**Mylotarg^®^ (gemtuzumab ozogamicin for Injection)**

**NDA No. 21-174**

**Briefing Document**

**Prepared for the**

**Oncologic Drugs Advisory Committee (ODAC) Meeting**

**March 12-13, 2003**

**Bethesda Holiday Inn**

**8120 Wisconsin Avenue**

**Bethesda, Maryland**

Prepared by:

Wyeth Pharmaceuticals

Philadelphia, Pennsylvania 19101

**Table of Contents**

**Oncologic Drugs Advisory Committee Meeting**

**Briefing Document for Mylotarg(gemtuzumab ozogamicin for Injection)**

**NDA No. 21-174**

Summary [3](#summary)

Background [3](#background)

Acute Myeloid Leukemia (AML) [4](#acute-myeloid-leukemia-aml)

Therapeutic Options [4](#therapeutic-options)

Mylotarg (gemtuzumab ozogamicin) [6](#mylotarg-gemtuzumab-ozogamicin)

Post-Marketing Clinical Commitment
[8](#post-marketing-clinical-commitment)

Preliminary Work for the Clinical Commitment
[9](#preliminary-work-for-the-clinical-commitment)

Status of the Commitment [10](#status-of-the-commitment)

Prospective Observational Study [11](#prospective-observational-study)

Conclusion [11](#conclusion)

References [13](#references)

**Appendix 1:** *Mylotarg® (gemtuzumab ozogamicin for Injection) product
labeling* **Tab 1**

**Appendix 2:** *Abstract -- Preliminary Report of a Phase 2 Study of
the Safety and Efficacy of Gemtuzumab Ozogamicin (Mylotarg®) Given in
Combination with Cytarabine in Patients with Acute Myeloid
Leukemia**.*** **Tab 2**

**Appendix 3:** *Abstract -- Interim Analysis of a Phase II Study of the
Safety and Efficacy of Gemtuzumab Ozogamicin (Mylotarg®) Given in
Combination with Cytarabine and Daunorubicin in Patients \<60 Years Old
with Untreated Acute Myeloid Leukemia**.*** **Tab 3**

**Oncologic Drugs Advisory Committee Meeting**

**Briefing Document for Mylotarg(gemtuzumab ozogamicin for Injection)**

**NDA No. 21-174**

# Summary

On November 26, 2002, the Division of Oncology Drug Products sent notice
to pharmaceutical companies with drugs approved under 21 CFR Part
314.500 (Subpart H, accelerated approval regulations), inviting
participation in an open session at the March 12-13, 2003 meeting of the
Oncologic Drugs Advisory Committee (ODAC). Wyeth was asked to provide an
update on the status of Subpart H phase IV commitments for Mylotarg.

In the following sections, Wyeth provides background information on the
Subpart H accelerated approval of Mylotarg and on its labeled use and
safety. This document also provides information on acute myeloid
leukemia (AML) and its treatment options as this is relevant to the
conditions of Mylotarg use. A review of Wyeth's post-marketing clinical
commitments and their status is included.

# Background

On October 29, 1999, Wyeth submitted a new drug application (NDA) for
Mylotarg® (gemtuzumab ozogamicin for Injection). The Food and Drug
Administration (FDA) completed the review of the application according
to the regulations for accelerated approval, and concluded that adequate
information was presented to approve Mylotarg for the treatment of
patients with CD33 positive acute myeloid leukemia in first relapse who
are 60 years of age or older and who are not considered candidates for
other cytotoxic chemotherapy. This application was approved on May 17,
2000 under 21 CFR Subpart H, a program described in the regulations as
intending to make promising products for life threatening diseases
available on the market on the basis of preliminary evidence of safety
and efficacy. [^1]

In order to qualify for accelerated approval under Subpart H, FDA
indicated that the response rate demonstrated with gemtuzumab ozogamicin
should be comparable to that obtained with current standard therapies,
assuming a safety advantage. If there was no safety advantage with
gemtuzumab ozogamicin, the response rate would need to be better than
that with standard chemotherapy. The FDA stated that determining
historic complete remission (CR) and morphological remission (MR) rates
associated with conventional chemotherapy would be considered helpful.

Mylotarg was approved on the basis that the product has an effect on a
surrogate endpoint reasonably likely to predict a clinical benefit (in
this case an effect on CR and CR~p~ \[remission with incomplete platelet
recovery\]). Mylotarg was evaluated in preclinical studies, two phase I
studies, and three phase II studies of patients with relapsed AML. The
effectiveness of Mylotarg is based on overall response (OR) rates. There
are no controlled trials demonstrating a clinical benefit, such as
improvement in disease-related symptoms or increased survival, compared
to any other treatment. The safety and efficacy of Mylotarg in patients
with poor performance status and organ dysfunction have not been
established.

# Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is the most common type of acute leukemia
in adults. The American Cancer Society estimated that 10,500 new cases
of AML and 7,800 deaths from AML would occur in the United States in
2002.[^2] Among the new cases it is estimated that Mylotarg can
potentially treat approximately 2,600 patients within its indicated use.
Slightly more than one half of all patients with AML are 60 years of age
or older.

Untreated AML is a rapidly fatal disease, with a median survival time of
less than 3 months. With standard treatments for patients with de novo
AML a high rate of first remission is achieved, but approximately 75% of
patients with first remission ultimately relapse. The majority of
relapses occur within 2 years after remission is attained. The American
Cancer Society reported 5-year survival rates of 18.7% for patients with
AML.Error: Reference source not found Patients 60 years of age and older
have a lower remission rate, a reduced probability of remaining in
remission, and have a lower cure rate than younger patients.

Patients with relapsed AML have a particularly poor prognosis
(approximately 5% to 10% long-term disease-free survival). Significant
morbidity and mortality are associated with current therapies for
patients with relapsed AML, particularly for patients 60 years of age
and older and for patients with co-morbid conditions. While numerous
therapies and dosage regimens have been investigated in an attempt to
improve remission and survival rates in patients with relapsed AML, none
have emerged as a standard of care. Prior to the Subpart H approval of
Mylotarg, there were no agents specifically approved for the treatment
of patients with relapsed AML.

# Therapeutic Options

Most patients diagnosed with AML receive induction therapy to attain
remission and postremission therapy to maintain remission.[^3]
Approximately 50% to 70% of adults with AML attain complete remission
(CR) following treatment.[^4]^,^[^5] About 25% of these patients survive
3 or more years.[^6] Unfortunately, about 75% of patients relapse.

Induction chemotherapy with cytarabine and an anthracycline has been a
standard treatment of newly diagnosed AML for the past 20 years.
Complete remission can be achieved in 50% to 80% of adult patients less
than 60 years old with de novo AML when treated with continuous infusion
(CI) cytarabine and an anthracycline, depending on the prognostic
factors in the population treated. However, only 20% to 40% of patients
who achieve a remission have prolonged leukemia-free survival. The
induction CR rates for patients over the age of 60 are generally lower
due to a higher incidence of poor prognostic cytogenetic abnormalities
and from greater mortality from intensive therapy. Several
non-transplant strategies have been employed to intensify the induction
regimen with the hope of improving the remission rate, duration of
remission, and survival. While these strategies have produced promising
leads, none has emerged as providing a clear advantage to therapy with
cytarabine and an anthracycline followed by post-remission therapy for
patients with de novo AML. In addition, many of these approaches have
resulted in additional safety concerns.

Induction therapy typically consists of 7 days of cytarabine (ara-C)
plus 3 days of an anthracycline such as idarubicin or daunorubicin
and/or an anthracenedione such as mitoxantrone.Error: Reference source
not found Reported remission rates are variable. In large randomized
clinical trials, these regimens have been shown to achieve CR in 52% to
72% of patients.Error: Reference source not found In a report by Bennett
and colleagues (1997), 62% of patients experienced CR, and the median
5-year disease-free survival rate was 22%.[^7]

The most common toxicity associated with induction regimens is
myelosuppression. Thrombocytopenia frequently occurs and, if severe, can
lead to hemorrhage. Neutropenia coupled with mucositis makes severe
infections, fever, and sepsis common as well. Nausea, vomiting,
mucositis, and alopecia also frequently accompany treatment.
Cardiotoxicity is a common effect of the anthracyclines, especially when
used at high doses.[^8]^,^[^9]^,^[^10]^,^[^11]^,^[^12]^,^[^13]^,^[^14]

Patients must be closely monitored and must receive hematologic
supportive care and broad-spectrum antimicrobial therapy to combat
hemorrhage and infection, major causes of death in AML patients.Error:
Reference source not found Platelet transfusions may be necessary to
maintain platelet counts (\>20,000/uL). Red blood cell transfusions are
indicated when hemoglobin is below 8.5 g/dL and can help manage symptoms
of fatigue.[^15]

Disease-free survival and 5-year survival rates have been shown to
increase following postremission therapy and intensification
therapy.Error: Reference source not found^,^[^16] Postremission
strategies include low-dose maintenance therapy and intensive
consolidation therapy. High-dose, marrowablative therapy with allogeneic
hematologic stem-cell transplantation (HSCT) and high-dose chemotherapy
or chemoradiotherapy with autologous HSCT have been used as
postremission therapy for patients with
AML.[^17]^,^[^18]^,^[^19]^,^[^20]^,^[^21]

Relapsed AML is associated with poor probability of attaining second
remission or substantial disease-free and overall survival.Error:
Reference source not found Usually, the outcome is better the younger
and healthier the patient is, the longer the initial remission, and the
longer the duration since chemotherapy exposure. For patients 15 to 60
years of age, the probability of inducing a second remission is
approximately 50%, whereas for patients 60 years of age and older, the
probability is only 25%.Error: Reference source not found

There is no standard treatment for patients with relapsed AML. If
relapse occurs [\>]{.underline} 6 months after first remission,
re-administration of the original remission-induction regimen may be
effective.Error: Reference source not found Regimens consisting of
high-dose cytosine arabinoside alone or in combination with agents such
as mitoxantrone have been investigated. Other agents that have been used
to treat AML in first relapse include etoposide, and
4^1^-(9-acridinyl-amino) methane-sulfon-*m*-anisidine
(AMSA).[^22]^,^[^23]^,^[^24]^,^[^25]^,^[^26] Reported remission rates
are about 40% with durations ranging from 3 to 6 months, although
remission rates are considerably lower in patients over 60 years
old.Error: Reference source not found^,^[^27] Furthermore, adverse
effects such as cardiac, central nervous system, gastrointestinal, and
hematologic toxicity limit the use of these regimens, particularly in
patients who have already been exposed to chemotherapeutic agents. Some
patients with relapsed AML respond to allogeneic bone marrow transplant
(BMT) and autologous BMT with or without purging.Error: Reference source
not found^,Error:\ Reference\ source\ not\ found,^[^28]^,^[^29]

Monoclonal antibodies (MoAbs) that target specific antigens can be used
to deliver cytotoxic agents to specific cells within the body. Despite
the simplicity of this concept, the actual development of therapeutic
agents has been complicated by a number of technical difficulties,
including the selection of an appropriate target antigen.[^30]

CD33 is expressed on normal myeloid precursor cells and on leukemic
blasts of \> 80% of patients with AML but not on nonmyeloid cells or
nonhematopoietic tissues.[^31]^,^[^32] Antibody-targeted chemotherapy
consists of a MoAb conjugated to a cytotoxin or a chemotherapeutic
agent. To exert their effects, MoAbs conjugated to potent cytotoxic
agents must be internalized by the cell to disrupt critical
intracellular processes and induce cell death.Error: Reference source
not found The "linker" between the MoAb and the toxic agent is a key
element of this type of therapy. The toxic agent must remain bound to
the linker in the serum and be efficiently released within the target
cell without significant alteration in its activity.[^33] Mylotarg is
one example of this type of conjugate and is discussed in more detail in
the following section. Mylotarg contains a humanized anti-CD33 antibody
linked to a derivative of calicheamicin, a novel and potent cytotoxic
antitumor antibiotic.Error: Reference source not found Calicheamicins
are antibiotics originally isolated from soil microorganisms. In
preclinical studies, calicheamicins were shown to be up to 1,000-fold
more potent than other chemotherapy agents.[^34]

# Mylotarg (gemtuzumab ozogamicin)

Mylotarg provides a new method of drug delivery by utilizing an antibody
to target the cytotoxic agent to leukemic cells. It is the first
antibody targeted chemotherapy agent approved by the FDA, and is
composed of a humanized anti-CD33 antibody \[hp67.linked to a potent
antitumor antibiotic, calicheamicin. It is indicated for the treatment
of patients with CD33 positive acute myeloid leukemia in first relapse
who are 60 years of age or older and who are not candidates for other
cytotoxic chemotherapy.

Mylotarg as a single agent demonstrated efficacy comparable to that
reported in the literature for conventional AML treatment in similar
patient populations as measured by remission rate, relapse-free
survival, overall survival, and post-hematopoietic stem cell transplant
survival. Mylotarg demonstrated an improved safety profile in comparison
with conventional combination therapy. There was no alopecia. Rates of
myelosuppression, severe bleeding, and liver enzyme abnormalities were
similar to the rates reported for current combination therapies.
However, patients treated with Mylotarg experienced a reduced rate of
severe mucositis occurring during the time of severe neutropenia. As a
result there was a low rate of infections, and subsequently a lower
total duration of hospitalization for Mylotarg-treated patients. Our
data demonstrating that 4.8% of Mylotarg-treated patients were not
hospitalized during the treatment period and 21% of these patients were
hospitalized for [\<]{.underline} 7 days represents an improvement over
results reported in the literature for conventional chemotherapy. When
those patients who died during the treatment phase are excluded, these
numbers become 5.6% and 22%, respectively. Hospitalization is generally
regarded as universal in this population of seriously ill patients.
These data indicate an improved tolerability for Mylotarg compared with
conventional chemotherapy treatments in this seriously ill patient
population.

Patients 60 years of age and older with AML are a distinct subset of AML
patients; they have lower response rates to conventional antileukemic
therapies, which are associated with decreased survival rates. In the
Mylotarg studies, the median age was 60 years. The OR rate in all
patients was 31%, in patients \< 60 years old the OR rate was 34%, and
in patients 60 years old the OR rate was 28%. The observation of only a
modest decrease in remission rate in older patients is clinically
important in that it suggests that Mylotarg is an effective and safe
treatment for the older patient population.

With conventional therapy, remission consists almost entirely of CR, and
the response that was defined by Wyeth as CR~p~ (remission with
incomplete platelet recovery) is seldom observed. A review of the
literature and external databases showed that the incidence of CR~p~ was
 5% with conventional therapy. Patients treated with Mylotarg have a
higher incidence of CR~p~. This may be because of the effects of
Mylotarg on CD33 positive platelet precursors or because of decreased
bone marrow reserves. However, the clinical outcome for CR and CR~p~
patients after Mylotarg therapy is comparable, including a comparable
incidence of clinically serious bleeding incidents.

In phase II clinical studies, a 26% overall response was observed in
patients 60 years of age with AML in first relapse. A 30% overall
response rate was observed in all patients studied, regardless of
age.Error: Reference source not found

Similar to other antibody‑based therapies, a mild infusion‑related
symptom complex of fever, chills and, less frequently, hypotension and
dyspnea, associated with Mylotarg administration was observed in most
patients. These events were usually brief in duration and without
clinical sequelae. Transient and generally reversible liver function
test abnormalities occurred with moderate incidence, and were comparable
to those reported in the literature for conventional combination
chemotherapy.

As with all antibody-containing compounds, there is a potential for
production of antibodies against the antibody or chemotherapy component
of the agent. No patients developed an immune response to Mylotarg in
the phase II studies.

The major toxicity associated with Mylotarg was severe myelosuppression.
An acute infusion-related symptom complex occurred within 24 hours after
administration of Mylotarg.Error: Reference source not found

Hepatotoxicity, including severe hepatic veno-occlusive disease (VOD),
has been reported in association with the use of Mylotarg as a single
agent, as part of a combination chemotherapy regimen, and in patients
without a history of liver disease or HSCT. Patients who receive
Mylotarg either before or after HSCT, patients with underlying hepatic
disease or abnormal liver function, and patients receiving Mylotarg in
combinations with other chemotherapy may be at increased risk for
developing severe VOD. Death from liver failure and from VOD has been
reported in patients who received Mylotarg.

The overall benefit/risk of gemtuzumab ozogamicin for treatment of
relapsed AML is positive. The efficacy of gemtuzumab ozogamicin, when
administered in 2 doses of 9 mg/m^2^ IV with a 14-day interval between
doses, was comparable to that seen with conventional AML therapy in
similar patient populations. The risks of treatment with Mylotarg should
be compared with those of treatment with conventional chemotherapy
presently used for relapsed AML patients, which include alopecia,
mucositis, severe myelosuppression, bleeding, neutropenic fever,
infection, and abnormal liver function tests.

# Post-Marketing Clinical Commitment

The following post-marketing clinical study commitments were specified
in the approval of Mylotarg:

\"A randomized controlled trial of gemtuzumab ozogamicin, daunorubicin
and cytarabine versus daunorubicin and cytarabine as induction therapy
in patients with de novo CD 33 positive acute myeloid leukemia. This
trial should be designed to demonstrate superior survival in the
three-drug (gemtuzumab ozogamicin containing) group. Response rate
results can be used as supportive evidence; responses should be defined
as CRs or CRps of at least 4 weeks duration. If the three-drug regimen
cannot be designed with acceptable toxicity, a randomized controlled
trial designed to show that survival in patients treated with gemtuzumab
ozogamicin and cytarabine is not inferior to survival in patients given
daunorubicin and cytarabine should be initiated following discussion
with the division. Again, the definition of the supportive secondary end
point, response (CR and CRp), should include a pre-specified minimum
duration of response of 4 weeks. For either trial it will be necessary
to:

-   Clarify the purpose and the number of interim analyses planned,
    adjusting type I error as necessary. An independent, expert data
    monitoring committee will review bone marrow results, conduct the
    interim analyses, and make recommendations regarding continuation of
    the study. Responses should be determined by an independent
    pathologist blinded to the treatment arm.

-   Pre-specify subgroups and covariates that are likely to be used in
    the analyses. The relationship of CD33 quantitative expression to
    response should be examined.

-   Perform a thorough evaluation of toxicity, both hematologic and
    non-hematologic, in patients undergoing subsequent postremission
    therapy such as hematopoietic stem cell transplantation or high dose
    cytarabine, as well as in patients who receive no further therapy.

-   Perform long-term follow-up for relapse and survival in patients
    following postremission therapy, as well as for patients who receive
    no further therapy.

-   Perform the appropriate phase I trials to ensure that the toxicities
    observed with the dose combinations in the above trials are
    acceptable; and to identify any potentially significant
    pharmacokinetic drug-drug interactions.\"

# Preliminary Work for the Clinical Commitment

Phase I/phase II dose-ranging studies were needed prior to the
initiation of the aforementioned commitment study to determine dosing of
Mylotarg with other standard of care chemotherapy agents. Since Mylotarg
was approved as a single agent treatment, new assessments regarding the
use of Mylotarg with other chemotherapy agents were required. Many
variables needed to be evaluated including (but not limited to)
multiple-ascending dose studies to determine the safe use of combination
regimens and determining single dose versus two dose regimen of Mylotarg
concomitantly with each chemotherapy cycle.

The following overviews the status of the dose-ranging studies to date.

**A Dose-Ranging Study of the Safety and Efficacy of Gemtuzumab
Ozogamicin (GO) Given in Combination with Cytarabine and Daunorubicin in
Relapsed or Refractory Patients and in Younger de novo Patients with
Acute Myeloid Leukemia (Study 206)**

This pilot study is evaluating the safety and efficacy of administering
gemtuzumab ozogamicin concurrently with an anthracycline and cytarabine
in AML patients. The goal of the study is to define a combination
treatment arm utilizing gemtuzumab ozogamicin, an anthracycline, and
cytarabine which will be compared to an anthracycline and cytarabine arm
in a randomized phase III trial of de novo AML.

Wyeth has recently completed the first segment of Protocol 206-US, which
had 22 patients enrolled, and has conducted an ad hoc analysis of the
data from this segment, enabling development of a Phase III protocol in
collaboration with Southwest Oncology Group (SWOG). A brief summary of
the ad hoc analysis was provided to the Agency on December 23, 2002. An
abstract from that data is attached as Appendix 2.

**A Dose Ranging Study of the Safety and Efficacy of Gemtuzumab
Ozogamicin (GO) given in Combination with Cytarabine in Relapsed or
Refractory Patients and Older de novo Patients with Acute Myeloid
Leukemia (Study 205)**

In an attempt to improve the survival of older patients with AML, this
trial is designed to substitute gemtuzumab ozogamicin for standard
anthracycline dosing in remission induction therapy for de novo AML. As
toxicity of therapy is a major barrier to treating older AML patients,
the proposed study is a pilot trial to evaluate the safety and efficacy
of administering gemtuzumab ozogamicin with continuous infusion
cytarabine in AML patients. The eventual goal of the study is to define
a combination treatment arm which will be compared to
cytarabine/anthracycline therapy in a randomized trial of AML in older
patients.

This study is ongoing. A total of 21 patients have enrolled in phase I
of study 205. Complete data on these patients are not yet available. An
abstract from that data is attached as Appendix 3.

# Status of the Commitment

Based on the findings from studies 205 and 206 referenced above, Wyeth,
in collaboration with the Southwest Oncology Group (SWOG), designed the
following study:

Southwest Oncology Group (SWOG): A Phase III Study of the Addition of
Gemtuzumab Ozogamicin (Mylotarg) During Induction Therapy and
Post-Consolidation Therapy Versus Standard Induction and Consolidation
Therapy with Daunomycin and Cytosine Arabinoside for Patients Under Age
56 with Previously untreated de novo Acute Myeloid Leukemia (AML)

Wyeth, in cooperation with Southwest Oncology Group (SWOG), has
submitted the above-referenced study protocol to the FDA for review and
approval. Study initiation is anticipated for Second Quarter 2003. The
anticipated accrual is 640 patients over a four year period with an 18
month follow-up period from the time of the last enrolled patient. The
estimated completion timeline is 2008 with study results anticipated for
submission to the FDA in 2009.

This study will determine if patients without acute promyelocytic
leukemia (non-M3) AML, and who have not been previously treated, will
achieve a higher complete response rate when gemtuzumab ozogamicin is
added to standard induction therapy. The study will also determine if
patients who receive induction therapy with gemtuzumab ozogamicin plus
standard induction followed by post-consolidation therapy with
gemtuzumab ozogamicin will have improved disease-free and overall
survival. Patients will be randomized to receive either standard
induction therapy utilizing 7 days of cytosine arabinoside and 3 days of
an anthracycline, such as daunomycin or idarubicin (7+3), or the
experimental arm with 7+3+gemtuzumab ozogamicin. All patients with acute
myeloid leukemia express CD33 at varying levels and thus all patients
with acute myeloid leukemia will be eligible for randomization. Complete
responders will receive 3 cycles of alternate day high dose cytosine
arabinoside as consolidation. After completion of consolidation,
patients who received gemtuzumab ozogamicin during induction will
receive 3 additional doses of gemtuzumab ozogamicin at monthly
intervals. Patients on the standard therapy arm will receive no
additional therapy.

The objectives of this study are as follows:

-   To compare the overall survival (OS) and disease-free survival (DFS)
    of patients under age 56 with previously untreated, non-M3, AML who
    receive gemtuzumab ozogamicin versus patients who receive
    chemotherapy alone.

-   To compare the complete remission rate achieved by the addition of
    gemtuzumab ozogamicin to standard induction chemotherapy to that
    achieved with standard induction chemotherapy in patients under the
    age of 56 with previously untreated, de novo, non-M3 AML.

-   To estimate the frequency and severity of toxicities of the
    gemtuzumab ozogamicin regimen.

-   To evaluate the prognostic significance of FLT3 mutation prior to
    therapy, and of minimal residual disease in remission specimens
    collected before and after consolidation therapy and after
    post-consolidation therapy with gemtuzumab ozogamicin.

-   To evaluate the prognostic significance of the flow cytometric
    detection of minimal residual disease in specimens collected before
    and after consolidation therapy and after post-consolidation therapy
    with gemtuzumab ozogamicin.

# Prospective Observational Study

Mylotarg has a boxed warning on the label (see attached prescribing
information) addressing hypersensitivity reactions including
anaphylaxis, infusion reaction, pulmonary events, and hepatotoxicity
including veno-occlusive disease (VOD). It is important to note that
this boxed warning only addresses the safety of Mylotarg for use as a
single agent, and not in combination with other therapies.

On April 12, 2001, Wyeth, in conjunction with FDA, agreed to develop a
Voluntary Patient Safety Registry and to provide quarterly reports to
the FDA providing incremental and cumulative analysis after the
observational study commenced.

All centers that agree to participate in the observational study are
required to seek permission from every patient at their institution who
is going to be given Mylotarg, regardless of whether it is given on- or
off-label or if the patient is in another study or not. The study design
is that of a prospective observational registry conducted under
conditions of routine clinical practice by oncologists/hematologists
administering Mylotarg. The primary objectives of this registry are to
estimate the incidence rate of hepatic veno-occlusive disease (VOD)
among patients treated with Mylotarg and to identify risk factors
associated with the development of VOD after Mylotarg treatment.
Secondary objectives of the registry are to collect and report all
serious adverse events, and nonserious adverse events of special
interest comprised of hepatic, hypersensitivity, infusion-related,
pulmonary, and renal events, and to collect information on Mylotarg use
in various practice settings.

To date, this observational study has enrolled approximately 92
patients, and there are more than 50 sites participating. Wyeth
anticipates enrollment of approximately 500 patients in this prospective
observational trial. Quarterly "Prospective Observational Study in Usual
Care" reports have been subsquently submitted to the FDA. These
observations indicate that there has not been a significant change in
the safety profile of Mylotarg.

# Conclusion

Wyeth has been diligent in meeting all of our obligations for Mylotarg
and has done so in a timely fashion. Mylotarg is approved as a single
agent treatment. However, the post-marketing clinical commitment
required Wyeth to conduct studies using Mylotarg in combination with
other chemotherapy agents. Before this clinical commitment study could
be conducted, Wyeth had to conduct phase I/II dose-ranging studies to
determine a safe dose of Mylotarg when used in combination with other
agents. Now that the dose-ranging studies have established this safe
dose, Wyeth has developed a study protocol for our post-marketing
clinical commitment in cooperation with SWOG.

Wyeth continues to meticulously monitor any safety issues that may be
associated with Mylotarg as demonstrated through the Prospective
Observational Study, clinical study analysis, and routine post-marketing
surveillance. Any safety concerns are provided to the Agency for review
and discussion.

The Subpart H program has allowed Mylotarg to be available as a
treatment option to doctors with patients who are 60 years of age and
have AML in first relapse. Prior to the approval of Mylotarg, there were
no approved options. Mylotarg has demonstrated a clinically important
positive benefit in its target population. The Subpart H approval
program has provided great value to the medical community.

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