cancer.

But Bexxar has come with an added bonus: durability. To this day, I have
not required any additional treatment. From my point of view, as a
patient, Bexxar is simple, patient-friendly, effective and durable. It
allows patients to maintain quality of life, dignity and hope. It allows
those who administer it to create a personalized dose for each patient
to achieve maximum effectiveness and minimum collateral damage. The
combination of these attributes make Bexxar a unique option for those of
us who need all the options we can get.

Since I was treated with Bexxar, more than a quarter million others have
been diagnosed with non-Hodgkin\'s lymphoma. A large number of them have
been told that their disease is chronic, incurable and uniformly fatal.
We\'re told that some day we can expect this disease to be treatable,
that we might have a chance at a normal life. The trick, we\'re told, is
to stay alive long enough to see that day. Please allow Bexxar to be
among our treatment options so that we might be able to see that day. I
can\'t prove that it will keep us from dying, but I can tell you that it
has allowed me to keep on living. Thank you.

(Applause.)

CHAIRPERSON PRZEPIORKA: Thank you for your comments, Mr. Halbach. Next
is Pat Haut from Auburn, Michigan.

MS. HAUT: Hi. I want you first off to know that no one paid for me and
my sister to come here. I did this on my own. This is so extremely
important to me.

In 1985, I was diagnosed with non-Hodgkin\'s lymphoma. I went through
eight years of chemo, radiation, massive doses of vitamin A. My
oncologist has sent me to MD Anderson in Houston three times, because he
didn\'t know what to do with me. I also was at Harper in Detroit twice.
The first time I went there they wanted to do ‑‑ it was four years into
my chemo. They wanted to do a bone marrow transplant, they thought I was
a good candidate. When they ran all the tests they found out that my
first chemo damaged my heart. I had 35 percent heart function, so I was
not a candidate for a bone marrow transplant, so I went back home.

And then a few years later, I was on every kind of drug you can imagine.
I spent numerous days in the hospital. I kind of thought I owned Midland
Hospital, that\'s how I much I was in there. Anyway, then my doctor sent
me back to Harper because he thought things were going quite well and
that maybe I would be a candidate for the bone marrow transplant. So I
went back there. I talked to the doctors, went through all the tests,
and they had decided that, well, maybe they could do the bone marrow
transplant on me, my chances were not good. And I turned around and
looked at them and I said, \"The first time you rejected me. What
changed it?\" And they said, \"Really nothing.\" I said, \"Well, thank
you very much,\" and I walked out.

The last time I went to MD Anderson Hospital. My doctor suggested that I
have my bone marrow taken out, and maybe I would change my mind. I had
up to five years, they could freeze it, and I could change my mind.
Well, I never did. But in the meantime, in 1992, in October, I went to
the U of M Hospital and seen Dr. Kaminski, and he ‑‑ there was three of
us that went there, three women, and he looked at us and he said,
\"Which one of you is the candidate?\" I was never very ‑‑ I didn\'t
look like I was sick, but I was. But, anyway, he said I was not sick
enough to go through this, it was not a desperate thing. At the time, my
lymph nodes were so enlarged that I could not wear jeans, my left leg
was so swollen. I had a lot of problems with that. Otherwise I was
pretty good.

Anyway, so I went there, and then I didn\'t hear from him for quite a
while, and my oncologist said I had a ‑‑ I was not getting any chemo
because there was nothing that he felt would do me any good. I had the
best of the worst drugs. Anyway, in \'93, Dr. Kaminski called me and
told me to come down the next day, and I was a candidate for this
experimental drug. I was the 20th patient to have it, and I have not had
another treatment since. I am cancer-free. I go down to see Dr. Kaminski
now once a year. All my tests are done. And at one time, I believe I had
over 200 CT scans in my life. I cannot ‑‑ they cannot get blood out of
me because my veins are no good, but I am still here, and if it was not
for Bexxar I would not be here. I know that. It has given me life, and
that is the most important thing.

People do not realize how sick you get with chemo or anything. With
Bexxar I was never sick. When I took it I was the 20th patient, and I
was there for three weeks. I stayed right in the hospital for three
weeks, but the only time I was in my room was when they did the
treatment, which was one day a week, and then I had to have a scan for
an hour a day for five days. And other than that I was never in my room.
Dr. Kaminski used to leave me a note on my table saying, \"I was here to
see you, but you must be doing well.\" And then I came home for a week
and a half and I went back for a week and then I was in isolation for
one day, but it was wonderful. No one can imagine what you go through
when you go through plain old chemo. Thank you.

(Applause.)

CHAIRPERSON PRZEPIORKA: Thank you, Ms. Haut. Next is Frank Burroughs
from the Abigail Alliance for Better Access to Developmental Drugs. Mr.
Burroughs.

MR. BURROUGHS: Good afternoon. I\'m Frank Burroughs, and I\'m President
of the Abigail Alliance for Better Access to Developmental Drugs. First
let me make it clear that I do not represent in any way or our
organization represent in any way the pharmaceutical industry nor do I
or our organization own any pharmaceutical stock. We represent cancer
patients and only cancer patients and other people with life-threatening
illnesses.

First, I\'d like to dedicate my talk today to Johnny Clark. Texan Johnny
Clark died two weeks ago while he was waiting to get Iressa and Erbitux
that had a significant chance of saving his life like Abigail. You may
have heard of the Abigail Alliance for better access to developmental
drugs in three recent [Wall Street Journal]{.underline} stories, the
[New York Times]{.underline}, the [LA Times]{.underline} and Fox Cable
News and other places, and you\'re going to hear more about us as we
move forward to help save lives.

I\'m here for two reasons. One is to urge the rapid approval of Bexxar
and to make a very important point about Bexxar and other drugs. They
need to be approved sooner, at least conditionally approved sooner for
people who have run out of options. And it\'s not being done. Where\'s
Iressa? People can\'t get Iressa except in a very limited expanded
access program. The slow access to new drugs is nothing short of a
tragedy ‑‑ a tragedy. What if it was your daughter?

Bexxar is another example of a drug that\'s been around for a long time
that needed to get to people sooner. Bexxar\'s been available since 1990
‑‑ yes, 1990. A few people were able to get it in an expanded access
program for a few years, but a lot of people who could have benefitted
from it couldn\'t get it. They ran out of options, they couldn\'t get
it. Their last option was the loss of their lives. Bexxar should have
been at least conditionally approved years ago. Come on, these people
are out of options. It showed efficacy and safety. There was maybe ‑‑
certainly, there was more things to learn about the drug, but imagine if
you had run out of options.

If there is a bad car wreck down the road, guess what happens? Right,
they send out ambulances, they send out the paramedics and they try to
save the lives of those who are in the car wreck. But we\'re not making
an emergency response to cancer patients. Come on. Again, I repeat,
Bexxar should have at least been conditionally approved years ago.

What\'s going on is wrong and it\'s tragic. There are cancer patients
out there that we\'re leaving by the side of the road to die. There\'s
one. I\'m not the only one with this position, though I may be more
vocal than a lot of people. This is just one example, this is a March
letter to the FDA by the ODAC representative back last winter urging the
approval of Bexxar. He also urges better information about new drugs get
to patients and to the public.

In closing, let me say let\'s get Bexxar approved. It should have been
approved conditionally years ago. We have lost lives with Bexxar,
Iressa, oxaliplatin and other drugs that waited and waited to be
approved. We need changes now. We are talking about people\'s lives.
That\'s Abigail one month before she died. She was 21. Iressa had a
significant chance of saving her life. We could not get it. Let\'s
conditionally approve, early conditionally approve, and I\'m not talking
fast track, drugs like Bexxar and Iressa for people like Abigail. Thank
you very much.

(Applause.)

CHAIRPERSON PRZEPIORKA: Thank you for your words, Mr. Burroughs. And
next Mr. Tom McDermitt from Glenside, Pennsylvania, please.

MR. MCDERMITT: Thank for the opportunity to speak here today. I have to
say like the other folks I have not been financially reimbursed by
anybody. I have come here from near Philadelphia, I would have come from
Alaska.

I\'ve been a professional social worker for 26 years, I\'ve been a
professional cancer patient for almost that long ‑‑ 21 years. I was
diagnosed with non-Hodgkin\'s lymphoma in October of 1981, 34 years old,
stage III, follicular small-cleaved and large cell. My tumor was
inoperable, the size of a soccer ball. It had been previously
misdiagnosed as an abdominal hernia. A nine-month protocol of C-MOPP
CHOP radiation resulted in a three-and-a-half-year remission, but the
protracted throwing up was overwhelming, the fatigue was devastating.

My first recurrence in the spring of 1985 presented in the chest and
spine. I was successfully treated with MACOP-B. Side effects: Extensive
nausea, hand burns, mouth sores, intense fatigue. That bought me two and
a half years more. Over the next seven years, I had three more
recurrences and a change in pathology in 1988 to diffuse large cell and
diffuse mixed. During that time, those seven years, I underwent eight
more different regimens of chemotherapy and two different cycles of
radiation. The worst were the sisplatin regimens, the side effects were
even more damaging and included life-threatening infections and very
debilitating fatigue and dizziness, requiring six months of recovery
each time.

During those seven years, the remissions lasted anywhere from six months
to two years, with only a couple of months each of reasonable health.
For the most part, my life had come to a halt. Life had become
synonymous with struggle and survival. By 1992, my body could simply not
take anymore intensive chemotherapy. There was no quality to my life. I
was worn down, I was worn out. I asked my oncologist to simply put me on
less toxic palliative drugs and see how long I could keep the lid on.
Clearly, I was prepared to die rather than endure any more intensive
treatment, and I mean that. My pathology must have been fluctuating
slightly at that point back and forth as I was able to comfortably
survive two more years on the palliative drugs before the cancer became
pretty much resistant.

I was literally in the process of trying to accept that my time was up
when my doctor heard about two different antibody trials. After
researching the information, I decided to go with Bexxar with Dr.
Kaminski at Michigan. Sure I was apprehensive, but I wanted to try it
because of the compelling early results and certainly for me the allure
of few side effects. I was surprised by how well I treated the anti-B1
radioimmune therapy. I experienced only slight nausea and moderate
fatigue.

Following my return home, my platelets were diminished but not
seriously. I enjoyed 14 months of remission with a return to health.
But, hey, when the cancer returned during the summer of 1996 I was only
too willing to go back to Michigan and try again. That August again I
only experienced some very minor discomfort with the treatment. After my
return home there was the usual platelet loss, a few weeks of moderate
fatigue for about two months. As of now, I am very pleased and touched
to say that it\'s been six years, four months and counting since I have
been lymphoma-free. That\'s almost twice as long as I\'ve gotten from
any other remission by chemotherapy. I never thought it was possible, I
never thought I could get that kind of extended remission.

I say lymphoma-free because I developed significant side effects ‑‑
excuse me, I developed significant bladder problems, bladder cancer in
1995 from all the toxic chemotherapy. That has required minor surgery
every year as well as bladder installations. Thus began a parade of
long-term side effects from all those regimens, including very severe
damage to my bladder as well forcing me over the last two years to
remain fully catheterized at least 85 percent of the time, some loss of
hearing and balance, a compromised immune system, recent diagnosis of
osteoporosis.

You know, I think we all have come to realize that the definition of
survivorship has expanded significantly. It\'s not just about physical
survival and longevity anymore. Now we survivors are just as concerned
about the quality of our lives during treatment. New choices in
treatment have allowed us to pretty much get beyond that old notion of,
\"Look, just quit complaining and be grateful your cancer can be
treated.\" We\'ve moved beyond that, folks.

In addition, we know that survival is not necessarily a single stage or
outcome. Quite often it is a chronic illness extending over periods of
time with remissions, not cures, and it may lead to secondary cancers as
well. So coping with the physical and emotional effects may extend over
several years now. Accordingly, using the least invasive, most tolerable
yet effective treatment is even more vital now. So, yes, we do want
choices, and we are grateful for them, and we do welcome the opportunity
to have the alternative of Bexxar.

So this is my story with cancer and with Bexxar and 131. Back in 1995,
it literally gave me life, another choice other than dying. Over the
last seven years, it has given me the opportunity to have a productive
and gratifying life and the realistic hope for more. But, you know,
probably more than anything for me just the sheer pleasure of being able
to have a successful treatment without the grueling side effects and the
tremendous worry, anxiety, fears they generate, both in the short-term
and the long-term.

My work consists entirely now of counseling cancer patients, running
support groups, conducting coping seminars. I know the terrain of cancer
recovery. I know what patients struggle with. I know their stories, and
their stories are not unlike any stories that you\'ve heard here today,
except there\'s one difference, and that difference is those people
would absolutely crave the opportunity to have the kind of treatment we
were blessed with.

All the stories, all the cancer stories you hear are going to move you.
You know that, I know that and only hope that they go beyond that today
and provide some real impact, and along with the consideration of the
other data you have, move you to strongly recommend approval of this
treatment. Thank you.

(Applause.)

CHAIRPERSON PRZEPIORKA: Thank for being here, Mr. McDermitt. Next is
Leonard Greer from Rye, New York.

MR. GREER: Good afternoon, ladies and gentlemen. My name is Leonard
Greer, I\'m 64 years of age, and I live in Rye, New York. I participated
in the clinical trials for Bexxar in January 2000. I\'m appearing at
this hearing at my own expense.

My appearance today is because of as a result of receiving one treatment
of Bexxar almost two years ago, I am in complete remission. This was
achieved after multiple chemotherapy sessions failed to successfully
treat my cancer.

In September 1998, I was diagnosed with stage IV non-Hodgkin\'s
lymphoma. I was advised that my form of lymphoma was incurable but could
possibly be controlled by shrinking it with chemotherapy and if
successful, additional treatment would not be necessary for years, if at
all. I began chemotherapy in 1998. My lymphoma responded to the
chemotherapy both clinically and diagnostically. The scan in January
1999 showed that the size of the tumor had significantly decreased.
However, scans eight months later, in September 1999, showed that my
lymphoma had recurred and thus needed to be treated again. My oncologist
suggested investigation of treatment options such as Bexxar, and I thank
God today that the decision was Bexxar.

In January 2000, my baseline scans for the clinical trial showed that my
lymphoma was more prominent in January than it had been just four months
prior in September. I received Bexxar at New York Hospital in January
2000. I had virtually no side effects during or after the treatment,
whereas I did have negative side effects from the chemotherapy, such as
fatigue, nausea and low blood counts that could lead to life-threatening
infections. In April, 13 weeks later, most of the lesions had been
resolved, and all of the others had major decreases in their sizes.
Quarterly scans showed that Bexxar continued to reduce the size of my
lymphoma during the first year after treatment. Today, almost two years
later, according to my latest scan in September, I continue to be in
complete remission.

I believe that there are many people who have a similar form of lymphoma
and they could be successfully treated with Bexxar similar to myself. I
hope and pray that the Panel will look favorably upon the approval of
Bexxar, as I believe it saved my life and can save many others. Thank
you very much.

(Applause.)

CHAIRPERSON PRZEPIORKA: Thank you, Mr. Greer. Next, Alida Diab from
Princeton, New Jersey.

MS. DIAB: Good afternoon, ladies and gentlemen. My name is Alida Diab,
and I\'m here today to tell you about my experience with Bexxar, the
drug that saved my life. From my perspective, Bexxar is the greatest
breakthrough in the history of modern medicine, and I stand here today
as proof of its success.

I received Bexxar in October of 1998 at New York Presbyterian Hospital
under the care of Dr. John Leonard. At that time, I was in a poor
situation and honestly it wasn\'t looking good. Before that I had
received an aggressive chemotherapy regime in 1995, ten rounds of CHOP,
and that was the maximum that I could ever take. After relapsing two
years later, I was one of the first people to be treated with Rituximab
after it was approved in January of 1998. Six months later I was in need
of treatment again.

I had done extensive research on the Internet, and based on everything I
read felt positive that it would be the radioactive iodine in
conjunction with the monoclonal antibodies that would save my life.
Three months after receiving the drug in January of 1999, there was no
sign of disease and I thank God every day for Bexxar. I believe so much
in Bexxar that a couple of months later I bought a few shares of Coulter
Pharmaceuticals in my IRA retirement account. Four years later,
virtually unscathed, I\'m a successful business executive leading a team
of 15 employees. I would like to take this opportunity to convey to the
decision makers that the isolation associated with Bexxar treatment is a
minuscule price to pay for being able to live a normal life with no sign
of disease.

Chemotherapy treatment lasted for nine months, caused me to lose all my
hair, made me constantly exhausted and still was not a complete success.
Rituximab treatment was administered over a period of one month and then
six months later failed for me. With Bexxar, the isolation period was
only two days accompanied by some mild flu-like symptoms. This is in
direct contrast to the debilitating effects of chemotherapy. The very
same month I received Bexxar and the following two months after that in
the same year I won prizes for being the top advertising sales person
each of those three months. I beat all those other completely healthy
people in my office.

I would like very much to help others have the same opportunity to
receive the gift of life. I\'d also like to mention that I received no
financial assistance whatsoever for travel or other expenses. I used my
frequent flyer miles to get here. Thank you for listening and in closing
I ask for the speedy approval of this miracle called Bexxar.

(Applause.)

CHAIRPERSON PRZEPIORKA: Thank you, Ms. Diab. That ends our registered
speakers, but I would like to ask if there is anyone else who would like
to make a comment during this period?

DR. BRAWLEY: May I?

CHAIRPERSON PRZEPIORKA: Yes.

DR. BRAWLEY: I know this is unusual for a member of the Committee to
speak so early, but I just \--one minute of talking to the folks who
just addressed us. I want to say I appreciate those of you who talked to
us rather than down to us, and I have an open mind on this issue right
now, but I think we need to explain why we\'re here and why this is a
question, and I think the advocates and the survivors deserve that
explanation.

Very briefly, there are diseases where therapy, although causing a
partial or a complete remission, don\'t make a patient live longer.
Indeed, several of the stories that I heard suggest that those
individuals didn\'t necessarily need Bexxar even though they went to
complete remission and are doing well. There can be, by the way, an
advantage to treating someone who has symptoms from the disease in
improving their quality of life even though you don\'t live longer from
getting the disease.

And so there\'s a group of drugs that sometimes the only thing that
people get from them, they may seem to get a benefit but they only get
the inconvenience of that treatment and sometimes they even get harmed
or even get killed from getting that treatment that seems to be
beneficial to some folks. And, unfortunately, too, there are some folks
out there who are dishonest and just want to take advantage of sick
people to make a buck. I\'m not talking about anyone today at this
meeting.

So we have to rely upon the scientific method. Sometimes that involves
randomized trials to actually see if people benefit and to see if the
drug really is as good as it appears to be. We have to look at the
entire forest as opposed to one tree in the forest, and so that\'s why
we\'re here and I, again, want to say I appreciate the advocates and
survivors who spoke to us as opposed to down to us. Thank you.

CHAIRPERSON PRZEPIORKA: Thank you, Dr. Brawley, and if there are no
other comments, I want to express the gratitude from the Committee for
all of the individuals who made comments at the open public hearing, and
we will proceed now to the presentation by the Sponsor on Bexxar
anti-B1-I-131, Corixa. Dr. Zaremba, please.

DR. ZAREMBA: Madam Chairperson, members of the Advisory Committee,
ladies and gentlemen, good afternoon. Actually, I am not from Corixa,
I\'m from CBER. There would seem to be a little bit of confusion in the
program. And I am the Chairperson and the product reviewer for the
product under consideration today, tositumomab therapeutic regimen from
Corixa Corporation.

First, I would like to introduce you to the other members of the Review
Team. The clinical reviewers were Drs. Litwin, Mills, Luksenburg and
Shastri; the biostatistician was Dr. Misra; Pharm/Tox was performed by
Dr. Green; radiochemistry by Dr. Epps. Dr. Andrich was the bioresearch
monitor; Debbie Trout is the facilities specialist, and I especially
want to thank the work of Karen Jones, Craig Doty and Mike Noska, who is
no longer on the Committee but did quite a bit of work.

Now, we heard a number of impassioned pleas for the approval of this
product and some suggestion that the FDA has dragged their feet in this
approval, so with that end I would like to present some highlights of
the timeline, and I say highlights because if I put all of the things
that were submitted and considered by the FDA, we would be here until
six o\'clock, so these are just the highlights.

First of all, the BLA was submitted on September 14, 2000. I might add
that it was originally submitted in 1999, but after consideration, the
Center decided to not file it because there were really quite a lot of
missing data. But then eventually on 2000 it was submitted and accepted.
Now, there were quite a few study reports submitted. These all have
numbers so I\'ll give you an idea. The 004 was in chemo-refractory
patients, and that was one of the efficacy studies, but it only
contained data up to 5-31 of 2000. A couple of final study reports were
submitted for studies 000 and 01. One was the MTD study, the maximum
tolerated dose, and the other was a dosimetry study. Then there were
some other interim reports submitted for hot antibody versus cold
antibody. That was the 002. And 003 was used as first-line therapy.

Now, in December 14 of 2000, the CP98-020 interim study report, that was
the expanded access study. They also ‑‑ oh, I should point out that
there were 286 subjects in the first safety report, and then in December
they increased it to 308 subjects for our consideration. Now, in March
16, we issued an action letter which addressed a number of issues that
we had found after review. One was that for the product there was really
insufficient data on comparability since it was manufactured under three
different manufacturing schemes plus the current one for licensure.
Also, there were some questions about some of the testing that was
performed.

In addition, there was some inadequacy in the efficacy databases. There
was a single pivotal trial which had substantially different efficacy in
the transformed versus the non-transformed patient group, and some
supportive data was submitted as interim rather than final reports.
There was also apparently an inadequate safety database where there was
substantial missing data for acute hematologic toxicity and delayed
hematologic toxicity, and there was also thyroid and HAMA events that
were not always entirely clearly explained.

Now, in August 27 of 2001, this 003 second interim report was submitted.
That is the first-line therapy. But this only went to December 20 of
2000. They also updated the safety update with another patient, bringing
it to 309 now. Then in September of 2001, a final study report for
97-012 was submitted. I believe that was the first time that the
Rituximab refractory patients were submitted, and this was the second
efficacy study. Let\'s see, then there was another amended study report
for 002 which was the hot versus cold protocol, and now we saw a MIRROR
Panel review which was the first time for that, which was an independent
review, and now the data cutoff was January 2001.

Okay. In September 10, 2001, Corixa responded to the FDA letter of the
March 16. And then on December 11 of that year, this 004, the
chemo-refractory protocol was an amended final study report, including
more data up to January 2001 and now more data from the MIRROR Panel, up
to September of 2001. Then there was another safety update, which now
was up to 620 patients, which included 387 from the expanded access
study. There were long-term responders also that were from various
studies and the MIRROR Panel review. And, again, there was now
additional information for the study 020, the expanded access.

On March 5 of this year, there was another safety update which was
corrected for errors and gave additional hematology data collected from
audit at the clinical study sites for about 620 patients. March 12 of
this year, FDA gave to Corixa another action letter. They really needed
to demonstrate a meaningful therapeutic advance over existing treatment
because now in February Zevalin was approved for the same indication and
same patient population and additional safety data were needed.

On July 2 of this year, case report forms and report tabulations for
long-term responder subpopulations were submitted. And then in July 11,
a revised proposed indication was submitted to the FDA in which they
requested accelerated approval for chemo-refractory patients and
standard approval for Rituximab-refractory patients. In addition,
another amendment to the final study report for the Rituximab-refractory
patients was submitted at that time.

On October 4 of this year, amendment to the Rituximab-refractory group
was submitted, and on October 30, the independent review for additional
patients in that study with transformed histology was submitted. Now, on
October 31, Corixa completed their response to the FDA letter from
March.

December 10, one week ago, Corixa responded to the Bi Mo inspectional
findings. We really didn\'t have a lot of time to review that before
this meeting, I might say. There were outstanding issues on the clinical
trial. There\'s identification of the dose delivered versus the dose
prescribed for patients in efficacy studies, and the FDA will need to
confirm the safety profile of the proposed dose. In some cases,
apparently, some sites had patients they knew exactly what dose they
got; in others, they just wrote down the prescribed dose, so this is
something that we have to sort of work through.

All right. Well, now I\'m going to talk a bit more about the product
itself, or tositumomab therapeutic regimen. I will call it TTR, it\'s a
little easier to pronounce. Actually, it consists of both unlabeled and
I-131 labeled antibody. The antibody has also been called in anti-B1 in
a lot of literature of the past. It\'s a Murine IgG2a ‑‑ it showed me
Lambda on the screen. It was a Lambda light chain, I don\'t know why it
came out like that. It recognizes the CD20 determinant on B cells.

To give you an idea of the characteristics of the antigen it recognizes,
it\'s a transmembrane phosphoprotein with a molecular weight between 33
and 37 kilodaltons. It\'s present on the surface of pre-B and mature B
cells, and it\'s expressed on greater than 90 percent of B cell
lymphomas. It is now, however, present on stem cells, mature plasma
cells or other non-lymphoid normal tissues, and it is not shed or
internalized upon antibody binding.

To get back to the characteristics of the antibody, it\'s manufactured
by standard tissue culture and purification techniques and the iodinated
with I-131 as radiolabeled by the IODO-GEN method. The mechanism of this
is by electrophilic addition of the iodis ion to tyrosine residues.
Approximately eight tyrosines are iodinated and no hystodines.

The components of TTR, the unlabeled antibody is prescribed in two vial
sizes, a small one with 35 milligrams and a larger dosage vial of 225
milligrams, both of them at 14 milligrams per mil. The labeled
components also are supplied in two forms. One is a dosimetric vial,
which contains 12 to 18 millicuries of I-131, and a therapeutic vial,
which of course is more powerful, containing approximately 112 to 168
millicuries.

The TTR procedure is two-fold. Step one is imaging, in which an
unlabeled portion of antibody is first given, IV over 60 minutes,
followed then by the dosimetric form of the iodinated antibody, which is
given over 20 minutes and contains approximately five millicuries.
Approximately seven to 14 days after the imaging dose and imaging
sessions, then the therapeutic dose is given, and this is also ‑‑ first
there is an unlabeled dose given over 60 minutes, followed by a
therapeutic dose, which is patient-specific and it depends on the ‑‑
it\'s by the whole body clearance rate. This ranged also from about 112
to 168 millicuries.

In addition, the TTR procedure involves the thyroid protective agent,
which is given beginning about 24 hours prior to the first infusion of
the iodinated antibody, the dosimetric dose, and continues for 14 days
following the last infusion of the iodinated antibody, the therapeutic
dose.

There are a few remaining chemistry manufacturing and control issues. A
number of manufacturing issues do still remain to be resolved, and one
of the contract facilities needs to be inspected. Thank you for your
time. Now, I guess Corixa Corporation will take the stand.

CHAIRPERSON PRZEPIORKA: Thank you, Dr. Zaremba, and I do apologize for
misspeaking regarding your affiliation. I\'m certain your colleagues at
CBER will welcome you back with open arms right now.

(Laughter.)

And so we will then move on to the Sponsor presentation. The first
speaker listed is Dr. Fisher. Dr. Jacobs, will Dr. Fisher be introducing
the presentation? Okay. Dr. Jacobs will be introducing the presentation
from Corixa.

DR. JACOBS: Dr. Przepiorka, Dr. Siegel, members of the Committee, FDA
and guests, good afternoon. My name is Cindy Jacobs, I\'m the Senior
Vice President of Corixa Corporation. On behalf of Corixa Corporation,
we\'d like to thank you for the opportunity to present and review the
data from Bexxar.

The proposed indication for Bexxar is the treatment of patients with
relapsed or refractory low-grade non-Hodgkin\'s or transformed low-grade
non-Hodgkin\'s lymphoma. This includes patients with
Rituximab-refractory NHL. We requested accelerated approval for the
relapsed or refractory low-grade or transformed low-grade non-Hodgkin\'s
lymphoma patients last year upon completion of our first response to the
complete review letter. We then, in addition, this year, asked for
conventional or standard approval for Rituximab-refractory
non-Hodgkin\'s lymphoma patients. The accelerated approval is based on
the existence of long-term durable responses in patients who have
relapsed in refractory non-Hodgkin\'s lymphoma. The request for
conventional or standard approval is based on demonstrated efficacy in
patients that have Rituximab-refractory NHL.

In addition to Dr. Fisher and Dr. Armitage who will be speaking this
afternoon, we have with us today a number of lymphoma experts,
independent reviewers and clinical investigators who were involved in
the development of the clinical process of Bexxar as well as the
independent review of the data and as advisors. They are here with us
today to assist in answering any specific questions that you might have
on the interpretation of the data.

This will be our agenda for the presentation: Dr. Fisher will first
present the disease, the outcome and therapy for low-grade and
transformed non-Hodgkin\'s lymphoma. I will then present the efficacy
and safety overview, the basis for approval. Dr. Armitage will then
finish with the risk/benefit analysis.

I\'d now like to introduce Dr. Fisher who is the Samuel Durian professor
of medicine and the Chief of the Hematology/Oncology Unit and the
Director of the Wilmott Cancer Center at the University of Rochester.
He\'s also the Chairman of the Lymphoma Committee at SWOG.

DR. FISHER: Good afternoon, everybody. Thanks, Cindy. You wonder what I
do with my spare time after that introduction. What I wanted to do today
was really take a few moments of your time and help bring everybody
together in terms of the diseases we\'re going to talk today about, in
terms of the treatment options, in terms of what we can expect. And in
sitting back and listening to the moving testimony of the patients who
talked before, I was reminded of something that I see regularly in the
clinic, which is that our patients with lymphoma become lymphoma experts
as they go through. So my job is much easier, because they\'ve actually
told you much of this as they went through.

The low-grade non-Hodgkin\'s lymphomas are a group of indolent or
chronic diseases, as you\'ve heard about, diseases that are not curable
but that are not uncommon. The annual incidence in the United States is
well over 15,000 cases. Because these are chronic diseases and because
patients live for a prolonged period of time, the prevalence is
significantly greater than the incidence. And in the United States
recently there are about 64,000 cases at any one time in the year. So
that\'s the potential group of patients with indolent lymphoma alive.

As I said, unfortunately, it\'s a chronic disease, and as many of the
patients said, it\'s an incurable disease. Median survival from the time
of diagnosis, and we\'ll talk about different survival figures so we\'ll
try and be precise about when we\'re starting the clock, at initial
diagnosis is eight to 11 years in multiple series.

Why do these patients die, ultimately? Well, frequently, at the end of
their disease, about a third or more will have a malignant
transformation to a more aggressive presentation, frequently a large
cell lymphoma, and that histologic transformation with aggressive
clinical disease will be associated usually with a median survival of
less than one year and will frequently require more aggressive
treatment.

As you heard from the FDA just a moment ago, we\'re talking about
therapy directed at CD20, and probably most of you are aware why CD20 is
such an ideal target for treating these indolent lymphomas. First of
all, it\'s not expressed on the stem cells so that when you knock out
CD20, as the anti-CD20 antibodies do, you take out the CD20 positive B
cells, you will repopulate the repertoire from the stem cells.

Secondly, it\'s not expressed in the majority of plasma cells. That\'s
the immunoglobulin factory that makes immunoglobulin. And, therefore,
there are no significant changes in the circulating immunoglobulin.
Therefore, the immunodepression is not significant and not really a
problem in these patients. And most of all of these patients express
this CD20, which can be removed, as I said.

Now, how do you treat these patients? Unfortunately, it\'s now a very
complicated diagnosis and treatment. The discussion is not easy. It
would be easy if we had one therapy to cure patients, but we don\'t at
this time. Patients frequently present asymptomatic after a lymph node
biopsy, and some of those patients can be given a treatment called watch
and wait, which is really no initial treatment. That means they can go a
prolonged period of time, sometimes a couple years, without anything
other than perhaps some local radiation therapy. Other patients, and
even the watch-and-wait patients, ultimately, will inevitably develop
symptom management progressive disease, and then they will require
treatment.

Almost all of these patients are chemotherapy sensitive at the time this
happens. What does that mean? They can be treated with alkaline agents,
they can be treated with CVP, combinations of alkaline agents, they can
receive CHOP, they have a variety of different chemotherapy options.
However, the responses are all relatively limited. More recently, as
this group knows well since the advent of Rituxan on the market,
essentially every patient in this country who has access to the health
care system, has insurance, will get Rituxan at some point and
frequently multiple times, and they will be responsive. But, in fact,
those responses, as you well know, are also of short duration.

Toward the end, we get the relapsed or transformed manifestations, and
then as I said, frequently very aggressive chemotherapy, even stem cell
transplant is advocated often. The patients who don\'t show that
clinical transformation become refractory to chemotherapy and antibody,
and symptom management may be the only thing we currently have to offer
them in the latter stages of this incurable disease.

Now, this is a very important slide, because it sets the basis on which
the data will be presented today on which you will evaluate some of the
efficacy of this potential drug. This is data from St. Bartholomew\'s
Hospital, published in the JCO, which shows what happens when you treat
the patients the first time, the second time, the third time and the
fourth time. What is not shown on this slide are the response rates, and
not surprisingly they go down every time they relapse and every time you
retreat them. What is shown very well is that at one treatment the
median response duration, how long they stay in remission, is about 16
months, the second time down to 11, ten, and if you have four relapses,
the median response duration, the 50th percentile is three months, and
the response rate is low. This is not a surprise to the medical
oncologists. As you get later in the disease, the disease becomes
increasingly more refractory. And this is what will also be confirmed
when we show you data from the patients who entered the Bexxar studies,
have a similar pattern prior to Bexxar showing the same thing: More and
more relapses, less and less response, less and less duration.

Now, this is, unfortunately, where we show our failure. I\'ve been doing
this for over 25 years in terms of lymphoma treatment. A number of us,
the experts we have a lot of years of work on this disease and to date,
unfortunately, we have not changed the natural history of this disease
based on survival. This is data from Stanford over a variety of periods
and different regimens of their treatment, but what it shows you is that
the median survival is again in the range of seven to ten years, and
there is no apparent plateau or curability of these patients in that
regard.

Okay. Well, why did we turn to radioimmunotherapy? What do we think is
happening? Well, if you\'ll ‑‑ this is now only Powerpoint possible. Now
you\'re going to see modern technology at its best. When you have
Rituxan available, you had an unlabeled cold antibody, and if it could
bind the CD20 antigen, it could kill the cells, maybe by complement,
maybe by ADCC, maybe by intracellular single invade optosis. But there
are cells that are not reached by the antibody, and they\'re unaffected,
and so the cells that are in contact with the immune system and antibody
die.

With the Bexxar treatment, you have an antibody again going to CD20
binding those same cells but you have a cross-fire effect from the
radiation tag on the antibody that can result in more death of the
cells, and this is the theoretical underpinning by which this happens.

Well, really, why radiation therapy? Jokingly, the other day we were
saying when I first started out in this field I was told by my
predecessors the major, most effective drug treating lymphomas is
radiation therapy. The problem is that disseminated lymphoma, which is
what the majority of these patients present with, is not amenable to
local fields and cannot be encompassed with acceptable toxicity. Bexxar
is a way to target radiation to the site of the disseminated tumor.

How about the rationale for iodine? Well, there\'s an enormous safety
record in this country and the world over 50 years. The fact that
there\'s a gamma radiation allows you to do patient-specific dosimetry.
You can do scans and calculate doses. And the fact that the real
radiation therapy is coming from beta with a short path length will
limit the toxicity outside of the area where the antibody is actually
present.

Now, this is one of the complicating features of this discussion we\'re
going to have today. Everything is a bit of good news/bad news. The good
news: This is not a new product, this is not new in development. It
started in 1990, so you are seeing data that has follow-up as long as 12
years for some patients. The phase 1/2 study and then the first phase 2
multi-center study in the \'90s. The patient control trial you\'ll hear
more about starts in the last \'90s, a trial of the cold versus the hot
antibody. A trial of phase 2 looking at Rituxan failures, and then
finally expanded access.

So the good news is there\'s a lot of time to see the long-term effects
of this particular drug. The bad news is, of course, that the world
changes during that time, and so things that you might have said in
studies that were needed here might not have been known there or might
not have been available, so you have to balance those two effects.

Corixa took over this program in \'01, and today no matter how we got
there, the efficacy is not on a small number of patients, it\'s on 250
patients for data, and the safety and toxicity data is in over 600
patients. So that is a sizable database for us to deal with.

Now this is one of the most important slides and I\'d like you to focus
on this, and I suppose if you remember one thing from my talk, I\'d like
you to try and think about this slide, remember this slide, because this
is what you heard about from the patients who were talking today. Some
of them are shown on this slide. This is long-term durable response,
event-free survival plotted for all five trials, and the scale here is
not months, not weeks, but years. And out here beyond two years, two,
three, four and five years, what you see is a significant number of
patients in each study with between ten and 20 percent predicted to be
alive, disease-free, off all therapy with one treatment that took two
weeks out of their lives, and as you heard, did not result in major
toxicity that they perceived. This is something that those of us who
have been in this business for a long time have not seen in this kind of
circumstance, remembering that these are patients who on the average
have about four prior treatments. This is a new observation for us and
one that I think makes us stand up and take note of the efficacy of this
product.

Hopefully now with us on a common page and with that introduction, I\'ll
turn it back over to Cindy, and she\'s going to present the actual data
to you. Thank you for your attention.

DR. JACOBS: These are the agenda items that I will follow, both of which
will be to review the individual studies. The first two studies
evaluated the development of the dosimetry and the MTD of radiation,
followed by then the validation of the dosing methods at multiple
clinical sites.

This first study showed the pharmacokinetics, the tumor targeting and
the dosing methods, the pre-dose of the unlabeled antibody to block
non-specific binding sites and optimize the distribution was determined.
The maximum tolerated dose of radiation was also determined. The second
study was designed to show the reproducibility of the whole body dosing
methods at multiple centers and again preliminary safety and efficacy
for patients with relapsed and refractory low-grade non-Hodgkin\'s
lymphoma, with or without transformation.

Results from these two studies defined the Bexxar treatment regimen as
follows: First, a thyroid protective agent is started on day minus one
and continued through day 14 after the therapeutic dose. On day zero,
the dosimetric dose is given as 450 milligrams of unlabeled tositumomab
infused over one hour followed by 35 milligrams tositumomab radiolabeled
with five millicuries of Iodine 131. Total body counts by gamma camera
scans are taken on day zero, again on day two, three or four, followed
by day six or seven.

From these total body counts, the total body clearance is derived, and
the patient-specific activity in millicuries is calculated to give a
total body dose of 75 centigrade. Thus, on day seven to day 14, the
therapeutic dose can be given as 450 milligrams of unlabeled tositumomab
infused over one hour, followed now by 35 milligrams tositumomab
radiolabeled with Iodine 131 to deliver the 75 centigrade total body
dose. Thus, Bexxar treatment is administered as two doses over this one-
to two-week period.

Other results from these two studies are represented in the next three
slides. As was already stated, the unlabeled pre-dose of tositumomab
gave superior tumor targeting. We determined the clearance of
radioactivity which was dependent on tumor bulk, spleen size and bone
marrow involvement. This allowed the patient-specific dose to be
calculated and can be easily delivered in nuclear medicine departments
by personnel. The dose living toxicity was myelosuppression. The MPD was
75 centigrade total body radiation dose, which was attenuated to 65
centigrade for those patients who had platelet counts less than 150,000
at time of study entry.

This slide shows the preliminary efficacy for those patients who had
low-grade or transformed low-grade NHL in the studies. For the first
study, 42 patients had low-grade or transformed low-grade non-Hodgkin\'s
lymphoma. They had failed four median numbers of prior regimens.
Thirty-three percent had transformed histology. The overall response was
64 percent, and the CR rate was 38 percent. In the second study, again
the median number of failed prior regimens was four, 30 percent of the
patients had transformed histology, the overall response rate was 49
percent and the CR rate was 26 percent.

This is a time to progression curve for both of these studies. Durable
responses were observed for both studies, as shown in this figure. This
is an important finding in that the four- to eight-year Kaplan-Meier
estimate is 13 percent, which is not expected after a single treatment
in this refractory patient population.

Based on these early results, the pivotal study, 004, was designed in
1996. Sixty patients were enrolled at eight sites. These were for
chemotherapy-refractory. The study designed used patient-as-own-control
comparing the results following Bexxar compared to the last qualifying
chemotherapy. In 1996, there was no suitable comparator for this
refractory patient population. Patient-as-own-control designs have been
recognized as appropriate for registration. They are particularly useful
in disease settings like low-grade non-Hodgkin\'s lymphoma when previous
responsiveness in patients can predict future outcome.

All efficacy end points were reviewed by an independent panel, the
Masked Independent Randomized Radiology and Oncology Review Panel,
referred to as the MIRROR Panel. The procedures for the MIRROR Panel
were coordinated by an independent CRO. It was a masked reviewed by two
independent teams, each with an oncologist and a radiologist. For each
patient, the review of the last qualifying chemotherapy was randomly
assigned to one team and the results following Bexxar to the other team.
This included redacted radiographs and redacted medical notes.

This is a list of the last qualifying chemotherapies that were
prospectively defined in the protocol required to be appropriate for
multiply relapsed low-grade or transformed low-grade non-Hodgkin\'s
lymphoma. The primary end point was the comparison between the number of
patients with longer duration of response, defined as greater than 30
days following Bexxar, to the number of patients with longer duration of
response after their last qualifying chemotherapy. Secondary end points
were overall response, complete response, duration of response and time
to progression.

To be eligible patients had to have chemotherapy refractory disease
defined as follows: they had to have had at least two prior qualifying
chemotherapy regimens; there had to be no response or progression within
six months after completion of their last qualifying chemotherapy. Also,
complete documentation for that last qualifying chemotherapy had to be
available. The ANC had to be greater than 1,500, platelet count greater
than 100,000, less than or equal to 25 percent bone marrow involvement
in bidimensionally measurable disease.

Patient characteristics for the 60 patients are represented here. The
median number of the prior failed regimens was four, the range was two
to 13 prior regimens. Thirty-eight percent of the patients had
transformed histology. There was one patient that was retrospectively
reclassified as having mantle cell lymphoma. This patient is included in
all the efficacy analyses as an attempt-to-treat basis. There is a high
frequency of other poor prognostic factors known in this disease, and as
stated, patients were refractory to their last chemotherapy. The overall
response was 12 percent with only two percent complete response and no
response longer than six months.

This bar graph illustrates the primary end point. The x axis shows the
results for each of the 60 patients. The y axis shows the duration of
response in months. The yellow bars show the duration of response for
the last qualifying chemotherapy for the 60 patients. As you can see,
only seven patients responded to their last qualifying chemotherapy. The
blue bars illustrate the duration of response in those same patients
following Bexxar therapy. The plus signs above here are showing those
patients in continuing or ongoing response at the time of their last
assessment.

So, for example, this patient had almost a six-month response to their
last prior chemotherapy compared to 36 months following Bexxar
treatment, and that response is still ongoing. The side-to-side
orientation is simple: Those patients who had a longer duration to
Bexxar are to the right; those patients who had a longer duration to
their last qualifying chemotherapy are to the left; those patients who
did not have a response or an equivalent response are presented as E\'s
in the middle of the bar chart. As you can see, the primary end points
for comparing the number of patients that had a longer response to
Bexxar compared to the response to the last qualifying chemotherapy was
highly significant in favor of Bexxar.

This slide shows the overall response, and complete response was also
significantly different in favor of Bexxar. The overall response
following Bexxar was 47 percent compared to 12 percent; for the CR rate,
20 percent following Bexxar compared to two percent.

This slide illustrates the time to progression following Bexxar compared
to that following the last qualifying chemotherapy. Although the curves
overlap initially, you can see that 20 percent of the patients had
long-term durable responses following Bexxar therapy, some out to four
years.

This study is a randomized study comparing Bexxar to the unlabeled
tositumomab. This study was designed to show the relative contribution
of the radiolabeled antibody compared to the unlabeled antibody.
Seventy-eight patients were enrolled at nine sites. Again, they were
chemotherapy-relapsed refractory with or without transformation. As
stated before, patients were randomized to receive Bexxar or the same
amount of unlabeled tositumomab in the same manner. All of the
assessments of response were independently reviewed by the MIRROR Panel.
The primary end point was the comparison of CR rate; secondary end
points, response, duration of response and time to progression.

Both arms were balanced for patient characteristics, both arms patients
had a median number of two prior failed regimens. They were similar in
the frequency of poor prognostic factors. Seventy-three percent and 77
percent of patients responded to their prior chemotherapy, but the
duration of response was a median of six months.

The primary end point CR rate was 33 percent following Bexxar therapy
compared to eight percent with unlabeled tositumomab, which was
statistically significant in favor of Bexxar. The overall response
following Bexxar was 55 percent compared to 19 percent with the
unlabeled antibody.

Time to progression as the secondary end point was also statistically
significant in favor of Bexxar compared to the unlabeled antibody.
Again, there were a number of long-term durable responders with a
four-year Kaplan-Meier estimate of 35 percent. Thus, the addition of
Iodine, I-131, to the antibody did contribute to the overall response
and the time to progression in this study.

The protocol also allowed patients who progressed with the unlabeled
tositumomab to cross over to receive Bexxar therapy. There were 19
patients who did cross over. Of the 19 patients, 68 percent had an
overall response and 42 percent had a complete response. More details of
that information is presented in the briefing document.

The last study to be summarized is a single-arm study evaluating Bexxar
in patients who are refractory-relapsed following Rituxan. Forty
patients were enrolled at three sites. These patients had disease which
failed to respond or progressed after Rituxan therapy. Again, all of the
efficacy end points were independently reviewed by the MIRROR Panel.
These 40 patients had a median number of four failed prior regimens.
Thirty percent had transformed histology. Again, a number of poor
prognostic factors were seen. Eighty-eight percent of the patients had
no response or the response was less than six months to the prior
Rituxan. The overall response following Bexxar treatment was 68 percent.
The median duration of response was 16 months. Thirty-three percent of
the patients had a CR with the median duration of the CR not yet
reached. The median time to progression was one year.

This bar graph again illustrates the comparison of the duration of
response following Bexxar compared to the patient\'s response to
Rituxan. The x axis shows the results for the 40 patients; the y axis,
the duration of response. Again, the yellow bar shows the duration of
response for patients to their prior Rituxan therapy. The blue bars
illustrate the duration of response for those same patients after Bexxar
treatment with again the pluses showing those responses that are still
ongoing at last time of assessment.

When using a patient-as-own-controlled analysis comparing the number of
patients with longer duration of response to Bexxar compared to the
number of patients with a longer response to Rituxan, again, it was
highly statistically significant in favor of Bexxar.

This figure summarizes the time-to-progression curves for all patients
from the five studies that you have seen. The time to progression is
defined as the start of Bexxar therapy to the first documented
progression. In summary, all five individual studies consistently showed
a number of long-term durable responses after this single treatment.

Let\'s now turn to the integrated efficacy population. The integrated
efficacy population consists of 250 patients enrolled from the five
studies that you have just seen that had low-grade or transformed
low-grade non-Hodgkin\'s lymphoma and received Bexxar therapy at any
time. The patient characteristics again showed that the median number of
prior failed regimens was three. Twenty-eight percent of the patients
had transformed histology. Again, a high number of poor prognostic
factors. Eighty-four percent of the 250 patients had no response or less
than six months response to their prior therapy and were refractory to
their prior therapy.

The overall response was 56 percent with a median duration of response
13 months. The CR was 30 percent with a median duration of CR almost
five years. This is the time-to-progression curve for the 250 patients
in the integrated efficacy population. The dotted blue lines show the 95
percent confidence intervals. The timeline goes out to eight years with
an eight-year Kaplan-Meier estimate of 13 percent.

From the integrated efficacy population, two subpopulations were further
analyzed: the long-term durable responders and the transformed low-grade
patients. We will first review the Durable Responder Population. Upon
consultation with our lymphoma experts, we defined the Durable Responder
Population as those patients who had an independent-assessed response
and a time to progression of at least one year or more, again, confirmed
by the MIRROR Panel. Thirty-one percent, or 78 patients, met this
definition. Two patients were removed due to confounding factors
regarding their response to Bexxar. Seventy-six patients then are
retained in this Durable Responder Population. The median follow-up is
44.6 months.

The demographics for this 76 subpopulation are patients that have a
median number of failed prior therapies of three, 20 percent were
transformed, again, there were a number of poor prognostic factors, and
75 percent of them were refractory to their prior therapy. Seventy-six
percent of these patients had a complete response following Bexxar. The
overall response and the complete response approached five years. The
median time to progression is five years.

This is the time-to-progression curve for those selected 76 patients who
had a time to progression greater than or at least one year as the
Durable Responder Population. We then analyzed that the long-term
durable responders were present in patients who had poor prognostic
factors and found that patients who were refractory to their prior
therapy had bulky disease or had a high IPI score and could achieve
long-term durable responses, as shown in the next three slides.

As seen in the chemotherapy-refractory population in 04 and the
Rituxan-refractory population, these durable responders can be seen in
patients refractory to their last chemotherapy as well as relapsed from
their last chemotherapy. Patients with bulky disease, defined as lesions
greater than five to ten centimeters, also you can see that there are
long-term durable responders in those patients. Patients who were
intermediate high-grade or high-risk based on IPI score could also have
durable responses following Bexxar therapy. In summary, patients who
still have well-documented poor prognostic factors can have durable
responses following Bexxar.

Let\'s now look at the transformed low-grade subpopulation. There were
71 patients of the 250 who had transformed histology by the
investigators. These are the investigator-assessed histologies. At the
request of FDA, we had the histopathology reviewed by a retrospective
Central Pathology Review. Of the 71 patients, 53 patients had sufficient
material available for this retrospective pathology review of their
original low-grade diagnosis as well as their diagnosis of
transformation. The majority of the other 18 patients we were not able
to get sufficient material of their original low-grade diagnosis. Of
those 53 patients, 47 patients were confirmed by Central Review as
having transformation. Five could not be confirmed and one was
classified as an intermediate grade.

I will focus on presenting the data for the 47 patients. Of these 47
patients, the median number of failed prior regimens was four, the range
was one to nine. Again, there were a number of poor prognostic factors.
Sixty-five percent of the patients had bulky disease, and 56 percent had
an elevated LDH. The overall response in these patients was 40 percent
with a median duration of 14 months. The complete response rate was 23
percent, the median duration of CR was 36 months, or three years.

This is the time-to-progression curve for both the 71 total patient
subpopulation as well as the 47 that were confirmed by Central
Pathology. The time-to-progression curves are similar and again show
durable responses out to five years.

You\'ve now seen the efficacy profile from the individual studies as
well as the integrated efficacy population. We will now review the
safety data from the integrated safety population. The integrated safety
population consists of 620 patients. Two-hundred and twenty-nine were
from the five studies that you have just seen with patients that had
received the prescribed 65 or 75 centigrade total body dose. The other
21 patients had received less than 65 centigrade total body dose and
were removed.

Three hundred and eighty-seven patients were included from the expanded
access program that also had low-grade and transformed low-grade
non-Hodgkin\'s lymphoma and had at least 13 weeks of follow-up. There
were also four compassionate use patients that had long follow-up and
had been monitored by the Company.

Eighty-nine percent of the patients had any type of adverse event at any
time. Sixty-five percent of them were Grade III/IV, 23 percent were
serious adverse events. And, again, these are serious adverse events
regardless of relationship to study drug. Eighteen percent,
hospitalizations; infection and fever, 6.8 percent; 8.6 percent of the
patients died within 90 days of Bexxar; 1.3 were not related to
progressive disease. Again, all the adverse events that we will be
showing will be regardless to any relationship to Bexxar.

The infusions were well-tolerated. Most common were the Grade I/II
adverse events. Fever and pruritus were the most common for the
dosimetric dose, and chills and nausea were the most common for the
therapeutic dose. Grade III/IV adverse events were less in approximately
two percent of patients. Infusion rate adjustments was only five percent
following the dosimetric dose and four percent following the therapeutic
dose.

This shows the non-hematologic adverse events, and as you can see, the
majority were Grade I/II adverse events, with asthenia, nausea and fever
being the most common. The Grade III/IV adverse events were less
frequent. The most common was dyspnea followed by asthenia, nausea,
fever and pain. Twenty percent of patients had one or more serious
non-hematologic adverse events, again, regardless of the relationship of
study drug. The most common were fever at three percent, sepsis,
pneumonia and dyspnea at two percent. Grade III/IV hephanic and renal
toxicity occurred in less than one percent of patients.

Decreased thyroid function was defined as an elevated TSH or initiation
of thyroid medication. The four-year cumulative instance was 12 percent.
Of note, 11 percent of patients were identified with a diagnosis of
hypothyroidism at the time of study entry. Those patients are not
included in this analysis. And as you\'re aware, hypothyroidism is
easily diagnosed and treated as long as patients are monitored annually.
The two-year cumulative incidence of HAMA was ten percent. Some patients
did have delayed HAMA. This is most likely due to delayed immunologic
recovery. In summary, the infusion-related in other non-hematologic
toxicity was not remarkable.

Let\'s now review the hematologic toxicity, as myelosuppression was the
dose-limiting toxicity. The median time to nadir ranged from day 34 to
day 47. Grade III/IV neutropenia was 42 percent; Grade III/IV
thrombocytopenia, 36 percent; and Grade III/IV anemia, 11 percent. The
median duration for the Grade III/IV cytopenias ranged from 19 days to
30 days. Five percent of the patients did not recover to Grade II. The
majority did recover to their baseline grade.

Twenty-six percent of patients received one or more hematologic
supportive care measures at any time during recovery. Supportive care
measures are a surrogate for the severity of the hematologic toxicity.
Fifteen percent of patients had red blood cell transfusions; 12 percent,
platelet transfusions; 11 percent of patients received G-CSF; and seven
percent erythropoietin.

The consequences of neutropenia and thrombocytopenia were infrequent.
Less than two percent of patients had a Grade III/IV infection with
neutropenia, neutropenic fever or bleeding with thrombocytopenia.
Thirty-eight percent of the patients had any infection within six months
following Bexxar. Six percent of those patients had a serious infection.
The majority of these infections were Grade I/II that were viral
rhinitis, pharyngitis and flu-like symptoms. The six percent of serious
infections were predominantly sepsis and pneumonia. Twelve patients died
with a serious infection within 90 days of Bexxar therapy. Nine had
concomitant disease progression and three did not.

Eight point five percent of patients had bleeding events. One point six
percent of those were Grade III/IV bleeding events. Four patients died
with bleeding events within 90 days of receiving Bexxar therapy, three
with disease progression and one without.

In these studies, there was missing data mainly due to patient
withdrawal for progressive disease or death. Corixa did additional
analyses with FDA such that if data were missing during the key nadir
time, the occurrence of Grade III/IV toxicity that were assumed to have
occurred to provide a conservative or a worst-case analysis. So, for
example, 42 percent of patients had a documented Grade III/IV
neutropenia; 15 percent of patients had missing data during the key
nadir time and were assumed to have Grade III/IV events that were
missed, thus giving a total conservative or worst-case analysis of 57
percent Grade III/IV neutropenia. If one looked at any hematologic
toxicity using this conservative analysis, 65 percent of patients would
have had a documented Grade III/IV neutropenia/thrombocytopenia or
anemia in these studies.

The potential long-term safety concern for radioimmunotherapy is MDS in
associated leukemia. There were 19 reported cases in the 620 patients
with accrued incidence of 3.1 percent and annualized incidence of 1.7
percent per year. Of the 620 patients, 387 were from the expanded access
program which had shorter median follow-up of only one and a half years
and are less informative regarding the incidence of MDS. So in looking
at only the 233 patients with a median follow-up of 2.4 years, 18
reported cases occurred.

A centralized independent masked review by Dr. Bennett was performed for
these cases in the remaining 233 patients. It was determined in
retrospect that four patients had evidence of preexisting MDS prior to
receiving the Bexxar therapy and are removed from the analysis. One
additional patient had no morphological evidence that could be confirmed
by Dr. Bennett of having MDS. Thus 13 cases out of 229 patients gives a
crude incidence of 5.7 percent and an annualized incidence of 2.2
percent per year.

The combination of extensive chemotherapy and external beam radiation
treatments has been well documented in association with the development
of MDS and acute leukemia. It is not possible with the experience to
date to know what extent Bexxar may contribute to the incidence of MDS
in this patient population.

There is one other study, 003, which had Bexxar treatment to previously
untreated patients. Seventy-six patients were treated. The median
follow-up is 3.6 years, and there is yet to be any incidence of MDS in
this study. All patients are being continually followed for MDS, or
acute leukemia. As an update, through September 13 of this year, five
additional cases of MDS have occurred in the 387 patients on the
expanded access protocol, thus giving to date a total of 24 out of 620
patients with an annualized incidence of 1.8 percent per year.

There were no infusion-related deaths. Time from the dosimetric dose to
death was 38.7 months. Two hundred and fifty-four patients, or 41
percent, have died during the studies, 31 percent primarily due to
lymphoma progression, five percent due to complications from their
lymphoma or additional non-Hodgkin\'s lymphoma therapy, one percent for
incidental causes, two percent due to the MDS or acute leukemia, 12
patients died with other causes, of which three were attributed to study
drug. Eight of these deaths, or 1.3 percent, occurred within 90 days of
Bexxar therapy.

In summary, there is a low incidence of Grade III/IV infusion-related
adverse events, no infusion-related deaths. The non-hematologic AEs were
predominantly Grade I or Grade II. The four-year cumulative incidence
for hypothyroidism was 12 percent; HAMA, ten percent. The AEs were
primarily hematologic. There was limited need for supportive care and a
low incidence actually serious infections in Grade III/IV bleeding
events. The annualized incidence of MDS is 2.2 percent per year and
still being followed, and non-lymphoma deaths within 90 days was 1.3
percent.

I will now again summarize the basis for our request for approval. As
stated, we requested for accelerated approval last year for the relapsed
or refractory low-grade or transformed low-grade non-Hodgkin\'s lymphoma
patients. The basis for accelerated approval is defined as follows:
Clinical trials must be adequate and well-controlled, they must
establish that the product has an effect on a surrogate end point that
is reasonably likely to predict clinical benefit, the product must
provide a meaningful benefit over existing treatments, and the Company
must commit to subsequent trials to confirm that that surrogate end
point does predict clinical benefit.

Thus, our request for accelerated approval is based on the 004 pivotal
trial demonstrating longer duration of response compared to the prior
chemotherapy. Bexxar has induced long-term durable responses, and we
have done additional follow-up data at the request of FDA with these
submissions over the last year. No other single treatment to date has
been shown to induce extended responses out to five to eight years.
Corixa has also committed to additional trials. One trial is a SWOG
study that is already ongoing. The other trial is a randomized trial
comparing Bexxar therapy to Rituxan therapy. The primary end point for
that study is event-free survival.

We are requesting conventional approval as of this year. For
Rituxan-refractory patients based on a safety profile that is
predictable and manageable. The efficacy is based on the patients
enrolled in study 012 showing that more patients had a longer duration
of response to Bexxar than their prior Rituxan therapy, which was highly
significant in favor of Bexxar.

Dr. Armitage will now describe the potential role for Bexxar in this
patient population. Dr. Armitage is the Dean of the University of
Nebraska College of Medicine and is the Past President of the American
Society of Clinical Oncology and the American Society of Blood and
Marrow Transplantation.

DR. ARMITAGE: Thank you. As you heard, my task today is to try to take
all this information and put it in a clinical perspective. Now, in
addition to the administrative responsibilities you heard a minute ago,
I have for more than 20 years and do, spent a significant portion of my
time treating patients with lymphoma, and I\'m involved in clinical
research in this disease.

The reason I agreed to make this presentation is that I\'ve actually
treated several of the patients on the data being considered and have
found this drug to be the most active agent that I\'ve seen in patients
with multiply relapsed or refractory low-grade B cell non-Hodgkin\'s
lymphoma.

Now, certainly, the most striking bit of data incorporated in this slide
that you\'ve seen before is the fact that in addition to a high response
rate a significant and surprising proportion of these patients remain
well for extended periods of time, particularly striking given the
comparative simplicity of the treatments, certainly from the patient\'s
point of view.

Now, as we look at the data, what I\'m going to do is consider toxicity
and the response ‑‑ the activity of the drug, Bexxar, and try to, when
possible, consider it in light of what might have been expected or what
could be accomplished with other available agents. Certainly, the group
of patients we\'re going to talk about represent an unfavorable
population. These are people with multiply relapsed, usually refractory
lymphoma; certainly not a group where you would expect to see a
significant number of patients with long-term durable remissions.

I believe the data you\'ve seen does in fact illustrate an acceptable
safety profile. I\'ll talk about myelosuppression and myelodysplasia in
just a moment. The hypothyroidism, while it does occur, occurs at a much
lower incidence than we\'re used to seeing, for example, in patients
with Hodgkin\'s disease who receive mantle radiotherapy, and of course
this is an easily manageable condition.

This is the hematological toxicity, the primary toxicity with this
agent. Now, I think it\'s worthwhile remembering what this means.
Thrombocytopenia means less than 50,000 platelets that have Grade III
toxicity. Neutropenia is less 1,000 neutrophils and anemia is hemoglobin
less than eight grams. First of all, these are not striking numbers to
the medical oncologists in the room, and ones that we would see fairly
regularly with other intensive therapies that we would use to treat
patients with this or other diseases.

And you remember that you saw before that this number is larger than
that number, because there were some patients, usually because they for
one reason or another, dropped out of the study and whom there was a
number not measured that could have been a higher grade of toxicity. And
so a reasonable interpretation of this, it seems to me, is that this is
the lowest and this is the highest toxicity level we could have and most
likely it would really be somewhere in the middle if we had every bit of
information.

Now, how to put this in perspective because this isn\'t an easy thing to
try to judge but it\'s what we would expect. Now, what I\'ve chosen to
do is to compare this toxicity with that reported for the other
radiolabeled antibody, the yttrium labeled ibritumomabtiuxetan. Now, let
me caution you: It would be absolutely inappropriate or unfair to try to
use this sort of a comparison to try to argue that one or the other
drugs are better. What I want to use this for, though, is what I think
we need to be doing now, is trying to see if there\'s a red flag raised
to suggest that the agent being considered today, Bexxar, has an
unusually high toxicity that suggests that it might be dangerously
worse, and my interpretation of this data would be that\'s probably not
the case.

Now, hands down, the most concerning toxicity in the treatment of
patients with cancer beside toxic agents is the occurrence of
myelodysplasia and acute myeloid leukemia. Now, keep in mind two things
here. One is that to have this toxicity you actually have to live long
enough to get it, so you had to receive a therapy that benefitted you.
And, secondly, that the occurrence of myelodysplasia or acute myeloid
leukemia is related to the number of exposures to marrow-injuring
agents, the duration of exposure and the age of the patients, with
patients over 60 years seeming to be at particularly high risk.

You can see that in the data you just saw a few minutes ago that in the
patients on studies, 18 were originally thought to have this condition,
13 really did, with four having developed it subsequent to the Bexxar,
with four having had both morphological and cytogenetic evidence for the
condition before they were treated, not surprising in these group of
people with multiple exposures to marrow-injuring agents. And one
apparently really didn\'t have it. This leads us to this 2.2 percent per
year annualized incidence. While I suspect the statisticians in the room
can use that data, I also suspect that some of the hem/onc people in the
room, like me, don\'t know exactly what you do with a 2.2 percent
annualized incidence. And so for me, and I suspect for some of you, this
is more valuable, which is a cumulative incidence curve.

And you can see that in the area where we can still be reasonably
confident as you get farther to the right, of course, with smaller
numbers of subjects, you can be less confident about it. But in the area
where you can still be pretty confident of the result, we have about a
6.5 percent cumulative incidence of this condition.

Well, how do we put it in perspective? We know that that\'s less than
what\'s been described for the occurrence of this condition subsequent
to autotransplantation using total body containing therapy regimens.
I\'m one of the authors on a manuscript that will soon be published in
JCO where we actually reviewed the occurrence of myelodysplasia and
acute leukemia in patients treated for non-Hodgkin\'s lymphomas and in
patients with low-grade B cell lymphoma in various series, the incidence
has been on the order of somewhere between three or four percent to
about ten percent. So this number seems to fall within that range.

Perhaps the most comforting thing to make you believe that Bexxar is not
unusually likely to cause acute myeloid leukemia is what you heard a
minute ago, the zero percent incidence in patients who had this as their
initial therapy and a group of patients who have been not, for the most
part, repetitively treated with agents that we know are potentially
leukemogenic.

Now, currently, the two big questions in somebody with relapse or
refractory lymphoma, other than transplant, is should they receive
another cytotoxic regimen or should they be treated with an antibody?
So, first, let\'s consider what evidence there is that Bexxar might be
particularly beneficial to patients who now with multiply relapsed
disease would be a candidate for another cytotoxic regimen. The pivotal
trial addressed this issue where patients with disease refractory to
their last chemotherapy regimen they had received somewhere between two
and 13 with a median of four and then received Bexxar, addresses this
issue. This uses a patient-as-their-own-control analysis, which isn\'t
that unusual in this sort of a setting. I\'m actually not aware of any
randomized trials comparing new agents in patients with multiply
relapsed or refractory low-grade B cell lymphomas.

Now, one thing we have to worry about is that these patients might still
have been selected in some way to make them particularly good patients
where you expect a higher response rate might have been seen. And I\'ll
look at this in a few ways for you. One is this data. Now, this is a
complicated slide, and what this is is the response rate in those
patients that participated in the pivotal trial to their first or second
treatment, this is the average response, third or fourth treatment,
fifth or sixth or more than sixth. Remember, some patients had only had
two, a minority, some patients had as many as 13, but this looks at what
their response rate was when they were treated the first and second
time, the third and fourth time and so forth.

So this is the first data which I\'m aware that tries to reproduce the
Gallagher data that you heard from Dr. Fisher, the study from St.
Bartholomew\'s Hospital that was published sometime ago in JCO. And you
can see, as expected, these people became less and less likely to
respond to sequential chemotherapy regimens what you would have expected
to see.

And this shows, similar to the curve that he showed you earlier
comparing to the old St. Bart\'s data, the fact that the responses
became increasingly brief as the patients were repetitively treated.
These responses actually are a little bit shorter than the St. Bart\'s
data, but that\'s not surprising, I think, in that those patients had
almost all received only chlorambucil where these patients had almost
all received multiple agent chemotherapy. It\'s interesting that in none
of these groups did the remissions last as long as a year.

Well, another trap might be that the people had as their last qualifying
chemotherapy some really simple, not very aggressive regimen, but in
fact the last qualifying chemotherapy in about a quarter of patients
each was an alkylator-based regimen, an anthracycline or
anthracenedione-based regime, a fludarabine-based regimen or a
platinum-based regimen, the typical sort of salvage chemotherapy that
those of us who treat these patients have been used to utilizing.

Now, the response rate in this refractory group of patients is high.
Just slightly less than half of them had an objective response which to
me is an encouraging number, and don\'t forget this means the patients
might have benefitted, their symptoms might have gone away. Fourteen
patients had at least a year free of progression of their lymphoma, and
seven patients, or about one in eight, remained continuously well all
beyond three years.

Now, you might say ‑‑ again be concerned with those patients that
remained well for a long period of time were just the ones who got the
least therapy, and what this slide illustrates is that chemotherapy
history for those 14 patients who remained free of progression for a
year following the Bexxar in the pivotal trial, and you can see that
these are not undertreated patients at all, and most are fairly heavily
treated. Interestingly, the highlighted patients are those patients that
currently ‑‑ that remained well longer than three years, in complete
remission, well, for at least three years.

The alternative approach other using another cytotoxic regimen in these
patients with multiply relapsed low-grade B cell lymphoma is today
Rituximab, the unlabeled antibody that\'s an extremely popular therapy.
A study was done on 40 patients who had progressed after Rituximab, but
35 of those patients met the definition of refractory, that is no
response or response within six months. That has been used in previous
similar studies. Of those patients, 63 percent then, after failing
Rituximab, responded to Bexxar, and 23 percent of those patients, or
eight of the 35, remained well for at least two years. This is that same
data in tabular form showing the high response rate and then the median
duration, the proportion of patients achieving a complete remission and
the time to progression for all the patients.

Now, again, how do we put that in perspective, and there we have a study
that\'s been previously reported using the yttrium labeled Zevalin. And
once again, I would caution you, this is not a way to decide one or the
other drug is better; it\'s a way, for our purposes today, to be sure
there\'s not a red flag raised that the drug that\'s being considered
today is shockingly worse, that it has some problem we should consider.
And I would again argue that one wouldn\'t likely to conclude that
there\'s an obvious problem.

All right. So how do we then conclude, put this all in perspective?
Well, this is certainly an active drug in refractory low-grade B cell
lymphoma. Both patients who are refractory to chemotherapy and
refractory to Rituximab benefit. The most important observation is that
a significant proportion of patients, many more than you would have
expected in this group of advanced refractory disease, have durable
remissions. The treatment has been generally safe and well-tolerated and
does in fact provide an important option for some of these patients,
particularly ones who would not be a good candidate for bone marrow
transplantation.

The durable remissions are the most striking feature of this data. As I
said, certainly, I think, unexpected for, one, short therapy in a group
of patients with this chemotherapy history. These really were people
where the durable responders had a median of three prior therapies. The
majority were refractory to their previous treatment. Patients in all
risk groups had responses, and really it\'s quite unusual to see this,
and the only other condition where you see this sort of durable
responses in these patients is an allogenic bone marrow transplantation,
but that\'s treatment that would not have been available to most of
these patients based on age or availability of a donor. And it\'s a
treatment that\'s considerably more toxic; it has a whole different
order of toxicity.

So, finally, this is, to a great degree, the bottom line. This is the
integrated efficacy data curve showing the number of people here who are
alive, free of documented progression and free of another therapy,
showing that at five years somewhere between 15 and 20 percent of these
patients remain well. And this is an important outcome. As you heard
earlier, there are patients on this curve represented by those tick
marks who achieved life goals they would not have been able to do and
thought they weren\'t going to when they had multiply relapsed lymphoma.
They\'re someone who got married, they\'re somebody who had children.
The ability to take these advanced refractory patients and induce a
complete remission is important, and I believe it would be important
that this new drug be available for me and other clinicians to be able
to use to try to benefit such patients. Thank you.

CHAIRPERSON PRZEPIORKA: Thank you very much, Dr. Jacobs and colleagues
for their presentation. Before we take questions from the Committee for
Sponsor, I think we\'re due for a break. If we can be back here at about
3:20, we will convene and have questions for the Sponsor at that time.
Thank you.

(Whereupon, the foregoing matter went off

the record at 3:03 p.m. and went back on

the record at 3:22 p.m.)

CHAIRPERSON PRZEPIORKA: A number of members of the Committee have come
to me indicating that they have burning questions for the Sponsor, so I
wanted to actually take questions from the Committee to the Sponsor at
this point before going on to the FDA presentation. And I will ‑‑ while
we are getting a show of hands for who has questions, I\'ll take the
Chair\'s prerogative and start with the first question to Dr. Jacobs. Do
you have any information regarding safety of retreatment with Bexxar as
well as information on the delay of salvage therapy after treatment of
Bexxar in patients who have not gotten a response?

DR. JACOBS: Okay. The first question if we have data as far as patients
who have been retreated, safety. Could I have the slide as far as the
001 patients that were retreated? Do we have any safety data on that?
There were 14 patients in the 000 trial that were retreated with Bexxar,
and of those 14, seven did have responses, as you saw; five complete
responses. As far as the hematologic, the number of patients again, 14;
ANC less than 1,000 was 43 percent compared to our patient population
was similar. Platelets Grade III or IV was 21 percent; Grade III/IV
anemia, 14 percent. So it was comparable to the 620 patient population.
We did have a retreatment protocol that just completed 32 patients, but
that data is still being looked at. We just recently completed it, we
don\'t have that.

In regards to patients having additional therapy after Bexxar, we have
Dr. Leonard who has the most experience with his patients after
receiving Bexxar that have follow-up treatment.

DR. LEONARD: Good afternoon. I\'m John Leonard from Cornell. If you
could pull up B-111. Great. We looked and presented at ASCO a group of
our patients at Cornell who progressed after Bexxar, looking at the
issue of what their blood counts were at the time of progression. And of
155 patients, we had 68 patients who progressed. What you see here on
this slide is their blood counts at the time of progression. So on the
first row, you see the white count, ANC and platelets. This is
pre-radioimmunotherapy and then at the time of progression. And as you
can see, the counts were quite similar, both before radioimmunotherapy
and after.

Looking at the question of early progressors, the median time from
radioimmunotherapy to progression was 180 days, range was 42 to 839. So,
yes, there were a few patients that did have early progression, which
may have impacted their therapy. But the vast majority of patients, the
median again being 180, had their progression significantly later, after
the nadir period.

CHAIRPERSON PRZEPIORKA: Dr. Carpenter?

DR. CARPENTER: Do you or do others have open or planned studies
comparing Bexxar to Zevalin?

DR. JACOBS: We have actually a protocol that we will be submitting to
FDA comparing Zevalin and Bexxar in a patient population that is
Rituxan-refractory. The safety end points are the primary end point of
that study. That study will be submitted within the next month. We\'ve
had discussions with the FDA for including some additional information
and changes to that study.

CHAIRPERSON PRZEPIORKA: Dr. Martino?

DR. MARTINO: I have two questions, the first for Dr. Jacobs and then the
second for Dr. Armitage. The first question: I need some clarification
as to in 04 what data was available to allow the group to decide what
response and what length of response had occurred to the previous
standard therapy? In other words, what medical records, what x-rays were
available to make that decision, because, in essence, that is the basis
for then the comparison.

And the second question is to Dr. Armitage. I want an understanding of
the leukemias that occurred. Is there any pattern in the sense of as
more time passes are we seeing more leukemias or is there simply a basic
underlying rate of so many per year, is there a curve that can be
described?

DR. JACOBS: The documentation had to be thorough enough as far as all CT
scans evaluating the last qualifying chemotherapy and all accompanying
medical notes. Just for your information, as far as what happened then
with the MIRROR Panel review, the radiographs were all masked so there
were no dates. All materials from the physician notes were basically put
onto standardized case report forms so that the MIRROR Panel, the data
that they looked at from the physician, the oncologist, was the same for
that following Bexxar as it was for the last qualifying chemotherapy.
This was a difficult study to enroll because of the completeness of that
data for the last qualifying chemotherapy.

DR. FISHER: And so the question was acute leukemia that occurs after
cytotoxic therapy. We know from both the atomic bomb experience and some
subsequent data that acute leukemia after a potentially leukemogenic
marrow injury has about a ten-year window. It peaks about five years, so
the incidence rises for about five years and then tails off and after
ten years, is largely gone. Now, some of these patients had subsequent
therapies after the radioantibody and so will have further hits, if
you\'d like, that would make them at risk. But if this data follows what
has been previously described, the fifth year is about the peak of
incidence and it should ‑‑ incidence, the rate at which it happens,
should begin to tail off and patients more than ten years are pretty
much past the risk period.

DR. MARTINO: My question actually relates to the existing data related
to this drug. Is there a pattern that you can distinguish really is my
question?

DR. FISHER: The cumulative incidence curve I showed you and had reached
six and a half percent by five years. There are a few patients at risk
longer, but I think we can\'t be as ‑‑ you\'d be guessing if you tried
to be real confident about what\'s happening to the annual incidence
when you get very much past that time period, because there\'s so few
people at risk.

CHAIRPERSON PRZEPIORKA: Dr. Blayney.

DR. BLAYNEY: Thank you. I have two questions. One, do you have any
reason to suspect that sequelae of immunosuppression, long-term
immunosuppression might be a problem after this, particularly
opportunistic infections that practitioners might get sandbagged for,
longer than the six months which you followed patients for infection.

DR. JACOBS: Could I have the B cell recovery? In two studies, the
earlier studies we looked at, B cell recovery after Bexxar therapy, this
was in the first study 000, and the 003 study. As you can see, the B
cells do drop down approximately two months, three months, and most
recover by six months, and some patients took 12 months to 13 or 14
months.

The next slide is as far as hypogamma globulinemia, we looked at serum
IGG levels, and there really was no hypogamma globulinemia, most likely
due to the CD20 expression not being on plasma cells. As far as
infections, there were six percent serious infections. There was only
one pneumocystic infection and one other shingles that really was
probably commonly seen, but no increase as far as encapsulated
infections or those types of infections later on.

DR. BLAYNEY: Thank you. In your briefing document, you talked about
dosimetry of the isotope and how you modified that based on body fat
distribution. I wonder if you could expand a little bit on ‑‑ I didn\'t
hear much about dosimetry in your presentation. I wonder if you could ‑‑

DR. JACOBS: Actually, maybe I\'d like to have Dr. Wahl come up and go
into that, as he was part of those earlier studies.

DR. WAHL: I\'m Richard Wahl. I\'m Professor and Director of Nuclear
Medicine at John\'s Hopkins but I was at University of Michigan prior to
joining the Hopkins faculty and involved in the studies since 1990.

The adjustment for body fat is detailed in the briefing document, but in
brief at some time into the study it became clear when we were doing in
some patients specked three-dimensional imaging of the patients that
there was very little uptake of the antibody in adipose tissue. So the
assumption of uniform radioantibody distribution throughout the entire
patient which we had made initially under dosimetry was not quite
correct.

So in obese patients, we modified it so that if they were markedly
obese, we would not assume all of the antibody was uniformly
distributed. So there was a reduction or an attenuation in dose in the
obese patients, which was basically an adjustment at 37 percent above
the predicted lean body mass. We would not give a higher dose than that.
We would assume their body mass was not in excess of 1.37 times their
predicted lean body mass. And this simply again relates to the
biodistribution of the radiolabeled compound in vivo.

DR. BLAYNEY: Thank you.

CHAIRPERSON PRZEPIORKA: Dr. Brawley.

DR. BRAWLEY: Yes. Just a couple quick questions. Can you put up your
Slide Number 9 and Slide Number 48 from our packet and explain exactly
what the differences are? And then I have a follow-up to that.

DR. JACOBS: Slide Number 9?

DR. BRAWLEY: Yes.

DR. FISHER: I\'ll take you through this again, Otis, unless you want to
be more specific. This is data from St. Bartholomew\'s Hospital
published in the JCO, and what it shows is a group of patients followed
in that large single set of referral base that has basically a
significant part of Central London, so it\'s not quite population-based
but it\'s the same patients repeatedly and it shows what their response
duration is the first time they were treated, then they have a relapse,
another relapse, et cetera. So this is the median duration of response
with sequential treatment.

DR. BRAWLEY: Okay. Now let\'s compare that to Slide Number 48. That\'s
the same thing but that\'s for the treatment with Bexxar; is that
correct?

DR. FISHER: Well, that\'s not the same thing ‑‑

DR. BRAWLEY: Okay.

DR. FISHER: ‑‑ because the prior slide, the zero point starts every time
they get a new treatment. So what you could say was that you could
compare ‑‑ this starts at the Bexxar treatment. This does not take into
account their prior remissions or relapses. So if you wanted to see how
Bexxar did compared to a third or a fourth or a second, you could make
the comparison, but I\'m not sure that\'s a comparison you\'d want to
make. This is the result starting on the day you get Bexxar as to what
happens to the entire patient population. And remember that behind this
curve, before the zero time point, are a median of four treatments for
each of these patients, the results of which would have been reflected
on the prior St. Bart\'s curve.

DR. BRAWLEY: Okay. So the Bexxar curve there ‑‑ I\'m going to make the
comparison.

DR. FISHER: Could you speak up just a little, I\'m having trouble
hearing you.

DR. BRAWLEY: I\'m sorry. That\'s the first time anybody\'s ever had
trouble hearing me.

(Laughter.)

DR. FISHER: I\'m getting older, Otis.

DR. BRAWLEY: The people who are on their third treatment on the first
slide their curve looks a lot like the curve in this slide. Is that a
reasonable statement?

DR. FISHER: Let\'s look at this slide. This slide is in years, okay? And
so you\'re saying here that this curve, which is response duration and
out at three years, the data only goes out to about three years, if we
go back again to the next slide, that\'s about here on that curve. We
have follow-up six or seven years, and this is the number which on this
case, I\'m sorry, the statisticians will go nuts but I don\'t know, at
five years 25 percent, something like that.

DR. BRAWLEY: Okay.

DR. JACOBS: The other point on the Gallagher slide is that is the
duration of response for all responders. So it\'s not looking at all the
patients who responded that received that treatment, so\--

DR. FISHER: Duration of response curve, by definition, starts when you
are a responder. Time to progression, the zero ‑‑ the 100 percent here
includes all patients. So non-responders would sink that other curve. If
we gave you a time to progression on that other one, it would come down
significantly. That\'s the point you wanted to hear.

CHAIRPERSON PRZEPIORKA: Dr. Bridges.

DR. BRIDGES: First question is another dosimetry question. Was there any
specific dosimetry done to look at the dose and sites of bulk disease,
for example, if you had an epidural lesion, even though the whole body
dose is 75 centigrade, what the maximum might be to spinal cord in an
epidural lesion?

DR. JACOBS: We\'ll get Dr. Wahl back up here.

DR. WAHL: The briefing document gave a range of tumor doses, and
probably the highest tumor dose was in the range of just over 3,000
rads. The follow-up in dose with the relatively low energy beta of I-131
is substantially more rapid than with the more energetic beta, so that
at about one millimeter, only the dose falls off to five percent of the
tumor dose. So at a distance of one millimeter from it, at 0.1
millimeter it\'s about 33 percent. So those estimates were provided to
the Agency. It\'s a relatively rapid drop-off.

CHAIRPERSON PRZEPIORKA: Dr. Krook?

DR. KROOK: I\'d like to go back to this question that my colleague asked
over there about last qualifying chemotherapy. I\'ve generally been
involved in randomization studies, and one of the things, as I look at
the pivotal trial, we\'re comparing this, and I had to deal with this as
I looked at the data, it\'s a bit of historical trial although we\'re
using the patient as their own historical control. But one of the things
as I look at this is how good are the records, and I realize some of the
investigators are in the room. And I\'ll speak for myself again that
commonly when a patient\'s on study I\'m much more diligent at doing
things than I am when they\'re not. So if somebody\'s from the MIRROR
group, I don\'t know whether somebody\'s here that looked at this, what
were the records like that we\'re using as the last qualifying ‑‑ were
they reasonable to look at or was it a difficult task?

DR. JACOBS: We don\'t have anyone from the MIRROR Panel, but we do have
investigators that were on the 004 study. Maybe one or more of them
would like to come up and comment. Dr. Press, Dr. Zelenetz, Julie?

DR. VOSE: I\'m Julie Vose from University of Nebraska, and I was one of
the investigators on many of these studies that you heard presented
today. And I can tell you from what they expected us to show from the
last qualifying chemotherapy they were very diligent about getting
excellent medical records, about getting CT scans that were excellent in
quality, and there were many patients that unfortunately we did not have
that on and could not go into the study. So for those patients who
actually did go on the study, I can you, I personally documented or
looked through all the medical records very diligently and also the CT
scans.

DR. KROOK: The second part, and perhaps, Julie, you can comment on this
also, is that as I look at some of the discussion, and this may come in
later, with the FDA and the records there was quite a bit of discussion
as when to call a response a response and there were some that at least
as I looked at it that were progressions. And then they became a PR. I
don\'t know if you were involved in that or not, but there\'s a whole
discussion that was in there about that of how you define ‑‑ it appears
there was a moving target with defining what a response is in the data
that I looked at from the Company.

DR. PRESS: Well, I guess I\'ll begin just by mirroring what Julie said.
I\'m Oliver Press, I\'m a professor of Medicine at the University of
Washington and a member of the Fred Hutchinson Cancer Research Center.
I\'ve been entering patients on these trials since 1990. And I also
contributed patients to the pivotal trial and agree with Julie that this
was a difficult trial to accrue patients to because of the strict
requirements for detailed records and CT scans. The responses, as has
also been mentioned by Cindy Jacobs, were assessed by an independent
panel in a blinded fashion, and so if there were difficulties assessing
response, that would have come out in the panel. And, actually, the
concordance between the MIRROR-assessed responses and the
investigator-assessed responses was very good.

DR. JACOBS: I think I know what ‑‑ we had ‑‑ the Agency, when we had the
long durable responses last year, asked that we have ongoing MIRROR
Panel assessment of all the patients that were long-term durable
response. So we had another charter to deal with that and reconvened the
MIRROR Panel. I believe there was one or two patients that had at the
last MIRROR Panel had been thought to have progressive disease but in
review of them the follow-up evaluation had no treatment and was
assessed as in complete response. So there were a couple of patients
with ongoing MIRROR Panel reviews that that happened. We also had then,
yet again, a second MIRROR Panel review for those cases more in the
earlier trials that had happened or other questions that the FDA had. We
re-MIRROR\'d the 37 patients, and of those 36 were still as per the
original MIRROR Panel.

DR. VOSE: I just wanted to say one other thing too. As you heard from
some of the patients earlier, this is a very unusual treatment in that
the patients continue to have response over a period of time and in some
cases up to nine to 12 months do they continue to respond. So it\'s a
little bit of a moving target, as you mentioned.

CHAIRPERSON PRZEPIORKA: Before you sit down, Dr. Vose, a question
please. Can you give us ‑‑ we want to know a little bit about clinical
benefit, which sometimes is objective and sometimes is not. Can you let
us know a little bit about how difficult it is for patients to receive
this therapy and what specifics you have to educate them on in
comparison to other radiolabeled antibodies that you have used?

DR. VOSE: Sure. This is a therapy that is very easy to administer, both
from the standpoint of the physician, the nuclear medicine technologist,
the nuclear medicine physician, radiation oncologist, the nursing staff.
We have a very specific team that educates the patient and performs the
radioimmunotherapy, both for this agent and for other agents, and it\'s
very easy to administer from that standpoint as well as from the
patient\'s standpoint. They get, as you heard, two therapies a week
apart, outpatient, very minimal side effects, and compared to many other
therapies they received, chemotherapy agents, or radiation therapy for
that matter, it\'s very non-toxic. The education for the patients is
very easy as far as the restrictions that they have, very minimal
restrictions, as you heard earlier from some of the patients. And
compared to other radiomenaconjugates, it\'s very similarly administered
as an outpatient, so very easy to administer.

CHAIRPERSON PRZEPIORKA: Dr. Reaman?

DR. REAMAN: In those patients who are assessed to have durable
responses, do you have information on the percentage that had documented
complete remissions?

DR. JACOBS: Well, in the presentation, it was 76 percent of the patients
had CRs that were in the Durable Responder Population.

DR. REAMAN: Okay, 76 of the Durable ‑‑

DR. JACOBS: Seventy-six percent of the 76 patients. It is a little
confusing, yes.

DR. REAMAN: And in the secondary leukemias, any specific molecular or
cytogenetic patterns have been identified?

DR. JACOBS: Actually, we have Dr. Bennett here who reviewed those cases.
I\'d like to have him comment on that.

DR. BENNETT: Yes. John Bennett, University of Rochester. We have a lot
of information on the cytogenetics, both prior to Bexxar and following,
and they all show the typical alkylating agent deletions, minus five,
minus seven, plus eight. And of the ones that I picked up that were
prior to Bexxar, three that have cytogenetics had chromosomal
abnormalities. We have not seen any of the topo-2 type specific
translocations.

CHAIRPERSON PRZEPIORKA: Dr. George?

DR. GEORGE: A question I think probably best addressed for Dr. Fisher.
Could you describe the SWOG studies that are either ongoing or planned
with the randomized studies and how it relates to this discussion?

DR. FISHER: Excuse me. Give me just a minute. We can treat lymphoma, but
we can\'t treat the common cold, I apologize.

It isn\'t that difficult a question for me to answer either. The SWOG
studies are two studies we have done in Bexxar that are of interest. One
is completed. It is a Phase 2 study looking at CHOP induction
chemotherapy and then at minimal residual disease, the administration of
Bexxar sequentially. That study is still undergoing follow-up, but we
can tell you that Bexxar was administered with essentially no major
toxicity, no life-threatening toxicity and very good clinical and
molecular responses continuing with over about an 85 percent
failure-free survival at three and four years now, as we look at that.
So that\'s one study that was completed.

The other study that\'s ongoing is a randomized Phase 3 study, which was
originally going to compare CHOP ‑‑ this is in untreated follicular
lymphoma, as was the last one I described for you, so this was going to
be CHOP versus CHOPO Rituxan versus CHOP Bexxar, with CHOP Rituxan given
in the interdigitating way that Chuchman did and CHOP Bexxar given in
the way I just described at our prior pilot study.

Unfortunately, unfortunately I say with deep regret, in this country, we
cannot randomize patients upfront now to chemotherapy alone without
chemotherapy plus an antibody, and this study has accrued very badly. So
we have just amended that study to look at CHOP. We\'ll be chemo
immunotherapy versus chemo radioimmunotherapy, i.e. the CHOP versus the
CHOP Bexxar, and that is a Phase 3 study that\'s ongoing.

CHAIRPERSON PRZEPIORKA: Dr. Blayney.

DR. BLAYNEY: A question again I think for Dr. Wahl perhaps. On Page 86
of your briefing document, you make some dosimetry comparisons, normal
tissue tolerance, et cetera. One of the ‑‑ two of the tissues that seem
to be at risk are the testes in the male and the bone marrow dose. The
bone marrow, the red bone marrow doses with your compound looks to be
105 centigrade. How does that compare with total body irradiation that
one gets for the immunosuppression in the stem cell transplant setting,
first of all. And, second, do you have concern that this might lead to
infertility in the male because of the testes dose?

DR. WAHL: Well, the total dose of the marrow ‑‑ maybe I can address that
first ‑‑ is largely delivered by the blood to the marrow and the readout
of the toxicity to the marrow is probably best reflected by the
peripheral blood counts which were monitored in the Phase 1 dose
escalation. So the patient individualized dosing for Bexxar is designed
to give a dose which in the individual patient will be sufficient to
cause typically mild, relatively modest bone marrow reversible
depression end counts but not long duration toxicity. So I think that
this is in the range of other radiopharmaceutical therapies which are
designed to be non-myelo ablative.

The dose to the testes of about 100 rads is slightly ‑‑ I\'m referring
to the dose shown on Page 86 ‑‑ is slightly greater than the total body
dose. I think that it\'s more than most diagnostic procedures.
Certainly, it\'s less than the doses that Dr. Press would be giving for
total body radiation, I believe, potentially, but it would be a
consideration and I think issues regarding reproduction would have to be
carefully discussed with each individual patient. I doubt if it would
lead to infertility, certainly.

DR. BLAYNEY: You say you doubt?

DR. WAHL: I doubt, yes.

DR. BLAYNEY: Okay. The total body dose, I think it ‑‑ I\'m sorry, the
marrow dose has implications in patients who may have received
alkylating agents before, and I point out that the peak incidence of
therapy-related myelodysplastic alkylator agent is about six years, and
you haven\'t ‑‑ most of these patients have not been followed for that
length of time. So I think it is an issue, a safety issue going down the
road.

DR. PRESS: Dr. Press again from the University of Washington. I would
just supplement those comments by our studies with high dose Iodine 131
labeled tositumomab. We\'ve done a series of studies at the University
of Washington which haven\'t been presented today in which we treated
116 patients with doses of this radiolabeled antibody, which are on the
average five times higher than those which have been administered in
these studies that you\'ve heard about. Those doses do tend to be
permanently myelo ablative and so we give stem cell rescue with them.

Most of the patients on our transplant studies do maintain fertility if
no additional chemotherapy is given. We\'ve treated 40 patients with the
radiolabeled antibody at myelo ablative doses as a single agent and
another 74 in which they also get cytoxanity topiside. If they get
chemotherapy along with it, they\'re generally sterile, but the majority
of patients who get it as a single agent have remained fertile.

In terms of bone marrow dosimetry, we estimate we give about five times
the dose to the marrow, and that in our setting is myelo ablative
permanently in response to your first question.

DR. KAMINSKI: Good afternoon. My name is Mark Kaminski, and I\'ve been
involved in ‑‑ from the University of Michigan, Professor of Medicine
there. I\'ve been involved with Bexxar studies since 1990. In answer to
your question, Dr. Blayney, from the front-line study where previous
chemotherapy is not a confounding factor, there are two males who have
fathered normal children without bank sperm.

CHAIRPERSON PRZEPIORKA: Dr. Pelusi?

DR. PELUSI: If I can switch gears here for just a minute and ask you
were there any quality of life studies that were done on our patients?

DR. JACOBS: Yes. There was one quality of life study done, and Dr. Mike
Hamilton has some of that data to summarize that.

DR. HAMILTON: May I have B-73, 76 and 77. I\'m Michael Hamilton from
GlaxoSmithKline. I\'m in clinical development. So there was a secondary
end point of quality of life in the 004 study. Please keep in mind that
these are limited data, though. It\'s very hard to take these too far,
because only two-thirds of the 60 patients were able to fill out
baseline questionnaires and at least one follow-up questionnaire. You
can see that at baseline and at week 13, the patients had scores on the
EORTC, quality of life of questionnaire, that were below the normalized
general population score. But at week 38, they had recovered to levels
that were thought to be statistically improved. So if we can just run
through the next two slides.

This is a functional scale where 100 percent would be a normal
population, and you can see a general upward trend from the baseline to
week 38. And the next slide. A symptomology scale where zero would be no
symptoms and a general improvement in symptomology over that time. But,
again, you can see that with very small numbers, the 38 weeks is only 15
cases.

DR. PELUSI: If I can make a comment. You know, we seem to go round and
round a lot about quality of life on numerous occasions, and I\'m always
concerned that many times we miss the true experience of the family and
of the patient. And I know that quality of life studies are very
difficult to do, but they\'re not impossible to do. And that\'s a piece
of information I think that becomes very valuable to us in terms of
informed consent. If we go forward and we have something to offer to
patients, I think it\'s important to see really what are other people\'s
experiences, not only for us as clinicians to be able to plan for the
potential of different issues, but also for patients to make wise
informed decisions. And I really wish that we could really start to
incorporate whether it\'s quality of life or even phenomenology studies
in addition to this, because you don\'t need a lot of patients for that.

And the second just comment very quickly is we always lose the voices of
those patients who either don\'t do well with the treatment or are off
treatment. And that is another valuable piece of information for
patients, families and clinicians that we really can\'t lose. And as we
heard today, very compelling testimony by many people who are here, and
I just always wonder why do we have such a low accrual rate in terms of
the quality of life, so it\'s just a comment. But I think it\'s
something we truly have to look for in the future, because that is the
everyday living with or without this drug, and that\'s important to all
of us. Thank you.

DR. HAMILTON: Well, I just want to add that we do fully agree with the
importance of the quality of life end points, and in our committed
studies quality of life is built into those so that this is not just 40
patients and that\'s all we look at.

CHAIRPERSON PRZEPIORKA: Thank you, Dr. Pelusi. Dr. Kelsen.

DR. KELSEN: You plan to compare Bexxar to Zevalin, and I wonder if you
could tell me a little bit about the hypothesis that you\'ll be testing?
Will you be looking for superiority and if so in which way, or will you
be looking for non-inferiority?

DR. JACOBS: For the study that we have yet to submit to FDA but we have
discussed with FDA as of April of this year, the primary end point was
really safety Grade III/IV toxicities. The study was powered to look at
the possible difference between the safety, but as far as efficacy, it
would be a non-inferiority.

CHAIRPERSON PRZEPIORKA: Ms. Krivacic.

MS. KRIVACIC: Do you have any data regarding the use of your
hematological supportive care?

DR. JACOBS: I\'m sorry, I can\'t hear.

MS. KRIVACIC: Do you have any data regarding the use of the
hematological supportive care products, such as your G-CSFs and how that
interacted with the use of the Murine antibody, if at all?

DR. JACOBS: No. I don\'t believe we have any information regarding the
11 percent of patients who got G-CSF and their inaction; no, we don\'t.

CHAIRPERSON PRZEPIORKA: Thank you very much. I think that\'s all the
questions that we have from the Committee, and we will now move on to
the FDA presentation. Dr. Litwin, the Medical Reviewer. Dr. Siegel.

DR. SIEGEL: Yes. I\'d like to interject a quick comment here to clarify
some issues. We read ‑‑ I read in the [Journal of National Cancer
Institute]{.underline}, I guess last week, the FDA\'s interactions with
Bexxar have become one of oncology\'s great political mysteries and one
that has no obvious explanation. And we\'ve heard a lot of people here
talking about the fact that this drug has been studied for some 13 years
and the article actually included an analyst who speculated that, \"My
personal feeling,\" at least he indicates it\'s a personal feeling, \"is
that it was not a safety dosing or efficacy issue, it was a bureaucracy
issue or a process issue.\" I hope that those here who know the FDA,
know my group and other groups in the FDA, know that we don\'t spend
years of time reviewing applications for cancer, important cancer
indications for bureaucracy purposes. You may or may not always agree
with us on how we interpret the issues, but I can assure you that we ‑‑
and I\'d like to assure the patients who spoke, I think, very eloquently
of their experience, that we can\'t always come to the public and tell
you why we\'re ‑‑ what\'s taking so much time, but it\'s not because of
bureaucracy issues.

We can on occasion like this come to the public and tell you a little
bit, and I just want to give just a little bit of some of the issues
here and not at all in any way to ‑‑ I\'m going to mention some issues
that are resolved and not at all in any way to prejudice against or bias
against Corixa who has worked extremely diligently with our reviewers
over the last few years to resolve all these issues. And so they are not
issues that are important issues in the review, but I think they\'re
important just in terms of the public having an understanding of some of
the complexities of a product like this. And it just so happened that a
few minutes ago I looked through my files ‑‑ not a few minutes ago, an
hour or two ago, but during this meeting ‑‑ and have seven pages of
handwritten notes from a meeting we had almost two years ago today,
December 22. And reading through that was quite interesting.

It\'s important to note, for example, without going too much into a
territory to the extent that it might be getting into commercial trade
secrets, that this product over that period of time was manufactured in
three different facilities, and there were substantial differences in
the product to the extent even in the primary amino acid sequence, so
you\'re seeing data from products with different primary amino acid
sequence and with heterogeneity and variability and the amount of
glycosylation and with variability in de-amidization and isomerization
and other issues.

These are issues that in order to understand whether these data, these
data that have been generated over 12 or 13 years are relative to the
material that was proposed for commercialization two or three years ago
that had had very limited clinical experience but had some ‑‑ required
some substantial evidence, not necessarily clinical but some substantial
data and was a significant issue for review and concern. And I\'m
pleased to say, and this isn\'t true with some of the products that we
review, I\'m pleased to say that we did get excellent data and we are
quite comfortable with that issue, and it\'s not an issue for discussion
before this Committee, but it is a critical issue because it could have
turned out differently.

There were important issues at that time in long-term toxicity data, and
they simply were not there in the original application. We saw the
thyroid imaging in a substantial number of patients. We knew there was a
radiation to the thyroid. The TSH was to be measured in the protocol,
but about half of the patients had their six-month TSH, and if you went
past that, you got the time points where I think it was like 95 or 98
percent of the patients the data were missing. There was no way to know.

If we were here, similar but not as severe issues were occurring with
the HAMA data and the HING data. So if we were here two years ago and
putting worst-case scenarios up, you would be looking at 99 percent of
the patients or 90 percent of the patients with serious hematologic as
the worst-case scenario because there were that many where we just
didn\'t have long-term data. Long-term data in antibody responses can be
very important with a product such as this because in fact it suppresses
the B cells and it suppresses the ability to make antibodies. And
sometimes you see the antibodies arising relatively late, and the data
simply were not there at the time to address a lot of those concerns.

And so now when you see that the database went from 200 to 600 and you
see there\'s maybe ten or 15 percent range of uncertainty in some of
these toxicities, it\'s worth noting that that ten or 15 percent may
have represented half of the patients in the original database in which
we simply didn\'t have uncertainty or more. There were a lot of other
issues, not all critical, you know, who had transformed disease and who
didn\'t, who was refractory to the original therapy, who wasn\'t, and so
forth. There were issues in March that we\'ll get into this year even in
terms of regulatory policy related to the approval of Zevalin.

But, again, my point is simply not to raise issues or concerns nor at
all to be critical of the process over the last two or three years,
which has I think been a very productive process in addressing some very
important issues but simply to indicate that what we\'re looking at here
and what we\'re discussing here is a culmination of a process of
gathering data which allows us at this point in time to assess this
product in a way that we felt could not adequately done prior to this
point in time. Thank you.

CHAIRPERSON PRZEPIORKA: Mr. Ohye.

MR. OHYE: It seems to me you\'re saying, Dr. Siegel, that the, as they
say in many proceedings, that the jury should not take under
consideration the prior statements. Thank you.

CHAIRPERSON PRZEPIORKA: Thank you. I\'ll call the podium then. Dr.
Litwin.

DR. LITWIN: Good afternoon. I\'m Dr. Stephen Litwin, and I will present
for the FDA the results of our review and analysis of Corixa\'s
tositumomab therapeutic regimen, and I will refer to it during my
presentation by its initials, both for clarity and to save some time, as
TTR.

I appreciate that we\'ve had a long afternoon here, and I will try to go
quickly over those areas which Cindy Jacobs has so well addressed and
focus on those parts of the review which represent differences in terms
of our approach or any differences in position.

You\'ve seen the proposed indication. I\'ll give you a moment to take a
look at it. There were two major studies that supported the efficacy
claims. The first study was 004, and this was the primary efficacy trial
that supported the request for accelerated approval for treatment of
chemotherapy refractory patients with low-grade and follicular
non-Hodgkin\'s lymphoma with or without transformation. And this is the
same indication or a similar indication for which Zevalin received
accelerated approval last fall.

The second major study was 012. This was the primary efficacy trial that
supported standard approval for the treatment of Rituximab-refractory
patients with follicular non-Hodgkin\'s lymphoma, and let me just point
out that much of the data on this was as late as July of this present
year.

There are three other supportive studies which I will touch on in just a
few minutes. Those additional studies were the 002 study, 000 and 001.
I\'ll start with the 004 study. This was a multicenter single arm. It
was historically controlled with essentially the patient serving as his
own control with the present treatment, TTR, being compared to his last
qualified chemotherapy. The primary efficacy end point was the
proportion of patients who had a longer duration of response after the
current therapy, TTR, as opposed to when compared to longer duration of
response after their last qualifying chemotherapy regimen. And the
responses were based on MIRROR Panel or a Central Panel assessment.

The secondary efficacy end points have been mentioned. The study
population consisted of 61 patients who were enrolled at eight centers.
We analyzed those 61 patients. They included one patient who withdrew
consent and did not receive either of the doses. The Sponsor analyzed 60
patients. The results did not significantly differ on that.

Now, among these 61 patients who were registered, there were seven who
had responded to their last qualifying chemotherapy, the remainder had
not, and the median duration of this response to their last qualifying
chemotherapy was 4.1 months.

This is essentially a two-by-two contingency table with the four cells
in the center and the totals on the outside. If we look ‑‑ not working
very well ‑‑ if we look at the seven patients who had responded to their
last qualifying chemotherapy, we can see that three of those patients
had responses to the current regimen, TTR, and four did not. If we look
at the 54 patients who had no response to their last qualifying
chemotherapy, there were 25 who had a response to the TTR and 29 who did
not.

If we break down the categories of these responses, they break down into
three areas. Those patients who had ‑‑ well, let me point out that in
addition to judging the responses of the patient to his own last
chemotherapy, we also took into consideration, the analysis took into
consideration the duration of the response. This broke down into three
then patient categories: Those patients who had an equivalent duration
of response to both their last and the current therapy; those patients
who had a longer duration of response to TTR, longer is defined here as
at least 30 days or the third category, having a longer duration of
response after the last qualifying chemotherapy.

This is the same table taking into consideration a partition for the
duration of the response. If we look at the same seven patients who had
a response to their last qualifying chemotherapy, we can see that two of
them had a longer response to TTR and one had a long response to the
last qualifying chemotherapy. There were 29 patients who would be judged
as equivalent duration, because they had no response to either the
current regimen or to their last qualifying chemotherapy, and I think
the other two cells are self-explanatory. Those who responded to TTR but
no response to the last qualifying chemotherapy and more or less the
reverse.

Looking at these frequencies then of these categories, there are 29
patients, or 48 percent of patients, who had an equivalent duration of
response. Twenty-seven, or 44 percent, of patients had a longer response
with TTR, and five, or eight percent, had a long response with the last
qualifying chemotherapy. This was statistically analyzed by McNemar\'s
method and by the Sponsor and by the sign-rank test by our own
statistical staff. And although the methodologies were different, the
results were similar. They indicated a strong favorable outcome for the
TTR, which met the primary end point. Secondary end points we\'ve seen.
They include the overall response rate of 46 percent.

I\'ll turn now to the second major study supporting efficacy and that is
the 012 study. This was a single arm multi-center study. It was
conducted in patients who had relapsed after one or more courses of
Rituximab. The end points were overall response rate, complete response,
time to progression, time to treatment, failure and survival.

Because this study did not prospectively have designated powered primary
end point and because there were questions about the definition of the
timing of a refractory, that is refractory to Rituximab state, we
elected to analyze three different populations, both to compare them and
to gain some perspective as to the vigor of the results.

The three populations are shown here. The first, or the registered
population, is an intent-to-treat population. It\'s the 43 patients who
were enrolled. There were three patients who failed to receive any of
the study agent because of progressive disease. This is the treated
patient population. It was mainly analyzed for safety. And the last is
the indicated patient population of 30 patients which was restricted to
those patients who had follicular non-Hodgkin\'s lymphoma, had a
response duration to Rituximab of no more than six months, and it
excluded the three patients who had not received any study agent.

Looking at the outcomes of these, this is the registered, the first
population, the intent-to-treat population. We also elected to look at
the outcomes by investigator on-site assessment and the outcomes of the
Central MIRROR Panel since the investigator assessment was designated as
the primary outcome in the original submission. For the overall response
rates, the respective values are 60 percent and 63 percent. The median
durations of response, 1.9 years and 1.3 years. The complete response is
seen below.

I\'ve not touched on the treated patient population but have skipped to
the third population, that is the indicated patient subpopulation, which
conforms most closely to that indication which is being requested. The
overall response rate for the investigator assessment and the MIRROR
assessment are essentially the same, although if you keep in mind that
the numerator and the denominator were actually different for both of
these, 60 percent and 63 percent, the median duration of response was
not reached for the investigator assessment. It was 2.1 years for the
Central Panel.

We also did an exploratory analysis once again in study 012 to see if
patients who had responded earlier to Rituximab would have the same or a
heightened or lesser ability to respond to the current TTR therapy.
Among the 18 patients who had responded earlier to Rituximab, 11 of
those 18 had an overall response rate of 61 percent and a median
response duration of 2.1 years. In the 25 patients who had not responded
to Rituximab, 16 of the 25, or 64 percent, had an overall response rate
1.3 years median duration. These numbers, these numbers comparing the
two, are no different, and they indicate that there appears to be no
particular tendency for Rituximab-responsive patients to do better or
worse, at least within this unpowered assessment with the TTR therapy.

I\'ll turn now to the supportive studies, 002, 001 and 000. They\'ll be
much more brief. The 002 study was a two-arm multi-center open label
study. It was randomized between the arms, but the randomization was not
stratified. Population was the chemotherapy-relapsed or refractory
patient group. The two treatment arms, arm A was the treatment arm, was
the TTR therapy, which I\'ll call hot arm, and Arm B, which is the
unlabeled anti-unlabeled tositumomab, referred to as the cold arm. The
end point was complete response which differed from the others studies
that I\'ve been talking about thus far, with overall response rate being
the secondary end point along with others.

There were 78 patients enrolled in this study 002. There were 42 in Arm
A, the treatment or hot arm, 36 in Arm B. A series of prognostic
variables and demographic variables were analyzed. For the most part,
the majority of these were similar with just these three exceptions,
which I\'ll show here but I won\'t read. I\'ll let you ‑‑

Outcomes, the complete response rate for Arm A was 33 percent versus
eight percent in Arm B. I think you\'ve already seen this data. I\'ll go
through it quickly. The overall response rate in this controlled study
was 55 percent in the Arm A, or the treatment arm, 19 percent in Arm B.

This is a time-to-event curve. The upper data is the Arm A, the lower
data Arm B for duration of response given in years. The percent
responders on the Y axis, these curves do not differ significantly. This
is the years to time to progression. Arm A is significantly better than
Arm B. The years in time to progression are given in years on the x axis
and the percentage not progressing, this is somewhat inverse as some
people use, is given on the y. And it significantly different favoring
Arm A.

And, finally, the survival in years is compared. There was no difference
between Arm A and Arm B. On the other hand, between year one and two,
the curves are not together. They come together somewhat later. Patients
from Arm B, that is the cold arm, were permitted by protocol within
three months to cross over and receive the TTR treatment, and this
conceivably could have confounded the results and interpretation of a
survival difference between the two arms.

Study 000 was a single-center dose-escalation study. Its purpose was to
determine the optimal biologic dose of cold antibody and the maximal
tolerated dose for TTR. There were 59 patients enrolled. This was an
earlier exploratory study, and some of these patients had received prior
bone marrow transplants and had received different dose regimens. There
were 22 without prior bone marrow transplant who were treated at the
MTD.

The last study, 001, was a multi-center single-arm study. It assessed
reproducibility of the dosimetry methods. There were 47 patients
enrolled. The results for the dosimetry were satisfactory.

This is an overview of the study results of the five efficacy activity
studies that I\'ve just been describing. The first two were the major
studies. I\'ll just remind you again the 004 being for the
Rituximab-refractory group of patients, the 012, for those patients who
were ‑‑ I\'m sorry, I just turned that around ‑‑ the 004 for the
chemotherapy-refractory patients, the 012 for those patients who had
failed Rituximab therapy. The remainder of the three are supportive
studies.

All of them have more or less similar median prior chemotherapies with
the exception of the 002 study, which is less. The overall response
rates are in a relatively constricted range., from 46 percent to 63
percent. The complete responses range from 20 to 30 percent. The median
duration of responses from one to 1.3 years. The only data that we
don\'t have that is not reached is the 002.

There were two subset analyses that were done, which have been spoken
about but because of the importance of this, I will touch on them again.
Those were a long-term responder analysis and a low-grade transformed
analysis. The long-term responders were submitted by the Sponsor to show
that the TTR, current regimen treatment, provides, and this is actually
a quotation from regulations, a meaningful therapeutic benefit over
existing treatments in support of accelerated approval.

The low-grade transformed group, or subset or patients, were analyses
that we requested to assess the differences in activity in the
transformed versus the non-transformed patients since all of the
individual studies included both types of patients.

Long-term responders, they were defined as responding patients who had a
time to progression of over a year, a year or over, as per the MIRROR
Panel review. We, I think, came up with the same number of 78, down to
76 of the 271 patients we have identified in this efficacy activity
group. There are small differences in the numbers of patients that we
were analyzing. That\'s 28 percent of the patient population that were
identified by the MIRROR Panel as being long-term responders. And of
these, we looked at 68. We removed the eight who had had multiple
dosimetric doses, and I should emphasize that these patients were all
retrospectively identified across the five-activity efficacy studies,
the group starting with 271.

As you might expect, most of these patients were complete responders.
There were 21 percent who were partial responders. The median duration
of the response was 4.9 years with a range of 0.9 to 7.8 plus years. We
did a logistic regression analyses on a number of factors, both
predictive and demographic factors. These are the four that were
positive. The comparison is between the long-term responders, the group
of 68, which I\'ve just discussed, and the remainder of the population
of the 271 patients, that remaining number of patients who did not
qualify as long-term responders.

The four variables all deal with the state of entry at the time of entry
of the patients. They were less qualified chemotherapy end day to study
entry day, the response to the last qualifying chemotherapy in terms of
a complete response versus partial response, the duration of the
response to the last qualifying chemotherapy and the number of low
versus intermediate versus high tumor grades. And I think you can see
that all of the ‑‑ in all of these four parameters, it seems evident
that the long-term responders represent a more favorable initial
population. I think this is probably most marked in the first variable
or the third.

The second subset were the patients with transformation. There were 71
of the 271, or 26 percent, from these five efficacy studies who were
transformed histology. We reviewed and confirmed with sufficient
information to document 40 of the 59 we looked at, and there are a
remaining 12 under review. Looking at those 40 patients, the overall
response rate was 40 percent, the complete response rate, 26 percent,
median duration of response, 1.6 years.

I\'m going to turn now to the safety data. The most ‑‑ I\'m sorry,
safety was looked at in five areas. The most severe and serious safety
problem was, as we\'ve heard, hematologic, neutropenia, lymphopenia with
resultant infections, thrombocytopenia with hemorrhagic events. We
looked at infusional reactions. There was gastrointestinal toxicity. The
tositumomab protein monoclonal antibody was a Murine protein and we
looked at immune responses to the Murine protein. And, finally, delayed
toxicity as a result of irradiation, particularly hypothyroidism and
secondary leukemias of myelodysplastic disease.

The safety database that was provided included 620 patients. Of these
620 patients, 229 were enrolled in the five efficacy and activity
studies, which I\'ve listed here, which I\'ve just described to you, and
the remainder of 391 patients were treated under the expanded access
experience in CP98-020 or in some individual trials. I will refer to
this at this point as ISS-A and ISS-B. And this shows where these
patients came from. Once again, the ISS-A group is comprised of patients
enrolled from the five efficacy activity studies that I\'ve just
described. The ISS-B is mainly from the expanded access trial plus four
individual patients, and I\'ll call your attention here to RIT-II-003,
which is a study I have not talked about thus far. These patients
differed substantially from many of the others in that they were
untreated but the Sponsor has provided information on them as additional
and very useful information. There were 77 patients.

The safety profile in the ISS-A, the five efficacy activity studies,
showed a higher incidence for overall adverse events, Grades I through
IV. In the first 13 weeks, roughly 90 days, as compared to the expanded
access group, of 391 ISS-B, there was a less comprehensive collection of
data in the expanded access trial and no monitoring. It was under
reporting of the adverse events in the expanded access trial which was
recently confirmed during an inspection. These are the incidence of AEs
as Cindy described. These are regardless of relationship to the study
agent.

In the first two columns, I compare ISS-A to ISS-B. These are Grades I
through IV for various of the adverse events. The adverse events are
listed from the top down in order of incidence. And you can see there\'s
a two or three-fold difference, much higher in the ISS-A group for
virtually all of these adverse events. I\'ll show you more in the next
slide. This tendency is not as marked for the Grade III to IV comparison
between ISS-A and ISS-B.

This is a continuation once again in order of frequency. One can see up
to twofold or more differences between the incidence of these adverse
events between these two subsets of populations.

This next slide, are serious adverse events. They compare directly ISS-A
to ISS-B, 229 patients in the first, 391 in the latter. Once again,
there is a marked imbalance; that is there are many more serious adverse
events reported, mainly in the first 90 days in the ISS-A subset as
compared to the ISS-B. Now, the only comparison here which probably is
confounded is that of Myeloproliferative Disorder since this is a
time-dependent event, and the patients from ISS-A were enrolled much
before at a much earlier point in time than those in the expanded access
trial. Certainly this comparison is probably not fair.

I\'ll start now with the hematologic toxicity. Complete blood counts by
protocol were to be collected at least weekly beginning at week three
until the recovery from the nadir to at least Grade III or removal from
the study of the patient. Patients who had missing data during the
period of the expected data, which is weeks five to nine, or at the time
of recovery were assigned a worst-case scenario which Dr. Jacobs has
already given you the data on. And I\'ll show you the data for both the
documented Grade III and IV toxicity and the worst-case scenario.

For neutrophils, we had 51 percent Grade III or IV toxicity with the
worst-case scenario, that is the imputed values for patients who had
missing data during weeks five through nine shown below. For platelets,
42 percent. Once again, it\'s a higher figure as you might anticipate
for the worst-case scenario. For hemoglobin, 15 percent documented, once
again a higher figure if data is imputed. The percentage of Grade IV
toxicity is shown and once again worst-case scenario.

The toxicity, the Grade III or IV toxicity began earlier for platelets
at day 34, somewhat later for neutrophils. For both of these major
lineages it was 30 days in duration. In ten percent of the patients, it
was 62 days or more for neutrophils and 102 days or more for platelets.
And the maximum observed is shown below.

The target organ for the study agent TTR was a CD20 positive B
lymphocyte. These are determinations done by the Sponsor. I\'ll point
out two things to you in this data. First of all, they are selective.
They only involve study 001 and study 003, the 003 being patients who
were immunologically in much better shape. And I also would like to
point out that if you look at the ends, you\'ll see that many of the
patients were no longer available, there\'s a rapid decline as we move
along, so it makes the data somewhat harder to interpret. If we compare
the median at the baseline, there\'s profound depression of lymphocytes
at week seven and week 13, and even at month six, at which time this
value falls into the normal range by the CD20 positive lymphocyte
determination done in a laboratory, the median value is still well below
50 percent of the baseline value. I should also point out we agree with
the Sponsor, with Corixa, that immunoglobulin values did not seem to be
altered from the baseline.

Infections and fever. There were 84 patients of the 229, or 37 percent,
who had fever. Of those 84 patients, about half of them had fever after
study day 14, which would mean that the occurrence of the fever would
probably superimpose on the period of maximum neutropenia and
thrombocytopenia. And once again, of the 84 patients with fever, there
were 15 patients or 18 because there were three who had missing data and
we couldn\'t tell, or seven or eight percent, with fever associated with
neutropenia or febrile neutropenia.

To look at infectious events again, we pooled a series of preferred
terms related to infection. They are in order of incidence from left to
right in the second row, et cetera. The per patient incidence was 43
percent for any ‑‑ for patients having any of these findings. There were
149 events. The same strategy was used for hemorrhagic events. These
are, once again, in order of incidence, the highest being at the top.
Some of these are far more serious than others, obviously. There was a
12 percent patient incidence, 31 events.

Transfusions and growth factor use, in the ISS-A group, 229 patients
once again, 16 percent of patients received red cell transfusions, 15
percent platelet, 12 percent G-CSF or GM-CSF. The median duration of use
of the growth factors was 16 days. Epoetin alpha was given in seven
percent of the patients, and the median duration of use was 52 days.

A symptom complex primarily consisting of constitutional signs and
symptoms, gastrointestinal problems, pharyngitis, rhinitis, also
myalgias, arthralgias and in many cases rash was noted in association
with the infusion but not directly on the day of infusion but rather in
the period of seven days after the infusion.

After the dosimetric dose, 55 percent of patients during the days zero
to seven, dosimetric dose was given on day zero, 55 percent of the
patients had one or more of the findings that I just discussed on the
previous slide and 46 percent after the therapeutic dose. This is not
actually correct. It\'s the seven days after the therapeutic dose that
this incidence is taken from with 222 events reported.

Gastrointestinal toxicities. Even the early imaging studies demonstrated
that there was uptake of the radiolabeled in the Waldeyer\'s ring and in
the GI tract presumably due to binding to normal CD20 cells, and they
were both acute, which are the peri-infusional toxicities I\'ve been
describing, and delayed gastrointestinal toxicities throughout the GI
tract that were reported. I should note that acute toxicities were also
observed with the unlabeled antibody, and of course this would be
restricted to Arm B of the 002 study.

Once again, the same strategy is used for gastrointestinal toxicities.
Four preferred terms related to upper GI and six related to lower GI
toxicities are listed. The incidence was 38 percent for any of these and
24 percent for lower GI. Number of events are shown to the right.

Because of the known effect of iodide, radiolabeled iodine on the
thyroid gland, we looked at the possibility of hypothyroidism and most
particularly elevated TSH as an indication. Because of the limited
number of data points and later kinds of collection, we looked here at
as many patients as we could, the group of 620, which represents the
ISS-A and ISS-B groups. There were 362 values, TSH values, after
treatment, 34 patients who showed elevated TSH. The median time to TSH
elevation was slightly less than a year, the confidence intervals of
these data and the range are shown below.

This is a time-to-event curve. The x axis, which is I think very hard to
tell from the back, is in months, up to 96 months. Let me focus your
attention on 60 months, which is here. To the y axis we have the
cumulative percent of elevated TSH. The upper confidence interval and
the lower confidence interval are shown by the dotted lines. We have
cumulative incidence between 25 and 30 percent at that time point that I
picked out at 60 months.

HAMA was evaluated, both site and central assay were used for this data.
Once again, the data is taken from both combined ISS-A and ISS-B group.
There were 604 patients who were HAMA-negative at baseline, there were
16 patients who were positive. At least one had ‑‑ at least one
follow-up assessment was available at 515, and 51 patients were
HAMA-positive. The median time to HAMA was late for an antibody
response, 96 days. I point this out to you because I will show you the
data for the 003 group, which is essentially a group in much better
condition with respect to not having received chemotherapy. But the HAMA
response was late in this group. The range is shown below.

This is the same curve. On the x axis we\'re looking at months from the
dosimetric dose, up to 24 months. And on the y axis is the percent
cumulative incidence. These patients were all censored at the last
available values, and I should point out that as we move along in terms
of time, the numbers of available data drop very rapidly, and so the
data is less reliable. The dotted line show the upper and lower
confidence limits.

This is the HAMA evaluation in the 003 study, which, as I said, are
untreated patients. There were 77 patients who were looked at at
baseline, there were 73 who were negative, three who were positive and
one with no data. After treatment, 70 percent of these patients were
HAMA zero positive. The median time to zero positivity was 27 days. This
is the time-to-event curve for that. Years to HAMA, up to five years on
the x axis, present positive HAMA on the y, upper and lower confidence
intervals.

Myelodysplastic disease or acute leukemia. We\'re showing this in a
somewhat different way. These studies are arrayed in order of their time
of initiation so that at the top the 000 is the oldest study and they
progressively move down. I think one was turned around here, but with
that exception these studies are, in terms of time that they started,
with the expanded access study at the bottom as the latest.

The incidence figures are shown here, and they progressively move down
as one would anticipate as the possibilities of experience in the median
years for experience increase. The median years to the myelodysplastic
disease are shown in the final column.

Next slide. This is, once again, a graph of the incidence. The years are
shown up to 8.5 years. The cumulative reported incidence are shown on
the graph with the upper and the lower confidence intervals.

I\'d like to summarize now the efficacy and the safety. Efficacy. The
primary efficacy trial was conducted, and this is the 004 study, was
conducted in 61 chemo-refractory patients who demonstrated a
significantly higher proportion of patients with a longer duration of
response following TTR as compared to the last qualifying chemotherapy.
The overall response rate in this group, 46 percent; the complete
response rate, 20 percent and the median response duration, and you can
compare this to other licensed preparations, was 11.7 months.

The second major efficacy trial was the 012 in 30 of the
Rituximab-refractory patients. The overall response rate was 60 percent;
complete response, 30 percent and the median duration at or around two
years. Finally, supportive studies showed overall response rates from 48
to 63 percent and median duration of responses from one to three years
and complete responses, 27 to 33 percent.

Safety. Hematologic toxicity Grades III or IV were seen in two-thirds of
patients. The median duration of the Toxicity was 30 days. There was
prolonged B cell lymphopenia. We found an incidence of 43 percent of
infectious events, 12 percent incidence of hemorrhagic events. I\'ve
shown you how I derived those. There was a symptom complex noted of
infusional toxicities comprised of constitutional findings,
gastrointestinal problems, myalgia, rash, et cetera, in about 50 percent
of patients. There was clinical and serologic immune responses, a 20
percent cumulative incidence of HAMA at 18 months in the heavily
pre-treated patients and a 70 percent cumulative incidence of HAMA in
the chemotherapy-naive patients, once again at 18 months. And clinical
sequelae to the possible serologic response, anaphylactoid reactions of
serum sickness were infrequently observed.

Hypothyroidism, there was observed a 30 percent cumulative rate of TSH
elevation at five years and a projected observed 45 percent cumulative
rate at seven years. Once again, at these late points the data is thin.
Leukemias and myelodysplasia were observed with increasing cumulative
frequency, with 23 percent in the study with the longest follow-up,
that\'s five out of the 22 patients. And across all studies the
incidence is three percent with a median time of 2.1 years to the
development of these problems. And that\'s it.

CHAIRPERSON PRZEPIORKA: Thank you, Dr. Litwin. Do we have questions for
the FDA? Dr. Blayney.

DR. BLAYNEY: Thank you. First of all, I\'d like to compliment you, Dr.
Litwin, you and your team on the clarity of the briefing document
presentation. I enjoyed reading it. I\'d also like to say that in the
protocol ‑‑ the document contains several protocol amendments which took
over three or four ‑‑ almost four years, and to me this speaks that this
was not an easy clinical investigation to carry out, and that period of
time probably was necessary to get it right, as we\'ve heard today.

My real question and the question upon which the issue is joined is what
procedures did you and your team undertake to review this MIRROR review
of the data? I think many of the questions earlier have alluded to the
fact that looking at responses to previous therapies before a patient
was enrolled in a test of a new treatment is a difficult thing to do.
And we\'ve heard investigators talk about that. Did you have any way ‑‑
do we have assurances from you and your crew that this was independently
verified, audited or monitored in some way?

DR. LITWIN: Yes. We appreciated your concern with this problem, which we
were very concerned with at the time, and worked with the Sponsor to
make sure that every piece of data, including clinical information that
might bear on whether the ‑‑ what the state of the patient was was
collected. We had no independent monitoring of the collection of this
data with the exception of what material came in was able to be
reviewed. Dr. Mills, do you want to comment any further on this.

DR. MILLS: In terms of the MIRROR Panel, we did send an independent
review charter, and then had those looked at in terms of our
interpretations and understanding of those from the case report forms
that were submitted. We\'ve also looked at the quality of that data and
the follow-up onto it, in terms of the long-term responder group also.
And, admittedly, some of the early in terms of the prior chemotherapy
certainly was performed more in a clinical practice setting than was
indeed a clinical trial setting. But overall we felt that the
interpretations were adequate for us to be able to assess them.

DR. LITWIN: I would point out that the Dr. Mills was a co-reviewer and
actually reviewed most of the efficacy.

DR. BLAYNEY: So am I to understand that you saw case report forms that
were extracted from the clinical data and did some tests of that
extraction or the case report forms?

DR. MILLS: We actually looked at the clinical assessments of those, and
from our standpoint, both for radiographic assessment as well as for
oncologic evaluation, because there was an oncologist as well as a
radiologist interpreting these independently for us. Dr. Shastri
accompanied me in terms of the oncology review, especially focused on
the long-term responders to assess those. We looked also at the
radiographic evaluations and did require a number of the long-term
responders to be reevaluated by the MIRROR Panel to be able to get a
full and complete assessment.

DR. BLAYNEY: Thank you.

CHAIRPERSON PRZEPIORKA: Other questions? Dr. Krook.

DR. KROOK: As I reviewed what you put together, which I again
congratulate you, there were ‑‑ on Page 32, there were a fair amount of
protocol violations identified. Some of these, having been on numerous
auditing teams, we would disqualify the patient. And my question is does
that ‑‑ as you looked at this, you or Dr. Mills, did that have any
bearing on the situation. Some of these had informed consents signed
after the drug was given, as I read this. And then there was some iodine
that wasn\'t given or is this just what you kind of accept?

DR. LITWIN: There were a lot of protocol violations, many too many, and
the sponsorship actually shifted somewhere throughout the year of 2000,
so I think that was possibly part of the problem in this. Those protocol
violations that we think that we were most concerned with included
patients who didn\'t have any measurable lesions, which there were a
small but unfortunate number, and patients in whom the initial
radiographic studies were not complete as they should have been. But
there were also, and this is study-specific, a large number of
violations that concerned the use of the lugols solution and the proper
administration of the doses. And we remain concerned with whether the
dosing was given as accurate as it should be under these appropriate
circumstances. And that was a serious problem, it was present in many of
the studies, particularly 012 and 002, and I think it\'s got to be
weighed in with the balance of a group of studies that suffered from
many serious problems, at least in the initial periods.

DR. KROOK: Did it improve as time went on? I mean you listed 000, 001.
Did it appear that some of these improved as time went on, as additional
studies were done?

DR. LITWIN: I\'d say it\'s fair to say that the later studies, 002
particularly, were done better, but the expanded access trial, which is
of course a different type of trial, we felt had many serious problems,
as I think I\'ve illustrated on that slide showing ISS-B in which many
of the patients came from the expanded access trial and in which we felt
that the amount of monitoring was not adequate.

CHAIRPERSON PRZEPIORKA: I have a question, Dr. Litwin. I expect that the
package insert would have the instructions that were similar if not
identical to what was used in the protocol. And as this goes out to
community hospitals and other individuals who are not participating in
the protocol or taking part in the educational sessions that were
involved in the protocol, do you believe that the protocol ‑‑ the way
the protocol was written would be adequate to hand over to a nuclear
medicine physician anywhere else in the country and have this treatment
be administered safely?

DR. LITWIN: Dr. Mills?

DR. MILLS: From the standpoint this is a challenging protocol and that
the dosimetry model for administering the dose I think can be
accomplished by nuclear medicine physicians but not without adequate
training and full knowledge and understanding of how to assess this dose
in this dose statement that comes from the dosimetry. They are going to
need, they being the general community if this would be approved, would
need extensive training and follow-up to assure that they could perform
this dosimetry calculation to determine the dose appropriately. This has
been an issue even in the clinical trials that they were not ‑‑ the
clinical sites that had been participating were not always able to
accomplish the protocol reproducibility.

CHAIRPERSON PRZEPIORKA: Mr. Ohye.

MR. OHYE: Is this a subject we\'re going to ask the Sponsor to address?

DR. LITWIN: Oh, sorry I said that.

DR. JACOBS: We have submitted December 10 the training materials that we
would be using for not only the clinical trials but postmarketing
training at the sites, monitoring and assuring that the dosing is
correct and collecting all residual activities. So we will be working
with the FDA even in the postmarketing to assure that this is address in
training materials and our ability to make sure that the procedures that
we have are adequate to monitor those sites, re-train if needed and to
perform it in the correct manner.

CHAIRPERSON PRZEPIORKA: I think we\'re actually thinking about the
non-protocol sites. What do you provide to non-protocol sites to make
sure that they administer this drug appropriately?

DR. JACOBS: We also have submitted exactly the same ‑‑ similar training
for those sites that would be non-protocol sites. I was referring to
those as well. So there would be a procedure of oversight for training
and assuring that the dosimetry calculations are being correctly
performed when even a non-protocol site started initiating and using
Bexxar.

CHAIRPERSON PRZEPIORKA: And how many non-protocol sites were using the
validation of those training materials?

DR. JACOBS: When you say non-protocols, we\'re talking about more
post-commercialization as far as that. So non-protocol sites are you
talking about as far as EAP? The EAP, we had about 60 sites on the EAP
before it was closed down. Last year it was 80 sites.

CHAIRPERSON PRZEPIORKA: Other questions? If not, we will move on to the
questions to the Committee from the FDA. Dr. Keegan or Dr. Siegel, do
you have an introduction?

DR. KEEGAN: Not a specific introduction other than to note that we\'ve
ordered the questions to ask first about the indication for which the
Sponsor is requesting a standard or conventional approval, and the next
two questions deal with the indication for which the Sponsor has
accelerated approval. And if you have any questions about those as you
go along, please bring them up.

CHAIRPERSON PRZEPIORKA: So there are four questions that we need to
address, and the way we\'ll do this is I will read through the questions
in detail and ask for discussion from the Committee. Once we\'ve
exhausted the discussion or the discussants, we will take a vote with
the exception of any essay questions that Dr. Siegel and Dr. Keegan have
put in there, in which case we will not vote and they will simply have
to pay attention to us.

(Laughter.)

So the data is again summarized on the first page of the questions. The
second page starts the first question, Rituximab refractory follicular
lymphoma, the Zevalin therapeutic regimen was evaluated by ODAC on
September 11, 2001. The Committee recommended standard approval for
Zevalin for the treatment of patients with Rituxan-refractory follicular
lymphoma based on an overall response rate of 59 percent and median
duration of response of 6.8 months in a single-arm trial, supported by
preliminary survival data from a randomized control trial conducted in
chemotherapy refractory Rituximab-naive patients.

The supportive study in Rituximab-naive patients showed no evidence of
impairment of survival and 143 patients equally allocated to the Zevalin
therapeutic regimen versus Rituximab at the approved dose and schedule.
At the time of the original submission of the BLA, several of the trials
listed above were ongoing. In response to FDA\'s request for additional
safety and efficacy information, the final study report for CP97-012 was
submitted on September 7, 2001 and an amended final study reports for
CP97-012 was submitted on July 11, 2002. This is the only study that
assesses the activity of the TTR in patients whose disease is refractory
to only transiently responsive to Rituximab.

The Sponsor has requested an indication for the treatment of patients
with follicular lymphoma, a subset of the patients enrolled. In this
subpopulation, the overall response rate was 63 percent and the median
duration of response, 2.1 years. TTR activity was similar for the
overall survival population which included patients with low-grade
non-follicular and low-grade transformed lymphoma.

So the question is do the results, that is overall response rate of 63
percent and median duration of 2.1 years and the 30 patients enrolled in
the Phase 2 study, CP97-012, supported by the results observed in the
other patients enrolled in the study and the activity in studies
conducted in Rituxan-naive patients with chemotherapy-refractory
disease, constitute substantial evidence of clinical benefit? And we\'ll
start the discussion with Dr. Krook.

DR. KROOK: I would believe after reviewing this and listening that it
does constitute substantial evidence of clinical benefit. One of the
questions which I have is whether one could define, I think by the
regulations, adequate well-controlled trial. I think it\'s an adequate
trial. I have a little bit of a problem saying that it\'s well
controlled based on what I heard, what I read and otherwise. But I would
answer this question yes.

CHAIRPERSON PRZEPIORKA: Any other comments or discussion? Dr. Kelsen.

DR. KELSEN: Actually, it\'s more a question. If Zevalin is an improved
indication ‑‑ sorry, is an improved agent for this indication and
through no fault of the Sponsors because these things happen over time,
we have a drug, an experimental drug being proposed for the same
indication but it hasn\'t been compared to the drug which is already
licensed for that indication, it seems like an unusual circumstance,
I\'m just wondering about a precedent in the Agency\'s approach to this
problem.

DR. SIEGEL: Well, thank you for asking that question, it\'s a very
important one and one that it\'s also important to make clear. In this
particular indication, Zevalin has a standard approval, as was
recommended by ODAC, not an accelerated approval. The legal standards
for approval in that setting do not at all involve comparative efficacy
of safety to already approved regimens. So for hypertension, for
diabetes, whatever, there\'s lots of approved therapies. A new one comes
along it has to be safe and effective, it doesn\'t have to be as good or
better.

So for this indication, the standard is safe and effective. We cite in
the background the Zevalin data, as I think they are relevant. The
Committee did think in the past it was appropriate for approval. And I
would say this, that although the legal standard isn\'t written that
way, certainly in areas of treatment of acute myocardial infarction/,
cancer or other settings where we know we have a drug with an impact on
mortality, there largely has been a de facto standard that you\'d better
be as good if not better. So a new drug that has a lesser ‑‑ one series
of drug with a mortality effect or serious irreversible morbidity
effect, although the law doesn\'t require that the general advice of
advisory committees and the general approach to those settings has
largely been one to show ‑‑ to raise the bar to being as good but not
necessarily and not in fact often addressed by head-to-head studies.

Now, the answer to your question vis-a-vis the indication we\'re going
to come to shortly, which is for ‑‑ where most of the data are, which is
chemotherapy-refractory but not Rituxan-refractory patients, there the
approval, also as recommended by this Committee for Zevalin, is an
accelerated approval. An accelerated approval requires a demonstration
of meaningful therapeutic benefit beyond existing therapy. I think it\'s
‑‑ as you point out, however, where drugs are developed sequentially, a
new drug recognizing that standard and recognizing that another drug may
be ‑‑ is there as an existing therapy, can address that in trial design.
The Agency is quite aware that in a setting such as this and others that
we have seen that one cannot ‑‑ it becomes very difficult to accomplish
that if drugs are developed over the same time course, for one, for
example, to either have a head-to-head trial or a trial in patient
refractory to an earlier treatment if they\'re really developed over the
same time frame. And all I can say in that regard is that there are
substantial discussions within the Agency as to how best to interpret
our regulations and laws regarding what is an appropriate way to meet
the legal requirements.

The interpretation in oncology to this point in time has been the same
one that we gave to ‑‑ that we told Corixa in our communication of March
of this year, which is that they needed to demonstrate how they met this
standard of meaningful therapeutic benefit beyond existing therapy in
order to be eligible for the accelerated approval, and that we hadn\'t
seen that in their application, and we indicated, as has been covered
amply in the press and indicated by the Company too, that we would
expect additional clinical trials to be necessary. The Company has come
back to us with data about prolonged and durable complete responses that
have been presented that we\'ll be getting to in future questions.

So that\'s a very lengthy answer and to summarize it in two sentences,
for this particular indication in which there is not being sought an
accelerated approval, there\'s not a legal standard that requires a
head-to-head comparison or any advantage beyond existing therapy, simply
that the drug be safe and effective. For the next indication, we\'re
going to ‑‑ there is a standard. We are discussing how to interpret that
internally and would seek from this Committee discussion of the data,
the meaning and the implications of the data, and that will figure into
our internal deliberations of how to address that standard. Okay? Does
that sort of get at the question?

DR. KELSEN: I think I\'ve got the answer.

(Laughter.)

DR. SIEGEL: I bet that\'s the last question anyone\'s going to ask me,
right?

CHAIRPERSON PRZEPIORKA: Mr. Ohye?

MR. OHYE: Some of us were here when Zevalin was approved, and Dr. Pelusi
reminded me that it was in this room. And with reference to this first
indication, I think we\'ve seen data that\'s comparable if not superior
to what we saw at the time when Zevalin was approved. And with respect
to a duration response, we\'re seeing definitely more data. Thank you.

CHAIRPERSON PRZEPIORKA: Dr. Brawley.

DR. BRAWLEY: At the risk of getting in even more trouble, I am ‑‑ the
word \"substantial\" is key in the first question. I actually do believe
that the Company has demonstrated that this is an active agent. I am
very much concerned about the quality of the data that they have
presented, the protocol violations. In some sense, I wonder is it fair
to put us in the predicament of this drug which many of us believe to be
active but the data has not been presented as cleanly as I would like to
show that it\'s clearly active. And so I would hope behind me here is
the dream team of lymphoma, and I would hope that whatever happens today
Corixa works with that dream team to better develop this drug and to
better answer the questions that we have here. Even though we\'re going
to have to answer them today, I would hope they would address them in
the future. And I\'m certain that five, six years ago when many of these
trials were being run the dream team wasn\'t consulting for them.

CHAIRPERSON PRZEPIORKA: Thank you, Dr. Brawley. Other questions or
comments? Dr. Blayney.

DR. BLAYNEY: Yes. I think the answer to this question is yes, but I
think the question that hasn\'t been answered is about standard
radiation therapy. Chemotherapy-refractory patients do, in some measure,
respond and respond for a long time with standard radiation therapy, and
that question wasn\'t answered with this or with the previous agent. I
think the other thing, it\'s clearly not fair to compare Zevalin with
this agent because lymphoma is, as has been pointed out, a heterogenous
disease, and if you pick your patients, you can get a lot of different
response rates. So I think we need to bear that in mind. Thank you.

CHAIRPERSON PRZEPIORKA: Dr. Carpenter.

DR. CARPENTER: Unless I don\'t understand the presentation, very few of
these people had disease which was not Stage III or more, which would
not be appropriately managed with radiotherapy. So I think that
comparison\'s probably not the one we need to be focusing on here.

DR. BLAYNEY: I think if somebody relapses in an isolated area,
palliative radiation therapy ‑‑

DR. CARPENTER: Yes, but that\'s not who was in these studies.

DR. BRIDGES: I don\'t know if the question related to toxicity. Are you
concerned about the issue of toxicity and combining people that have
palliative radiation or even upfront curative for Stage I and II and
then have progressed. They may ultimately go through chemo, they
ultimately go through this treatment. Were those two issues that you
were sort of addressing there?

DR. BLAYNEY: I was more concerned about a regulatory and comparative
issue. I mean somebody who gets a response to systemic therapy and then
relapses in an isolated area, perhaps as a low-grade lymphoma, can
respond quite a long time. I think the other issue is that some place
needs to be addressed is about dosimetry and about dose-limiting
toxicity to isolated body parts, which you may be thinking about and I
think needs some attention once, if the label is actually drawn about
where and when normal tissue tolerance for this agent on the top of
previous radiation, radiated fields needs to be looked at or at least
addressed by the clinician who\'s using the drug.

CHAIRPERSON PRZEPIORKA: Dr. Kelsen?

DR. KELSEN: Well, since you\'re talking about toxicity, the one toxicity
that disturbs me the most as a solid tumor guy is myelodysplasia or
acute leukemia, so could I just ask a non-comparative but comparative
factual question? With the product that\'s already available, Zevalin,
do you see the same incidence of MDS and acute leukemia? Is that
something we should be worried about or is there an understanding they
haven\'t done a heat-to-head comparison? Is there something that would
leap out at you that one is more likely to cause this devastating
toxicity than another? I don\'t know the answer to the question. Maybe
the Sponsor\'s experts could address it for us.

DR. KEEGAN: Actually, in terms of Zevalin data, I can tell you that when
we looked back at the data that were available last year with the
population involved for a substantially shorter period of time, the rate
was about 1.7 percent, 1.4 percent, versus the three to seven percent
depending upon which group you look in for these trials. But in the
absence of a head-to-head comparison, I think it\'s a little bit
difficult. But I would like to emphasize that implicit in the question
that\'s asked, is the sense of is there net clinical benefit? Do the
risks associated with this therapy ‑‑ do the benefits conferred by this
therapy outweigh the risks? And that was also why the Zevalin data was
summarized to show you the kinds of information that were available in
comparative data on time to progression and survival that were available
for Zevalin that helped address that sense of net clinical benefit. And
so you\'re being asked do you have that same satisfaction with the data
that are presented here?

DR. KELSEN: Yes. I asked that question specifically because if I
remember the little bit of data we saw, again not comparing it, but just
listing them, I clearly got an impression there wasn\'t a big
difference. But I don\'t remember seeing that particular piece of
information, and that seems to me to be the most dangerous toxicity.

DR. FISHER: Dr. Kelsen, could we make a comment? You seemed to invite us
up to make a comment. Rich Fisher again. The comment I would make is,
just as a lymphoma person, is two things. One, the follow-up is
significantly shorter on the Zevalin data, and so that affects the
incidence. I don\'t think ‑‑ there are cases on both that are not
grossly dissimilar but I don\'t think you can make detailed comparison.
And, secondly, the patients are much more heavily pre-treated on some of
these, which would increase the incidence. That being said, I don\'t
think we can make more statements than that for you.

DR. KEEGAN: Yes. I would just amend Dr. Fisher\'s remarks. I think,
actually, in looking across the Zevalin data, the amount of prior
chemotherapy, the median amount prior to chemotherapy was actually quite
similar in their safety database.

CHAIRPERSON PRZEPIORKA: And from the point of view of a hematologist,
the curve that was placed up there looks very similar to the curves of
any lymphoma getting chemotherapy and radiation, and we have to remember
that this drug is radiation just like any other radiation. There\'s
nothing magic about it. Dr. Blayney.

DR. BLAYNEY: In the old days when radiation was used to treat lymphoma,
the incidence of second leukemia was pretty small, background type with
radiation only. It\'s the combination with which these are likely to be
used that\'s leukemogenic.

CHAIRPERSON PRZEPIORKA: Dr. Carpenter.

DR. CARPENTER: I just think when the Zevalin data were presented to us
the median follow-up was on the order of two and a half years. And as
has been pointed out by several people who have commented on this, the
peak time to see the leukemia and myelodysplasia is on the order of five
to six years. There\'s adequate follow-up with this drug to begin to see
what you\'re going to get. I don\'t think without longer follow-up on
the Zevalin that you can safely make a comparison.

CHAIRPERSON PRZEPIORKA: Dr. George?

DR. GEORGE: I don\'t want to be a wet blanket here but the ‑‑ I\'m still
concerned with the substantial evidence of clinical benefit issue. I\'m
impressed by the long-term remissions that were observed on this and
other studies, but I was trying to ‑‑ and I have difficulty separating
my approach to this on this Committee advising the FDA as opposed to
what I would say if I were reading this in the literature. I would say
that\'s very interesting, I would like to see a lot more additional
study of this before I could draw a firm conclusion. So I don\'t know
how I\'m going to come down on this right now, but I just have to say
we\'re talking ‑‑ we have to remember we\'re talking about 30 or 40
patients here and to be approving something that would be used, I
suppose, in a much wider population.

CHAIRPERSON PRZEPIORKA: Dr. Martino?

DR. MARTINO: The question forces us to look at this particular piece of
the data. I think what our job is is to make an overall decision,
ultimately, and in answering this question, one cannot help but also be
influenced by everything else that has been presented. It really is not
an item in isolation. It\'s simply the way the question is worded that
forces that point.

CHAIRPERSON PRZEPIORKA: Mr. Ohye.

MR. OHYE: I was just trying to address Dr. George\'s comment and that I
think we\'re dealing here ‑‑ we also have to think in terms of an even
playing field, and if you think back to what happened on September ‑‑ I
beg your pardon, if you think what happened in September, happened to be
the 11th, when we reviewed Zevalin, we didn\'t have a large body of
data, and more particularly we didn\'t have any long-term data as
compared here.

CHAIRPERSON PRZEPIORKA: Dr. Brawley? Dr. Krook?

DR. KROOK: I have to agree that the issue is substantial. It is a
relatively small study but it took a long time to get this together, and
it\'s probably never going to be done again. And I look at the duration,
I look at the people or the patients who are treated who have this, and
I\'m impressed by the duration and what\'s occurred. I mean usually we
wind up going with arm number five or number six of some chemotherapy,
and to me this looks better than what I can do at arm four or five.

CHAIRPERSON PRZEPIORKA: Dr. Siegel?

DR. SIEGEL: I just wanted to clarify a couple of issues regarding
regulatory standards. The question was not intended to force you to look
at these data in isolation. We recognize that data in closely related
indications are supportive of each other and are a guidance on evidence
of effectiveness as well as a related guidance on evidence of
effectiveness in oncology indications, it\'s very clear about that. So
this question ‑‑ and, specifically, that\'s why it refers also to the
Rituxan-naive patients. It\'s asking ‑‑ the direct evidence of data are
the patients who are Rituxan-refractory. We\'re asking about that
indication, but we certainly recognize that the other data for
Rituxan-naive patients are relevant from both a safety and efficacy
point of view and wouldn\'t want to imply otherwise.

The notion of substantial evidence of ‑‑ actually, it\'s of efficacy,
safety and efficacy, comes from our legal standard, and it can be
interpreted how you see fit. In part, that\'s why we put the Zevalin
data here as there was certainly a feeling at that meeting that a
database, albeit somewhat different in size and in nature and in patient
populations and we certainly agree with other comments that you can\'t
make a head-to-head comparison but just wanting to ensure that a
Committee was reminded about nature of other decisions on a related
question.

Finally, there\'s one other point. Oh, adequate and well-controlled
trial, yes. There was a comment on this being a well-controlled trial.
An open labeled trial in most people\'s minds is not a controlled ‑‑
with this one arm, it\'s not a controlled trial. Oddly enough, our
regulations as well as our guidance document do refer to several
different types of control groups in a trial and recognize that
historical controls actually can be considered a controlled trial.

Now, I\'m not going to sit here as an advocate of single arm trials or
historically controlled trials. We believe in cancer trials, however,
that when you\'re looking at tumor response rates that in fact in most
cancers there\'s a reasonably strongly presumption that an untreated
group would not have a substantial response rate, a spontaneous response
rate, and someone can actually make determinations about response rates
from those trials, and that\'s why we do approve drugs, whether for
accelerated approval or not. They need to be adequate and
well-controlled trials, just as a matter of explanation. that is why we
are able to approve drugs on the basis of trials that I think many in an
academic community, many of my European colleagues would look at that
and say, \"Not a controlled trial.\" They may still approve the drug,
but they would say that\'s not a controlled trial. So it\'s somewhat of
a semantic thing, but it is very clear in our regulations, and the
guidance about them that single arm trials can be considered controls
with historical control groups and their guidance makes clear that
implicit historical controls in cases such as this can be used.

CHAIRPERSON PRZEPIORKA: Dr. Taylor?

DR. TAYLOR: I guess I\'m a little bit concerned. I don\'t disagree that
we have to have it on an even playing field, but we\'re looking at more
data, so we have longer data, and then those followed the longest we had
a 23 percent of incidence of MDS or acute leukemia. So we have more
information, and we shouldn\'t ignore that. And you can say, well, it\'s
a small number of patients, and I don\'t disagree. But each of the
columns for the longer they were followed they had more. And then we\'re
willing to accept a response rate on a small group of patients. I think
you have to accept that we have longer data and not ignore that longer
data.

CHAIRPERSON PRZEPIORKA: Hearing no other comments, I\'ll call the
question and start the vote. So for Rituximab-refractory follicular
lymphoma, do the results overall response, 63 percent, median response
duration, 2.1 years, and 30 patients enrolled in the Phase II study
supported by results observed in other patients enrolled in this study
and the activity and studies conducted in Rituxan-naive patients with
chemotherapy-refractory disease constitute substantial evidence of
clinical benefit? Dr. Martino.

DR. MARTINO: Yes.

DR. PELUSI: Yes.

DR. BRAWLEY: I believe there\'s substantial evidence of clinical
benefit, but I do not believe the evidence demonstrates that, so, no.

DR. TAYLOR: No.

DR. BRIDGES: Yes.

DR. LITWIN: Yes.

CHAIRPERSON PRZEPIORKA: Yes.

DR. KELSEN: Yes.

DR. REAMAN: Yes.

DR. CARPENTER: Yes.

DR. KROOK: Yes.

DR. GEORGE: No.

DR. BLAYNEY: Yes.

CHAIRPERSON PRZEPIORKA: The final tally is ten yes, three no.

The second question follows very quickly thereafter.
Chemotherapy-refractory low-grade and follicular lymphoma with or
without transformation. Number two, are the overall response rates and
durations of responses observed across the five clinical trials
conducted by the Sponsor, in light of the toxicity profile observed,
likely to predict clinical benefit in patients of
chemotherapy-refractory low-grade and follicular lymphoma with or
without transformation? We\'ll start with comments on this question. Dr.
Krook?

DR. KROOK: It\'s somewhat similar to before is that if one looks at the
response rates which were shown as we go further in line with cytotoxic
chemotherapy, one has to believe that this is at least as good, if not
better, than anything I can do with an extra, or anybody can do with an
extra line of cytotoxic chemotherapy.

The second issue is the toxicity issue, which in my belief is that at
least the patients which were looked at were heavily pre-treated and
have been through a lot, and we heard this from our patient advocates.
And that the toxicity to accept because you have taken something for
lymphoma or taking a pill such as thyroid, I think that\'s a very small
thing in light of things. So I believe that the answer would be that
there is a clinical benefit in people like this, with and without
transformation.

CHAIRPERSON PRZEPIORKA: Dr. Martino.

DR. MARTINO: I am particularly persuaded by the fact that these are
trials where patients have had several chemotherapies beforehand, and in
spite of that we are seeing a reasonable number of responses and in
spite of that we\'re seeing patients for whom that response lasts a
reasonable length of meaningful time with relatively mild toxicity
compared to most of the things that we give these patients. So I
actually find the data in total to be something which I think will add
considerably to what we can offer patients with probably less toxicity
and less of a price tag in terms of toxicity than is our usual behavior.

CHAIRPERSON PRZEPIORKA: And I just wanted to echo the two previous
speakers in how amazing this data is to get a 20 percent response rate,
complete response rate in patients who are so heavily pre-treated with
minimal toxicity. However, I also am concerned about the hematologic
toxicity as well as the potential for leukemia in these patients. That
is clearly not something I would jump to as first-line therapy in
patients with stage III or stage IV disease but definitely for patients
for refractory disease or refractory relapse diseases, it\'s clearly
much better than anything we can do currently. Dr. Pelusi?

DR. PELUSI: I have to agree, but I think it\'s great that we would at
least have another option. And, again, I think one of our biggest roles
is giving the informed consent saying, we really know that this data
does exist in terms of the risk for long-term issues, but I think that
patients are becoming very savvy and they need to be able to have the
choices put on the table for them.

CHAIRPERSON PRZEPIORKA: Dr. Krook?

DR. KROOK: I would like to make it\'s more of a comment than anything
else to my colleagues who\'ve been before us, particularly the patient
advocates with lymphoma. One of the things which I\'ve learned being on
this Committee, occasionally we have people which I respect who have
come up here and said, \"Hey, I\'ve been in duration for a long time,\"
looking at it as not a curative treatment. Again, it\'s another tool and
the armamentaria is, as she says, if you look at the curves and we have
long durations but we still have a lot of people who in the first year
or two fail to respond and something else had to be done. So this isn\'t
the end as we see these people come. That\'s just a comment.

CHAIRPERSON PRZEPIORKA: Dr. George.

DR. GEORGE: I feel differently about this. This is for an accelerated
approval. One thing I had to comment on, though, was the study design.
When I first looked at this, it was interesting that the patients that
were on this study I was trying to characterize in my own mind what they
were, what kind of patients. They were heavily pre-treated, obviously,
but one interesting quirk in the design was they had to be less than six
months from their last qualifying chemotherapy, I mean their duration of
remission or response.

And the interesting thing about that is in the way the analysis was
first presented, although it really wasn\'t emphasized in the final
analysis, was to compare the lengths of remission to the first ‑‑ I mean
to the new treatment to the previous one. Well, it\'s almost impossible
for that first treatment to be longer because it was sort of
artificially short. I mean it was required to be short or the next one
would have to had to be really short, had to be less than 30 days, less
than that. And the median remission in the first week was three months
at best.

So you\'re talking ‑‑ it is true that that was a very bad group and so
it\'s good to see these long-term remissions, but in the kind of
analysis that was looked at, there was a little quirk there that would
make it very difficult for you to ‑‑ it\'s not a balanced playing field,
so to speak.

But in this case, I have a question, I guess. Is it relevant to discuss
the follow-up studies or the things that would be required at this point
or should we do it some other ‑‑

CHAIRPERSON PRZEPIORKA: I think that may be part of Question 4.

DR. SIEGEL: I think we\'re asking that in Question 4, yes.

DR. GEORGE: Oh, that\'s coming.

DR. SIEGEL: Yes. I would like to interject here that I couldn\'t agree
more with your comment about that particular analysis. It\'s troubled me
all along. It was developed and agreed to a number of years ago, but to
have the outcome in one side of a statistical analysis be determined by
the entry criteria, you could have gotten a response rate of zero simply
by not enrolling anybody who had responded, and you won\'t have any
durable responders. And that\'s why we presented the data in terms of
looking at the subsets of those who had had ‑‑ who are non-responders to
the prior therapy and showing that nearly half of those had responded
and those who were responders and showing that nearly half of that small
group had responded and had some pretty durable responses. I think you
can get meaningful information, but the statistical analysis is biased
and somewhat problematic because of the design.

CHAIRPERSON PRZEPIORKA: Other comments? Then I will call the question.
Number 2 for chemotherapy-refractory low-grade and follicular lymphoma
with or without transformation. Are the overall response rates and
durations of responses observed across the five clinical trials
conducted by the Sponsor, in light of the toxicity profile observed,
likely to predict clinical benefit in patients with
chemotherapy-refractory low-grade and follicular lymphoma with or
without transformation? Dr. Blayney?

DR. BLAYNEY: Yes.

DR. GEORGE: Yes.

DR. KROOK: Yes.

DR. CARPENTER: Yes.

DR. REAMAN: Yes.

DR. KELSEN: Yes.

CHAIRPERSON PRZEPIORKA: Yes.

DR. LITWIN: Yes.

DR. BRIDGES: Yes.

DR. TAYLOR: Yes.

DR. BRAWLEY: Yes.

DR. PELUSI: Yes.

DR. MARTINO: Yes.

CHAIRPERSON PRZEPIORKA: Even without a calculator the tally is 13 yes,
zero no. Okay. Thank you.

On to the third question. The issue of long-term responders. The Sponsor
has retrospectively defined and identified a subpopulation of patients
with long-term responses. The Sponsor defined these according to the
following criteria: Achieved a CR, CCR or PR to the treatment, and the
time to progression from study entry was less than one year ‑‑ rather,
was at least one year. These criteria were not prospectively discussed
or agreed upon with the FDA, and the Sponsor has provided no clear
rationale or justification for these criteria based on literature review
or other sources. The 76 patients meeting these criteria constitute
two-thirds of all patients who have responded to the treatment. The FDA
further segregated this subset into 78 patients who received the dose
and schedule for which marketing approval is being sought and eight
patients who received a different dose and schedule. The efficacy
results are summarized in the table above Question 3.

The question is does the findings of a subpopulation of patients with
long-term responses demonstrate that the treatment provides meaningful
therapeutic benefit to patients over existing treatments; that is,
improved patient response over available therapy? Dr. George, do you
have any comments?

DR. GEORGE: I know how I\'m going to vote on this and so I have to be
careful. I was waiting for other discussions, but I think the answer is
clearly no in this case. I won\'t elaborate.

CHAIRPERSON PRZEPIORKA: Any other discussion? Dr. Carpenter? No?

DR. CARPENTER: I think you\'re just going to have to look at what else
is out there for people that have had a median of four prior treatments.
And the choices are simply ‑‑ the available choices are simply not very
good. Is this an ideal drug, I think the answer is it\'s almost
certainly not, it\'s got some problems. But does it provide a clear
advantage to available other therapies? In this population, many of whom
are not appropriate for things like high-dose therapy, I think it
probably does.

CHAIRPERSON PRZEPIORKA: Dr. Kelsen.

DR. KELSEN: Could I ask a clarification from the FDA? It seems to me
like this addresses the issue of Zevalin directly. As I would read this
would be Zevalin has received accelerated approval, is available
commercially. Is there clear and compelling evidence that this drug is
superior to Zevalin? Is that the correct way to read your question?

DR. SIEGEL: Well, first to say there would be no intent for the words,
\"clear\" and \"compelling,\" to be in there, okay? There\'s nothing in
our regulation or standards that would suggest that meaningful
therapeutic benefit is clear and compelling ‑‑ that there\'s a standard
of clear and compelling to be met in making that determination.

The answer is, in part, yes, but I think we were just discussing the
fact that this question is somewhat less than optimally worded.

DR. KELSEN: Could you reword it?

DR. SIEGEL: Yes. Well, I can tell you what we need from you, okay?
Because I think that there are complex issues here. Partially, we\'re
looking at long-term responders, and I think it would be fair to say
that it would be impossible, at least for this Committee, to make a
determination as to whether Zevalin does or does not have similar amount
of long-term responders because they didn\'t have as much long-term data
available at the time of presentation.

I think that raises some interesting issues as to whether documentation
of long-term response is a benefit if there are other therapies for
which you don\'t know whether that exists. And I think that one can make
a strong case on either side of that question.

I think that it is also true that in exploring the question of how to
deal with available therapies particularly in light of the issue you
raised earlier where there aren\'t head-to-head comparisons, we
communicated to this Company back in March an approach that was
consistent with what oncology companies have been told over the last
several years by the Division of Oncology, which is that to the extent
that there is a drug with treatment with indications for refractory
patients, the next drug to come along should either study patients
refractory to that or demonstrate benefits that that drug hadn\'t shown
if that\'s an existing therapy. And I think as we have further explored
approaches to accelerated approval throughout the Agency, we\'ve
discovered that there\'s different nuances to the way that is looked at.
And so the fact of the matter is that there\'s a lot of discussion going
on internally with how we deal with the accelerated approval,
regulation, the underlying fast track law.

And I think that ‑‑ so I say that to get to then not to reword the
question but rather to tell you what would help us the most. And that
would be not to ask you to try to interpret a legal standard that has a
lot of subtleties that need to be fully explored and can\'t be and
haven\'t been fully explored to you, but rather to use ‑‑ what would
help us the most would be to hear from you based on your expertise in
dealing with this disease as to what are ‑‑ what is the clinical meaning
of these long-term responders? Is this something that is out of the norm
of what one has seen with chemotherapy and other therapies? Is this
something that as is purported to be by the Sponsor, these whatever
percent they are going out for a number of years, something that\'s
telling us something important about this drug, what is it telling us,
what is our expectation? And we will, I think, to the extent we can get
your expert opinion on those matters, we will take that information and
do our best to apply appropriate regulatory standards. All right?

CHAIRPERSON PRZEPIORKA: I will just comment then that it has been stated
and pounded into young oncologists\' heads never to do analysis of
survival of responders versus non-responders. I can tell you from
someone who\'s been trying to figure out how to come up with criteria
for response that are meaningful, it\'s sometimes important to look at
that information to see whether or not a response by one definition
gives you really long-term survival as opposed to a response by a second
definition. But I don\'t know that that actually gives you any
information about clinical meaning.

And so in this situation I think we already have a response definition
and they\'ve achieved their goal using the standard response definition.
And the fact that their responses are longer than others may and or may
not actually have any substantial meaning. We may get into the situation
where we do a study and there are five percent responders that are
complete responses and last for ten years. So is that clinically
meaningful? What happened to the other 95 percent who got no response
whatsoever? So I personally would not start walking down that slippery
slope whatsoever.

On the other hand, Dr. Blayney also pointed out that patients with
lymphoma who get radiation are known to have good, long responses, and
this is radiation. So this is a nice way to give radiation to someone
who doesn\'t have all their disease in one field but can get the
benefits from high-dose radiation that we would not be able to give to
this population with any kind of chemotherapy at this era. Dr. George?

DR. GEORGE: My response to this question when I said it was no was
precisely because of the last part of the question which has to do with
does it provide meaningful therapeutic benefit to patients over existing
treatments or, for example, improved patient response over available
therapy? That\'s what I think we don\'t know, and I guess I\'m just a
diehard in favoring controls compared to trials to answer that kind of
question. And I won\'t make go so far as to claim it\'s the only way to
get that answer, but it\'s pretty darn close, and it\'s by the far the
best way. And so if you just stopped the question and said, does it
provide benefit to patients, I\'d say yes.

CHAIRPERSON PRZEPIORKA: Dr. Krook.

DR. KROOK: Probably speak as the gentlemen or the physician who\'s been
on ODAC the longest since I\'m about three years off. But I\'m also, as
a lot of people in the room are, we all treat ‑‑ a lot of clinicians
treat lymphoma here, and my problem with the question, and as I listen
to the discussion, I may come to know, I think there are other available
treatments. I mean I\'ve been through this where we\'re trying to
approve a drug for third-line pancreas cancer. I mean the nature of that
disease is different than what we\'re dealing with. I have, as my
colleagues in the room, you may find somebody who can do fairly long
with something fairly simple and the problem it becomes is to
individualize the therapy, and what I think this offers us is, as
somebody said, it\'s really radial therapy with a monoclonal antibody,
and that\'s what\'s different about this.

You know, we\'ve got people who have probably responded who have 13
different previous chemotherapies. Look at the list up here. We have
alphabet soup as we used to say in oncology. So I think there\'s other
available therapy that may do equally well in an individual patient as I
see them from day to day in this group. Now, if you talk about people
who\'ve transformed, that may be a little different than the person who
still had follicular lymphoma.

CHAIRPERSON PRZEPIORKA: Dr. Martino?

DR. MARTINO: I think this data does have a suggestion that there are
some people for whom this is good long-term therapy. The question deals
with the issue of comparing to other things, which leads you to simply
making leaps of faith. There have been no comparison data presented, so
one can either guess or pretend one knows things one doesn\'t know.

CHAIRPERSON PRZEPIORKA: Dr. Blayney?

DR. BLAYNEY: I don\'t see how this helps you with the label. There are
some people who are going to respond, either the label or approval.
There are some people who, for whatever reason, have been
retrospectively identified who respond for a long time.

On the subject of long-term responders, I\'m very concerned about the
myelodysplastic acute non-lymphocytic leukemia aspect of this treatment.
You\'ve shown between two and three percent per year incidence of this.
Very few people have been treated at full dose who are out six years
where it looks like the peak is. So that if you do a
back-of-the-envelope calculation, you\'re talking about 12 to 18 percent
at six years developing a myelodysplastic syndrome which will be fatal
because they had received a treatment that radiates the bone marrow in
totality, one out of seven. And I think that ought to give oncologists
pause when they use this treatment and not move it to first line. I
realize that\'s a little bit off the subject, but you do raise long-term
responders, and that\'s something that I think is quite concerning.

CHAIRPERSON PRZEPIORKA: Seeing no other hands, I will call the question.

DR. SIEGEL: Yes. I would ‑‑ I think it\'s quite clear from the
discussion, it was actually clear before the discussion, that this
question is asking for interpretation of ‑‑ I mean the reason your
answer, well, how does it help us, the question mirrors regulatory
decision that exists as reflected in the fast track language from 1997
as well as the accelerated approval regulation that requires us to make
certain determinations. However, I think that because of issues, as I
said, that extend beyond oncology and how we interpret that, it\'s
probably neither necessary nor helpful to have a vote. The comments to
date about what these response data and what these durable data mean
clinically are very useful. If they\'re further, I would encourage that,
but I would like to take the prerogative of not asking for a vote on
this question.

CHAIRPERSON PRZEPIORKA: Okay. So Dr. Siegel has withdrawn this question,
and we\'ll move on to Number 4.

DR. BRAWLEY: Given that, can I make one ‑‑

CHAIRPERSON PRZEPIORKA: Dr. Brawley, yes.

DR. BRAWLEY: Very briefly.

DR. SIEGEL: Please.

DR. BRAWLEY: Okay. I believe that there is meaningful therapeutic
benefit with this drug. I do not believe it has been proven that there
is benefit over existing treatments.

CHAIRPERSON PRZEPIORKA: Dr. Reaman.

DR. REAMAN: Can we ask Dr. Siegel to amend the question rather than
withdraw the question?

DR. SIEGEL: Sure. If you\'d like to. I hear a pretty clear consensus
here that people are cautious about how to interpret response data and
to translate that to benefit, that they feel that this drug is
benefitting some patients and that there is not adequate data of
appropriate design to compare this to existing therapies. And I think
sounds like there\'s consensus on those issues, and that\'s useful
advice to us. I don\'t feel a need for a question with a vote. However,
if you would like it amended in a certain way, that\'s fine. I\'m seeing
heads nod. I think I heard the message, and I ‑‑ okay. Then I\'m not
sure exactly what to ask for a vote on. We could leave it as written or
we could change it to something else, but the important thing here is to
get the advice.

CHAIRPERSON PRZEPIORKA: Okay. Moving on then to Number 4, please comment
on the types of information that should be obtained in additional
studies to further characterize the safety and effectiveness of the
regimen. Specifically comment on the following: The Sponsor has proposed
a trial of Rituximab versus the therapy in patients with lymphoma who
have received at least one and no more than two prior chemotherapy
regimens. The primary objectives of this data is demonstration of a
longer time to progression, alternative therapy or death in the treated
patients. Survival is a secondary objective.

Also, please comment on the need to conduct studies to further assess
delayed toxicities, including MDS, secondary malignancies,
hypothyroidism and HAMA. Does anyone have comments on either of these?
And I noticed they didn\'t include quality of life, but if anybody wants
to address that, please feel free. Dr. Pelusi?

DR. PELUSI: Well, I guess I will address that. I do think we need to
look at quality of life studies, and I think we need to really look at
the impact on families, and many times we look at quality of life based
on the patient, but, you know, this is a time and a place where it may
behoove us to really look at the impact on the main caregiver, because
during this phase that is going to be important to let other family
members know what could be expected down the road with this drug.

CHAIRPERSON PRZEPIORKA: Dr. Kelsen.

DR. KELSEN: I noted during the discussion that the Sponsor plans to
compare this agent to Zevalin head to head, and I would support that
very strongly.

CHAIRPERSON PRZEPIORKA: Dr. Carpenter?

DR. CARPENTER: I think sort of broader studies of where you\'re going to
get this information is probably ‑‑ it\'s an early disease, it\'s not
going to be complicated by nearly the issues of all the prior therapy
because it\'s early, and that\'s going to be ‑‑ it\'s going to get
substantial follow-up, and there\'s going to be a comparator without the
radiation, which gets at the issue at hand. To me that\'s the ideal
place to get some of these longer-term issues solved and just encourage
the longer, careful follow-up of that group of patients in that study,
because that\'s already ongoing, those data are being collected, that if
it\'s focused on that, that\'s the ideal place to answer this kind of
question.

CHAIRPERSON PRZEPIORKA: Dr. George.

DR. GEORGE: I\'m a little confused. I don\'t ‑‑ are there two studies
being proposed, the Rituximab and the Zevalin study?

DR. CARPENTER: Yes.

DR. GEORGE: Who should I be asking, I don\'t know. But Zevalin was
talked about briefly so that there would be these two, at least.

DR. KEEGAN: Yes.

DR. GEORGE: One is ongoing.

DR. KEEGAN: Dr. George, I think maybe the Sponsor will have to describe
this. We\'ve not seen a detailed proposal, the Bexxar-Zevalin study,
only a concept issue. So we don\'t ‑‑ I couldn\'t describe it for you;
perhaps they will.

DR. JACOBS: Actually, there are three studies: The SWOG study which is
already ongoing, the randomized trial comparing Bexxar to Rituxan, which
has been submitted to FDA, and we\'ve actually, over the last six months
to a year, have been negotiating on the final protocol. In April of this
year, we also discussed doing a randomized trial of Bexxar to Zevalin,
and we\'ve had discussions with our experts, and we\'ll be submitting
that protocol so the FDA ‑‑ we\'ve had these preliminary discussions,
but that protocol will be coming in January. We were going to submit it
prior to this meeting, but there were other additional changes that were
coming from the Rituxan versus Bexxar that were appropriate to just
standardize it and make those changes in the protocol prior to sending
it in.

CHAIRPERSON PRZEPIORKA: And I wanted to add a comment that in this
proposed study of Rituxan versus Bexxar for patients who have received
at least one and could be no more than one, chemotherapeutic regimen
that the eligibility criteria reflect the potential serious toxicities
long-term for those patients and not include those individuals for whom
a much less toxic therapy would be appropriate. Other comments from the
Committee? Dr. George?

DR. GEORGE: Just a little follow-up on that, I guess. With this concern
of myoelastic disease and secondary malignancies, I think the study is
going to have to be long enough. I mean it is going to have to be one of
these certainly five plus years of follow-up. So that\'s an issue, but I
don\'t see how you can do it short term. I mean you\'ve got long-term
studies going on.

CHAIRPERSON PRZEPIORKA: And I would agree with Dr. George. I\'ve had
some serious concerns reading through the documents that the current
incidence of AML or MDS was based on physician-reported cases whereas
there may be some patients who are out there not seeing their
physicians, their physicians don\'t know about them, and so I\'m in
agreement with Dr. George, there has to be a very close follow-up long
term for all patients on those studies. Dr. Martino?

DR. MARTINO: Is there no interest ‑‑ a question to the Company really ‑‑
is there no interest in looking at this agent prior to chemotherapy? I
mean one of the things that impresses me about this drug is that it ‑‑
granted that there are some long-term issues, but it appears to me that
this is easier than a lot of other things that we do. So I\'m just
curious as to have we no interest in really looking at this as a first
relapse, so to speak?

CHAIRPERSON PRZEPIORKA: Actually, it\'s more specifically to Dr.
Bridges. Would you consider using something like this in patients with
stage III or IV lymphoma?

DR. BRIDGES: I think that could clearly be an area of use. The studies
there we\'ve looked at watchful waiting is a choice and we\'ve shown
that watchful versus aggressive therapy with the regimens that exist
today don\'t offer a survival advantage. I think it would be a good
population of patients to consider an initial trial.

DR. KEEGAN: Could I ask for some additional discussion on two points.
Dr. Przepiorka, you mentioned that you thought that patients who were
entered with minimal pre-treatment should be patients who are higher
risk. Could there be some comment on how that patient population might
be characterized? Would it be IPI or something else?

CHAIRPERSON PRZEPIORKA: Well, I think we had mentioned ‑‑ I think that
the scope ‑‑ the answer to that question is, will take more time than
the Committee has, but the thing that comes to light, to the first, top
of my mind is the patient who comes back with localized disease and this
would be their first relapse. I\'d be concerned regarding long-term
toxicities in that population, somebody who has localized disease and no
symptoms.

DR. KEEGAN: And the other question is, I just wanted to raise the issue,
and the reason we presented the data from 003 in the previously
untreated patients was the sterlingly high incidence of an immune
response to this Murine antibody and first-line for which we actually
have no information on whether that might prevent readministration of
any Murine antibody in the future. We certainly would expect that the
presence of an immune response to a Murine antibody might alter the
biodistribution and therefore make it unsafe to administer Murine
antibodies. Is there a concern about use of this upfront for that reason
in terms of just blocking ‑‑ preventing patients from taking other
Murine products in the future?

CHAIRPERSON PRZEPIORKA: Dr. Blayney?

DR. BLAYNEY: In the upfront setting, you have a reasonably, as has been
demonstrated, immune intact person who\'s capable of mounting an
antibody, and I don\'t know what the long-term sequelae in terms of
other diseases that we may not even have thought about that tissues in
the body that might be innocent bystanders to immune epitopes expressed
and respond on the mouse antibodies. So I think there\'s opportunity to
look at other long-term sequelae in that setting as well.

CHAIRPERSON PRZEPIORKA: Dr. Keegan, back to you, does the FDA have any
evidence from any study that HAMAs interfere with humanized antibody
therapy?

DR. KEEGAN: I was going to say not with humanized or chimeric antibody
therapies. We do have data with imaging agents where Murine antibodies
were used as the imaging agent and readministration in that setting, and
I\'m going to let Dr. Mills describe that.

DR. MILLS: The concern that I would have for you is if we generate a
HAMA in these subjects, you\'re going to alter the biodistribution of
any Murine antibody in the future that\'s going to be administered to
these subjects. Knowing that Bexxar is indeed a Murine antibody that
would raise for it. You also should understand, though, that Zevalin,
the radiolabel for the therapeutic and the diagnostic is also a Murine
antibody. So the presence of a HAMA would be a relative
contra-indication that we would want to consider in a clinical trial if
we generate it with early administration of Bexxar. So, again, the
concern is for every time in the diagnostics studies where we\'ve
studied extensively the presence of HAMA, all of the Murine antibodies
were altered in the biodistribution on the follow-up administration 100
percent.

DR. KEEGAN: Specifically, what happened was that the antibody was
generally delivered directly to the reticular endothelial system, so it
was rapidly cleared frequently from the blood and dumped in the liver
and spleen rather than going to the usual sites. So we do have precedent
with imaging agents that would suggest that HAMA will likely prevent the
ability to reuse this product in the future, at least in a significant
proportion of patients. There may be some patients where that might not
happen. The data are not extensive. And a follow-on to that comment,
then I would presume that the Committee might find it useful to study
specifically retreatment in a carefully controlled setting.

DR. MILLS: And we could assess that presence of an altered
biodistribution by using the diagnostic label, not the therapeutic label
to see if indeed the findings we\'ve seen on diagnostic studies
previously will occur again in the presence of these therapeutics.

CHAIRPERSON PRZEPIORKA: That\'s actually a very important study because
if in fact that is true, then we as oncologists are not used to ordering
HAMAs routinely for our patients. But if in fact it does alter
diagnostic studies using other Murine antibodies, we would certainly
like to know about that.

DR. SIEGEL: In that regard, it\'s worth noting, because we\'ve also
observed this, it doesn\'t change the overall risk/benefit but it\'s
something one needs to know about is that a number of laboratory tests,
including a number of endocrinological tests, involve use of Murine
antibodies in vitro to assess the presence of materials in the serum and
the presence of HAMA in the serum. We\'ll invalidate those ‑‑ there\'s
ways around that and it doesn\'t figure into the overall risk/benefit,
but it is worth knowing that so you don\'t misinterpret certain studies.

CHAIRPERSON PRZEPIORKA: Additionally, I think one thing that might be
added to this list is fertility, although Dr. Press has told us about
his patients who have demonstrated their fertility after therapy. I\'m
thinking the denominator may not be very large and we\'re just hearing
about a few in the numerator. And as we look at upfront protocols for
this type of therapy, we should have hard data on that so that patients
can make the correct option.

DR. MILLS: Just one other point to make with that is that there were
some comments earlier about the amount, the centigrade that were
administered to any of the target organs. Do not be reassured by
comparing those numbers to external beam radiation therapy centigrade.
There is no known relationship, and so while we identified the number
and we feel it\'s reproducible, the relationship to any safety tolerance
that\'s been established with external beam is purely speculation.

CHAIRPERSON PRZEPIORKA: Ms. Krivacic?

MS. KRIVACIC: I think the other issue that I would like to see from a
patient perspective is the issue of administering concomitant meds as
well, such as your growth factors, and if this has an impact in terms of
any kind of adverse events, because I think with the Zevalin trial that
was something that was brought up and there was some discussion about
that if there was indeed some interaction. So that would be something
I\'d like to see.

CHAIRPERSON PRZEPIORKA: Other comments from the Committee? Mr. Ohye.

MR. OHYE: I have one general comment, if I may, at the end of this
meeting. I know there was some criticism about the length of time it
took to get Bexxar approved, but as I look at the regulatory history as
sort of dispassionate, old broken-down regulatory guy, I think kudos are
in order for both the Agency and Corixa for taking a very difficult and
challenging approval process and getting your arms around this, taking
data that are 12 years old, sending people in the field to audit data,
examining subpopulations very carefully to make sure that you didn\'t
miss anything. And I think kudos are in order to Corixa for coming on
board and recognizing that there was an important drug here, and
congratulations for bringing this through.

CHAIRPERSON PRZEPIORKA: Any other comments from the Committee? Hearing
none, I call this meeting adjourned. Thank you and good night to
everyone.

(Whereupon, at 6:02 p.m., the Advisory Committee meeting was adjourned.)