# Title Page

+-----------------------------------------------------------------------+
| **GENASENSE**                                                        |
|                                                                       |
| **(oblimersen sodium) Injection**                                     |
+-----------------------------------------------------------------------+
| **FDA Advisory Committee Briefing Document**                          |
|                                                                       |
| **NDA 21-649**                                                        |
+-----------------------------------------------------------------------+
|                                                                       |
+-----------------------------------------------------------------------+

# table of contents

# [1. Title Page 1](#title-page) {#title-page-1 .TOC-1}

# [2. table of contents 2](#table-of-contents) {#table-of-contents-2 .TOC-1}

# [3. List of Abbreviations and Definitions of Terms 6](#list-of-abbreviations-and-definitions-of-terms) {#list-of-abbreviations-and-definitions-of-terms-6 .TOC-1}

# [4. summary 8](#summary) {#summary-8 .TOC-1}

# [5. Introduction 10](#introduction) {#introduction-10 .TOC-1}

# [6. Background 11](#background) {#background-11 .TOC-1}

[6.1 Pharmacology 11](#pharmacology)

[6.2 Clinical Background and Treatment of Advanced Malignant Melanoma
12](#clinical-background-and-treatment-of-advanced-malignant-melanoma)

[6.3 Rationale for the Development of Genasense
15](#rationale-for-the-development-of-genasense)

[6.4 Nonclinical Data 17](#nonclinical-data)

[6.4.1 Nonclinical Pharmacology 17](#nonclinical-pharmacology)

[6.4.2 Nonclinical Safety Evaluation 17](#nonclinical-safety-evaluation)

# [7. Clinical Pharmacology 19](#clinical-pharmacology) {#clinical-pharmacology-19 .TOC-1}

[7.1 Pharmacokinetics 19](#pharmacokinetics)

[7.2 Metabolism 21](#metabolism)

[7.3 Plasma Protein Binding 21](#plasma-protein-binding)

[7.4 Special Populations 21](#special-populations)

[7.5 Dose Selection 22](#dose-selection)

# [8. Efficacy results in randomized Phase III Study 24](#efficacy-results-in-randomized-phase-iii-study) {#efficacy-results-in-randomized-phase-iii-study-24 .TOC-1}

[8.1 Design and Methods for Protocol GM301
24](#design-and-methods-for-protocol-gm301)

[8.1.1 Study Objectives 24](#study-objectives)

[8.1.2 Study Design and Treatment Regimen
24](#study-design-and-treatment-regimen)

[8.1.3 Entry Criteria 25](#entry-criteria)

[8.1.4 Efficacy Assessments 26](#efficacy-assessments)

[8.1.5 Statistical Considerations 28](#statistical-considerations)

[8.2 Study Population 29](#study-population)

[8.3 Efficacy Results 35](#efficacy-results)

[8.3.1 Overall Survival 35](#overall-survival)

[8.3.2 Progression-Free Survival 38](#progression-free-survival)

[8.3.3 Antitumor Response Rate 43](#antitumor-response-rate)

[8.3.4 Duration of Antitumor Response
47](#duration-of-antitumor-response)

[8.3.5 Durable Response Rate 48](#durable-response-rate)

[8.3.6 ECOG Performance Status 49](#ecog-performance-status)

[8.4 Efficacy Conclusions 49](#efficacy-conclusions)

# [9. Safety results 51](#safety-results) {#safety-results-51 .TOC-1}

[9.1 Randomized Phase III Study in Advanced Malignant Melanoma
51](#randomized-phase-iii-study-in-advanced-malignant-melanoma)

[9.1.1 Safety Assessments 51](#safety-assessments)

[9.1.2 Overview of Treatment-Emergent Adverse Events
52](#overview-of-treatment-emergent-adverse-events)

[9.1.3 Treatment-Emergent Adverse Events
54](#treatment-emergent-adverse-events)

[9.1.4 Other Safety Evaluations 61](#other-safety-evaluations)

[9.2 Other Completed Studies 62](#other-completed-studies)

[9.3 120-Day Safety Update 62](#day-safety-update)

[9.4 Overall Safety Conclusions 62](#overall-safety-conclusions)

# [10. Conclusions 64](#conclusions) {#conclusions-64 .TOC-1}

# [11. References 66](#references) {#references-66 .TOC-1}

List of In-text Tables

[Table 1: Determination of overall response
27](#__RefHeading___Toc68561773)

[Table 2: Disposition of patients not treated
29](#__RefHeading___Toc68561774)

[Table 3: Demographic characteristics by treatment group:
Intent-to-Treat Population 30](#__RefHeading___Toc68561775)

[Table 4: Melanoma history and disease characteristics at baseline by
treatment group: Intent-to-Treat Population
31](#__RefHeading___Toc68561776)

[Table 5: Previous cancer treatment by treatment group: Intent-to-Treat
Population 32](#__RefHeading___Toc68561777)

[Table 6: Stratification information by treatment group: Intent-to-Treat
Population 33](#__RefHeading___Toc68561778)

[Table 7: Number (%) of patients by maximum number of cycles initiated
by treatment group: Intent-to-Treat Population
34](#__RefHeading___Toc68561779)

[Table 8: Descriptive statistics for cumulative (total) dose of study
drug across all cycles: Safety Population
35](#__RefHeading___Toc68561780)

[Table 9: Survival time analysis: Intent-to-Treat Population
36](#__RefHeading___Toc68561781)

[Table 10: Survival time (in days) by percentile: Intent-to-Treat
Population 38](#__RefHeading___Toc68561782)

[Table 11: Progression-free survival analysis: Intent-to-Treat
Population 38](#__RefHeading___Toc68561783)

[Table 12: Progression-free survival (in days) by percentile:
Intent-to-Treat Population 39](#__RefHeading___Toc68561784)

[Table 13: Sensitivity analyses performed for time to progression and
progression-free survival: Intent-to-Treat Population
41](#__RefHeading___Toc68561785)

[Table 14: Antitumor response rates during the treatment phase by
treatment group: Intent-to-Treat Population
44](#__RefHeading___Toc68561786)

[Table 15: Response rates by subgroup: Intent-to-Treat Population
46](#__RefHeading___Toc68561787)

[Table 16: Duration of antitumor response in responding patients by
treatment group: Intent-to-Treat Population
47](#__RefHeading___Toc68561788)

[Table 17: Overview of treatment-emergent adverse events by treatment
group: Safety Population 53](#_Ref67816011)

[Table 18: Treatment-emergent adverse events that occurred in ≥ 20% of
patients in either treatment group by preferred term: Safety Population
57](#__RefHeading___Toc68561790)

[Table 19: Grade 3 and Grade 4 adverse events resulting in
discontinuation: Safety Population 58](#__RefHeading___Toc68561791)

[Table 20: Shifts in laboratory parameters: Safety Population
61](#__RefHeading___Toc68561792)

List of Figures

[Figure 1: Mean G3139, N-1, and N-2 plasma concentration-time profiles
20](#__RefHeading___Toc68561793)

[Figure 2: Kaplan-Meier survival curves by treatment group:
Intent-to-Treat Population (N = 771) 37](#__RefHeading___Toc68561794)

[Figure 3: Kaplan-Meier progression-free survival curves by treatment
group: Intent-to-Treat Population (N = 771)
39](#__RefHeading___Toc68561795)

[Figure 4: Plots of hazard ratios and 95% confidence intervals for
progression-free survival: Intent-to-Treat Population
43](#__RefHeading___Toc68561796)

[Figure 5: Durable responses: Intent-to-Treat Population
48](#__RefHeading___Toc68561797)

# List of Abbreviations and Definitions of Terms

  -----------------------------------------------------------------------
  Abbreviation or   Explanation
  specialized term  
  ----------------- -----------------------------------------------------
  AJCC              American Joint Committee on Cancer

  ALT               alanine aminotransferase (serum glutamic pyruvic
                    transaminase \[SGPT\])

  Apr               April

  AST               aspartate aminotransferase (serum glutamic
                    oxaloacetic transaminase \[SGOT\])

  Aug               August

  *bcl-2*           messenger ribonucleic acid (mRNA) name for *BCL2*

  *BCL2*            B-cell leukemia/lymphoma 2 gene

  Bcl-2             B-cell lymphoma break point 2; a protein that
                    suppresses apoptosis and is upregulated in many types
                    of tumors

  BCT               biochemotherapy

  BUN               blood urea nitrogen

  CI                confidence interval

  Cl                clearance

  Cl~r~             renal clearance

  C~ss~             concentration at steady state

  CT                computed tomography

  CVD               cisplatin, vincristine, and DTIC

  DNA               deoxyribonucleic acid

  DTIC              dacarbazine

  ECOG              Eastern Cooperative Oncology Group

  excl              excluding

  FDA               Food and Drug Administration

  ICU               Intensive Care Unit

  IL                interleukin

  IV                intravenous

  Jan               January

  LD                longest diameters

  LDH               lactate dehydrogenase

  Mar               March

  MedDRA            Medical Dictionary for Regulatory Activities

  mRNA              messenger ribonucleic acid

  N-1               the 17-mer metabolite of G3139

  N-2               the 16-mer metabolite of G3139

  NDA               New Drug Application

  NJ                New Jersey

  PET               positron emission tomography

  RECIST            Response Evaluation Criteria in Solid Tumors

  SD                standard deviation

  t~1/2~            half-life
  -----------------------------------------------------------------------

# summary

Advanced malignant melanoma is one of the most chemoresistant types of
human cancers. Virtually no recent progress has been made in the
treatment of patients with this disease. In the past 30 years, the Food
and Drug Administration (FDA) has approved only 2 agents, dacarbazine
(DTIC) and interleukin-2 (IL-2), which were approved on the basis of
overall response and durable response, respectively. Neither agent has
ever been shown to affect survival. The most recent randomized study of
DTIC yielded an overall response rate (complete response plus partial
response) of 7%. Nonetheless, no other drug or any combination of drugs
has ever shown a survival benefit when compared with DTIC alone, and it
remains a regulatory standard of care.

Melanoma is characterized by overexpression of Bcl-2, a protein that
prevents or substantially retards the onset of programmed cell death
(apoptosis) induced by cytotoxic chemotherapy. Genasense blocks
production of Bcl-2, and its use with chemotherapy is being tested as a
means of improving current levels of therapeutic efficacy. The utility
of the approach in any disease may depend upon the intensity of the
apoptotic stimulus (ie, the inherent effectiveness of chemotherapy) with
which it is paired.

In a New Drug Application (NDA) filed in 2003, the Sponsor presented
data for the largest randomized clinical study ever conducted in
patients with advanced malignant melanoma. In the study, 771 patients
were randomly assigned to receive DTIC alone or DTIC in combination with
Genasense. When compared with DTIC alone, the Genasense/DTIC combination
has yielded:

-   A trend toward improvement in overall survival by log-rank analysis
    (P = 0.18)

-   A statistically significant increase in the overall response rate
    (11.7% vs 6.8%; P = 0.019), along with an increase in the "durable
    response" rate (3.4% vs 1.3%; P = 0.057), with responses seen in
    M1a, M1b, and M1c disease

-   An increase in the number of complete responses (1.3% vs 0.5%)

-   A statistically significant increase in time to disease progression
    (hazard ratio = 0.73; P = 0.0003)

-   An acceptable safety profile for use as an outpatient treatment in
    all age groups studied

-   A favorable benefit:risk comparison

The aggregate of these data shows an internally consistent benefit for
patients across all efficacy endpoints and subgroups. The Sponsor
believes that the Genasense/DTIC combination represents an important
step in the development of more effective treatments for patients with
advanced melanoma.

# Introduction

NDA 21-649 was submitted to the FDA for the use of GENASENSE
(oblimersen sodium) Injection in combination with DTIC for the treatment
of patients with advanced melanoma who have not received prior
chemotherapy.

This document provides a summary of the key nonclinical and clinical
findings related to the efficacy and safety of Genasense in humans.

# Background

## Pharmacology

Genasense (oblimersen sodium, Bcl-2 antisense oligonucleotide, G3139)
belongs to a class of drugs known as antisense. Antisense represents a
pharmacologic mechanism for selectively reducing production of a
specific protein. In making an antisense drug, a series of nucleotides
are engineered in a sequence that is complementary to the normal
("sense") strand of messenger ribonucleic acid (mRNA), the precursor to
final translation of the protein. When the antisense drug binds to its
complementary sequence of mRNA, the mRNA is enzymatically cleaved, which
prevents translation of the protein.

Genasense is a synthetic, 18-base, single-stranded phosphorothioate
oligonucleotide and has a molecular weight of 6058.3 daltons. The
phosphorothioate modification substitutes a sulfur atom in place of a
nonbridging oxygen atom on the phosphate group along the backbone of the
molecule, which is comprised of alternating phosphorothioate and
2-deoxyribose sugar groups. This modification yields greater stability
and a longer half-life to the molecule. Genasense selectively targets
the first 6 codons (ie, 18 bases) of the mRNA open reading frame that
encodes a protein known as Bcl-2. As shown in Figure 1, formation of the
mRNA/antisense duplex recruits an enzyme (RNase H) that breaks apart the
mRNA strand and releases the antisense strand, allowing the drug to bind
and cleave additional Bcl-2 mRNA molecules. Cleavage of the Bcl-2 mRNA
eliminates the ability of the molecule to generate Bcl-2 protein.

Figure 1: Binding of antisense to mRNA recruits RNase H, which fragments
mRNA and prevents production of Bcl-2 protein

## Clinical Background and Treatment of Advanced Malignant Melanoma

Melanoma is predominantly a disease of adults.([^1]) The tumor arises
from melanocytes that are most commonly in the skin, although the
disease can also arise from sites in the mucosa or internal
organs.(Error: Reference source not found)

Melanoma is an increasingly common disease worldwide, with an annual
increase in incidence of approximately 3% to 7%.([^2]) This increase is
evident in the United States, Japan, and Australia, among other
countries,([^3],[^4],[^5]) and may be partly attributed to the earlier
detection of melanoma.(Error: Reference source not found) It is
estimated that 54,200 persons were newly discovered to have melanoma and
7,600 individuals died as a result of melanoma in the United States in
2003.(Error: Reference source not found)

A variety of clinical factors have been reported to predict survival in
advanced-stage melanoma. Positive factors include female gender, no
impairment of performance status, and young age.([^6],[^7]) Patients
with metastases confined to the skin, subcutaneous tissue, lymph nodes,
and lung appear more likely to respond to any type of therapy and have
superior survival relative to patients with metastases to other
sites.(Error: Reference source not found) Factors associated with short
survival include high lactate dehydrogenase (LDH; \> 500 IU/mL) and
metastases to brain or liver.(Error: Reference source not found)

No curative treatment exists for advanced malignant melanoma, and
approved treatment options (ie, DTIC and IL-2) are extremely limited.

**DTIC:** DTIC, the only cytotoxic agent approved by the FDA for
malignant melanoma, received marketing approval in 1975 on the basis of
response rate only. This drug is considered to be the most active single
agent for the management of advanced malignant melanoma and historically
induces objective tumor responses in 10% to 20% of
patients.([^8],[^9],[^10]) These response rates were reported prior to
the publication of the Response Evaluation Criteria in Solid Tumors
(RECIST).([^11]) Nearly all of these responses are partial, although
complete responses have been observed.(Error: Reference source not
found,[^12],[^13]) In a more recent study that utilized RECIST
measurement criteria, an overall response rate (complete response plus
partial response) of only 7% has been reported with single-agent DTIC,
which is probably a more accurate reflection of its activity
alone.(Error: Reference source not found)

The toxicity of DTIC has been well established. Commonly reported side
effects include severe nausea and vomiting, myelosuppression, loss of
appetite, flu-like syndrome, injection site reactions, and fatigue.
Hypersensitivity reactions have been reported and include anaphylaxis,
breathlessness, erythematous and urticarial rashes, anxiety, and other
manifestations. Hypotension, hepatic toxicity, hepatic vein thrombosis,
and hepatocellular necrosis have occurred more rarely.

**DTIC plus other chemotherapy:** The addition of such agents as
cisplatin, nitrosoureas, and vinca alkaloids has been reported to
increase response rates in single-institution Phase II studies.([^14])
In particular, the "Dartmouth regimen" (ie, cisplatin, DTIC, carmustine,
and tamoxifen) showed unexpectedly high objective response rates in
early single-institution, nonrandomized studies.([^15]) However,
subsequent Phase II/III studies have shown no statistically significant
advantage over DTIC alone.(Error: Reference source not found,[^16])

In the definitive study of this combination chemotherapy, Eastern
Cooperative Oncology Group (ECOG) investigators randomized 240 patients
to receive either the Dartmouth regimen or single-agent dacarbazine at a
dose of 1000 mg/m^2^ every 3 weeks.(Error: Reference source not found)

At baseline, the median age was 52 years in patients who received the
Dartmouth regimen. The median Karnofsky Performance Status Score was 90;
42% of these patients had disease involvement limited to the skin, lymph
nodes, and lung.

Final results (non-RECIST) showed a nonsignificant difference in
response rate for the Intent-to-Treat population: 16.8% among patients
who received the Dartmouth regimen and 9.9% among those treated with
single-agent DTIC. There were no complete responses in either treatment
group. The median survival time was 7.7 months versus 6.3 months for the
Dartmouth regimen and DTIC alone, respectively. (Time-to-progression was
not reported.)

Considerably more toxicity was observed with the Dartmouth regimen than
with DTIC alone. Significantly higher rates of Grade 3 and Grade 4
neutropenia, anemia, leukopenia in the absence of neutropenia, and
thrombocytopenia occurred among patients treated with the combination
regimen. Discontinuations due to toxicity occurred in 25 (21%) patients
and 3 (2%) patients treated with the Dartmouth regimen and DTIC alone,
respectively.

To date, no large randomized study has shown that the addition of any
other cytotoxic or hormonal drug to DTIC has increased time to
progression or survival.

**Interleukin-2:** An NDA for high-dose IL-2 was reviewed by the FDA in
1997 in an evaluation of 8 nonrandomized clinical studies in which 270
patients were enrolled.([^17])

Patients were carefully screened prior to initiation of IL-2 therapy and
were required to have an ECOG Performance Status of ≤ 1. Stress testing
(echocardiography or other) and pulmonary function testing were
routinely required in most of these studies, in addition to extensive
laboratory testing.

The median age of patients treated was 42 years. More than 70% of
patients had an ECOG Performance Status of 0. In 31% of patients,
disease involvement was limited to the cutaneous/subcutaneous tissue and
lymph nodes.

The overall response rate (not based on RECIST) was 16% (n = 43),
including 6% (n = 17) of patients with a complete response. The majority
of the 43 responding patients in these 8 studies combined had favorable
disease characteristics (ie, disease limited to the lymph nodes,
subcutaneous tissue, and/or lung; LDH status was not reported) at
baseline. Only 3 of the 17 patients with complete response had an ECOG
Performance Status \> 0 at baseline. Multivariate analyses showed that
Performance Status (specifically, a Performance Status of 0), female
gender, and young age were significantly associated with response. Ten
of the 17 patients who achieved a complete response had responses that
lasted longer than 24 months, compared with 3 of the 26 patients who
attained a partial response. After cessation of IL-2 therapy, 5 of the
17 complete responders and 10 of the 26 partial responders underwent
surgical resection or received local radiation, and 5 of the responding
patients remained free of disease for a prolonged period thereafter.

Toxicities from the high-dose IL-2 regimen were severe, and 6 (2.2%)
patients died as a result of a treatment-related toxicity. Severe
adverse reactions were primarily characterized by findings that
resembled septic shock. Hypotension was the most commonly reported
adverse event, affecting 64% of patients. Other commonly occurring
events of particular concern included dyspnea, confusion, elevated
bilirubin and transaminase levels, oliguria, and increased creatinine
levels, thrombocytopenia, anemia, and rash. Grade 3 or 4 occurrences
were often reported for hypotension (45% of patients), oliguria (39% of
patients), and thrombocytopenia (17% of patients), as well as for
vomiting and diarrhea. High-dose IL-2 treatment routinely requires ICU
level monitoring.

IL-2 was approved on the basis of the small number of patients who
achieved durable responses. In practice, use of high-dose IL-2 has
generally been restricted to administration in young patients with good
performance status by teams with considerable experience in managing the
side effects of the drug. Administration of this agent is primarily
reserved for the treatment of melanoma confined to the skin and
subcutaneous tissue.

**Biochemotherapy**: Before multiagent chemotherapy was shown to be no
more effective than DTIC alone, investigators from the MD Anderson
Cancer Center reported improved response rates by adding IL-2 and
interferon-alpha to the combination of cisplatin/vinblastine/DTIC (CVD)
("biochemotherapy" \[BCT\]).([^18]) Subsequently, drug doses and
schedules in the regimen evolved to reduce toxicity, and the ECOG
coordinated a US Intergroup study (E3695) that randomized patients with
advanced melanoma to CVD or to BCT.([^19]) The study underwent an
expansion of its planned sample size from 294 to 482 patients to adjust
the hazard ratio to more appropriately reflect anticipated survival
benefit, but was terminated early after an interim analysis by a data
safety monitoring board showed no evidence of possible benefit. At the
time of its initial report at the 2003 American Society of Clinical
Oncology annual meeting, this study of 416 patients was the largest
study ever conducted in this patient population.

At baseline, two thirds of the patients had an ECOG Performance Status
of 0. Compared with CVD chemotherapy, results of E3695 showed that BCT
provided no significant difference in overall response rate, complete
response rate (BCT = 1.4%; CVD = 3.0%), progression-free survival, or
median survival (BCT = 8.4 months; CVD = 8.7 months). Life-threatening
Grade IV toxicity was observed in 39% to 63% of patients, with a 1.5%
treatment-related mortality reported.

In conclusion, available treatment options for patients with advanced
melanoma, especially those ≥ 65 years of age and those with symptomatic
disease, provide limited benefit and an unacceptable toxicity profile
for most. Improved therapy for patients with advanced melanoma remains a
major unmet need in medical oncology.

## Rationale for the Development of Genasense

In the 1990s, an extensive body of literature accumulated that showed
the importance of apoptosisa series of biochemical reactions that lead
to cell death. These data forced a reexamination of a central concept of
human cancer. Whereas the disease was formerly thought to consist of
cells that were rapidly dividing out of control, new research indicated
that solid tumors were more generally characterized by an imbalance
between the proportion of cells that lived or died. Moreover, it was
recognized that even slight imbalances in the relative fraction of
cancer cells that survived were sufficient to cause overgrowth of the
tumor and death of the patient. Thus, considerable efforts were
redirected towards identifying proteins that were critical regulators of
cell survival.

The target of Genasense is a protein called Bcl-2, which was originally
described in association with a [B]{.underline}-[c]{.underline}ell
[l]{.underline}ymphoma. Subsequently, Bcl-2 was shown to be a homolog of
a normal protein (known as Ced-9) that had been linked to cell survival
in *Caenorhabditis elegans*. Bcl-2 is now broadly described as a key
"anti-apoptotic factor" (ie, a protein that can prevent or delay the
onset of programmed cell death).

Bcl-2 is normally found within the membrane of the cell's mitochondria.
Current data suggest that this protein negatively regulates either the
size or voltage potential of a mitochondrial transmembrane pore. That
is, high levels of Bcl-2 block the pore, and lower levels permit the
pore to open.

Cancer chemotherapy, formerly thought to be directly lethal to cancer
cells, is now believed to trigger a highly regulated program of cell
suicide, or apoptosis. After exposure to a lethal dose of chemotherapy,
a "death signal" is sent to the mitochondrion, which stimulates the
release of cytochrome c from the mitochondrion into the cytoplasm.
Cytochrome c then activates a cascade of enzymes (collectively known as
caspases) that fragment proteins and break up DNA, which ultimately
results in death of the cell.

By controlling the pore through which cytochrome C is released, Bcl-2
acts as a negative regulator of apoptosis  an anti-apoptotic factor 
that can prevent or substantially retard the onset of programmed cell
death. As such, increased expression of Bcl-2 effectively acts as a
survival factor for cancer cells, allowing them to withstand the
cytotoxic effects of chemotherapy. Thus, Bcl-2 appears to function as a
fundamental (although not sole) cause of the inherent resistance of
cancer cells to chemotherapy.

Antisense represents a general pharmacologic approach to selectively
reduce production of a specific protein. The goal of Genasense therapy
is to relieve the block in apoptosis associated with Bcl-2 and thereby
maximize the effectiveness of coadministered cancer chemotherapy. Thus,
Genasense can be viewed as a chemosensitizing agent that may enable
conventional anticancer drugs to function more effectively.

Melanoma was one of the earliest targets for Genasense therapy, since
more than 90% of tumors from patients with advanced disease have been
reported to express Bcl-2.([^20]) In a Phase I-II study originally
reported in *The Lancet*, 33 patients with advanced malignant melanoma
were treated with Genasense plus DTIC,([^21]) and several noteworthy
responses were reported.(Protocol GM103) One patient, who had not
received prior cytotoxic therapy, had a biopsy-proven complete response
to G3139 (6.5 to 7.7 mg/kg/day) and DTIC (800 to 1000 mg/m^2^). This
patient survived for 2.2 years after receiving the first dose of study
medication. Two other patients, both of whom had received prior
cytotoxic therapy, had partial responses after receiving maximum G3139
doses of 6.5 mg/kg/day. One of the 2 patients survived for 1.7 years
after receiving the first dose of study medication, and the other
survived for 2.7 years after receiving the first dose of study
medication. Serial biopsies of superficial melanoma lesions from several
patients showed that G3139 treatment was associated with a decrease in
Bcl-2 protein. These findings suggested that the combination of G3139 at
doses [\>]{.underline} 6.5 mg/kg/day plus DTIC might prove useful for
treatment of patients with malignant melanoma.

## Nonclinical Data

### Nonclinical Pharmacology

The nonclinical pharmacology of G3139 is primarily based on a review of
the relevant published literature. G3139 was selected for development
from among 40 phosphorothioate oligodeoxynucelotides in a screening
process designed to detect downregulation of *bcl-2* mRNA expression.
The nucleotide sequence of G3139 was designed to be antisense to the
first 6 codons of the open reading frame downstream from the AUG start
site of the *bcl-2* mRNA sequence.

The effects of G3139, alone and in combination with many cytotoxic
drugs, have been assessed in a wide variety of cancer models.([^22]) The
results have been broadly consistent: decreased expression of *bcl-2*
mRNA and protein, reduced cellular viability, increased apoptosis,
reduction of tumor size, prolongation of survival in tumor-bearing
animals treated with G3139 plus chemotherapy, and synergistic cytotoxic
activity with anticancer drugs.

### Nonclinical Safety Evaluation

The nonclinical development program was designed and conducted by the
Sponsor in accordance with recommendations given by the Division of
Oncology Drug Products on 17 Aug 2001 as part of End-of-Phase-II
discussions for Genasense. The FDA confirmed acceptance of the overall
content of the nonclinical development program in pre-NDA dialogue on 08
Apr 2003.

Key nonclinical findings that pertain to the safety of G3139 include the
following:

-   The kidney is the major tissue of distribution for G3139.

-   Plasma concentrations of G3139 and the N-1 and N-2 active
    metabolites (ie, metabolites of 17 and 16 bases in length,
    respectively, which result from sequential nuclease cleavage of the
    18-base parent compound) are achieved rapidly, increase with
    increasing dose, and are relatively consistent across species.

-   G3139 is not teratogenic or mutagenic.

-   Induction or inhibition of P450 isozymes by G3139 is unlikely at
    clinically relevant G3139 concentrations.

-   The toxicity of G3139 is dose related and consistent with the class
    toxicity profile for oligonucleotides when administered to rodents
    and monkeys. This profile is independent of nucleotide sequence,
    indicating that the toxicities of these compounds do not result from
    their targeted pharmacologic effects. This profile consists of
    increased coagulation time, complement activation, uptake of test
    article in kidney and liver resulting in tubular nephropathy and
    Kupffer cell activation, and immune stimulation, including
    splenomegaly, lymphoid hyperplasia, and mononuclear cell
    infiltration in many tissues.

-   The toxicologic effects suggest an adequate safety margin for the
    proposed human use of this drug product.

# Clinical Pharmacology

## Pharmacokinetics

The clinical pharmacokinetics of G3139 and its metabolites, N-1 and N-2,
were investigated in 2 primary studies:

-   Protocol GPK101 was a Phase I study conducted to evaluate the
    pharmacokinetics and safety of G3139 given in combination with DTIC
    to 24 patients with advanced malignant melanoma. In the
    pharmacokinetic portion of this study, G3139 7 mg/kg/day was
    administered as a continuous intravenous (IV) infusion for 7 days
    and DTIC 1000 mg/m^2^ was administered IV over a 60-minute period
    beginning 120 hours after the start of the G3139 infusion.

-   Protocol GL208 was a Phase I/II study of G3139 in patients with
    advanced chronic lymphocytic leukemia. G3139 3 to 7 mg/kg/day was
    administered as a continuous 5-day IV infusion in Cycle 1. (Protocol
    GL208 was conducted in patients with chronic lymphocytic leukemia
    and is not further discussed in this document.)

The mean G3139, N-1, and N-2 pharmacokinetic parameters in Protocol
GPK101 are shown in Figure 1.

[]{#__RefHeading___Toc68561793 .anchor}Figure 1: Mean G3139, N-1, and
N-2 plasma concentration-time profiles

![](media/image2.wmf){width="5.991666666666666in"
height="4.103472222222222in"}

The single dose level (7 mg/kg/day) administered in this study did not
permit rigorous determination of dose proportionality or evaluation of
changes in clearance (CL) and renal clearance (CL~r~) with increasing
doses of G3139. The exposure (mean C~ss~ ratio) of patients to the N-1
and N-2 metabolites was approximately 45% and 19%, respectively, of the
exposure to G3139. Plasma concentrations for G3139 and the N-1
metabolite reached steady state in approximately 10 hours.

The mean half-life (t~1/2~) for G3139 was 2.4 hours and was consistent
with the attainment of steady state by approximately 10 hours. The mean
t~1/2~ of 2.3 hours for the N-1 metabolite was similar to that for G3139
(there were insufficient data to calculate a t~1/2~ for N-2). The total
clearance of G3139 for an average individual (70 kg) would be expected
to be approximately 6.09 L/h. The mean renal clearance for G3139 was
estimated to be 0.058 L/h in this study. The results for total and renal
clearance suggested that renal clearance represented only a small
portion of the total clearance for intact G3139. These results are
consistent with literature reports for other phosphorothioate
oligonucleotides.([^23],[^24],[^25])

## Metabolism

Although no formal human in vivo metabolism studies were conducted by
the Sponsor for G3139, the plasma time course of the N-1 and N-2
metabolites of G3139 was determined in the primary pharmacokinetic study
GPK101. The exposure (mean C~ss~ ratio) of patients to the N-1 and N-2
metabolites was approximately 45% and 19%, respectively, of the exposure
to G3139 in this study. The mean half-life for the N-1 metabolite was
similar to the half-life for G3139 (2.3 vs 2.4 h, respectively).

Published studies report that phosphorothioate oligonucleotides are
rapidly metabolized in both plasma and tissues following administration
in mice, rats, monkeys, and humans (Error: Reference source not
found,[^26],[^27]). These studies present evidence that the metabolism
of phosphorothioate oligonucleotides results in sequential removal of
nucleotide bases to form N-1, N-2, etc, metabolites in plasma and/or
tissues.

## Plasma Protein Binding

A Genta-sponsored study evaluated the extent of protein binding of G3139
in human plasma.([^28]) The ^3^H-G3139 was incubated at 0.025 to 0.2
μg/mL in normolipidemic human plasma for up to 2 hours. The majority of
the radioactivity was found in the lipoprotein-deficient fraction, which
includes albumin. In this fraction, 85% of the radioactivity was protein
bound.

Phosphorothioate oligonucleotides in general have been found to be
highly bound to plasma proteins. Plasma protein binding ranges from 65%
to 99% for various sequences of oligonucleotides in mouse, rat, dog, and
human plasma.(Error: Reference source not found,Error: Reference source
not found,[^29], [^30],[^31],[^32]) Phosphorothioate oligonucleotides
have been primarily found to bind to albumin (low affinity, high
capacity) and alpha-2 macroglobulin (low capacity, high affinity). The
binding to bovine serum albumin has been shown to be salt- and
pH-dependent, suggesting that it is likely to be a nonspecific
electrostatic interaction.([^33]) Binding to alpha-1 acid glycoprotein
has been found, in general, to be negligible.(Error: Reference source
not found)

## Special Populations

Based on the human biopharm pre-NDA discussion with the FDA on 23 Sep
2003, the Sponsor committed to conduct 2 studies in special populations.
Protocols for the evaluation of Genasense in patients with renal and
hepatic impairment were designed in concurrence with the FDA and were
submitted to the Agency on 25 Nov 2003.

## Dose Selection

**Target Plasma Concentration:** Given its high potency, extensive
preclinical data have shown that G3139 concentrations below 1 μg/mL were
sufficient to achieve maximal downregulation of intracellular Bcl-2
protein in vitro.([^34]) Such concentrations can easily be achieved with
doses of about 2 mg/kg/day. Early clinical studies also suggested that
G3139 plasma concentrations \> 1 μg/mL downregulated Bcl-2 in both tumor
cells and peripheral blood mononuclear cells. This concentration was
then established as a minimum target.

**Dosing Interval Relative to Chemotherapy:** Limited in vivo data have
shown that G3139 treatment in advance of, or coincident with, cytotoxic
chemotherapy maximized the chemosensitizing effect.([^35]) Overlap of
G3139 treatment with chemotherapy did not appear to increase
chemosensitization compared with G3139 pretreatment alone. By contrast,
regimens in which chemotherapy was administered first, followed by
treatment with G3139, were demonstrably inferior and yielded efficacy
results that were similar to the use of chemotherapy alone.

**Route of Administration:** Preclinical toxicology studies suggested
that subcutaneous or continuous IV infusion schedules were better
tolerated and maintained more stable steady-state plasma drug
concentrations compared with bolus IV injections. Together with the
short plasma half-life of G3139 and the relatively long half-life of
intracellular Bcl-2, this information suggested that continuous IV
infusion was an appropriate route of administration.

**Daily Dose and Schedule:** Phase I studies of G3139 broadly examined 2
dosing schedules using continuous IV infusion: daily for durations of 5
to 7 days; and daily for durations of 14 days (or longer). Both
schedules were examined in combination with myelosuppressive
chemotherapy.

With the 5- to 7-day schedules using G3139 in combination with DTIC
chemotherapy, thrombocytopenia was found to be limiting at a daily G3139
dose of 12 mg/kg/day.(Error: Reference source not found,[^36]) On
14(+)-day schedules, a somewhat different safety profile was observed.
Dose-limiting reactions, including severe fatigue and reversible
increases in hepatic enzymes (aspartate aminotransferase), occurred at a
G3139 dose of 6.5 mg/kg/day, which was declared as the maximally
tolerated dose on that schedule.([^37])

A G3139 dose of 7 mg/kg/day for 5 days by continuous IV infusion,
followed by DTIC on Day 5, was selected for extended evaluation for
several reasons:

-   This dose consistently yielded plasma drug concentrations that
    comfortably exceeded target concentrations for maximal Bcl-2
    downregulation. Limited data also suggested that maximal
    downregulation of Bcl-2 was achieved within 5 days of drug exposure.
    Preliminary data suggested that, while extended treatment might
    prolong the duration of Bcl-2 downregulation, it did not appear to
    yield a further decrease in the absolute percentage of
    downregulation (ie, Bcl-2 levels were maximally decreased by Day 5).
    Lastly, since the treatment goal was maximization of chemotherapy
    efficacy, it was believed desirable to limit the Bcl-2
    downregulation to a duration when the apoptotic stimulus was maximal
    (ie, the time of chemotherapy treatment).

-   Although the selected dose approximated the maximum tolerated dose
    on the extended-dosing schedule, it was less than the maximum
    tolerated dose on the shorter schedule (when used in combination
    with DTIC).

These observations suggested that the selected dose would provide an
acceptable therapeutic index, especially for seriously ill patients who
were expected to enroll in the randomized study.

# Efficacy results in randomized Phase III Study

A Phase III study was conducted to compare the efficacy and safety of
G3139 in combination with DTIC versus DTIC alone.

## Design and Methods for Protocol GM301

### Study Objectives

This study was conducted to compare the efficacy and safety of G3139 in
combination with a conventional chemotherapeutic agent (DTIC) approved
for use in metastatic malignant melanoma versus DTIC alone.

The primary endpoint was survival. Secondary endpoints included
progression-free survival, response rate, duration of response, durable
response rate, and performance status.

### Study Design and Treatment Regimen

This study was conducted using a randomized, multicenter, open-label,
parallel-group design. Prior to randomization, patients were stratified
on the basis of known prognostic factors (ie, ECOG Performance Status,
liver metastases, and lactate dehydrogenase level) to prevent uneven
distribution in treatment groups.

All patients were treated in 21-day cycles. During each cycle, patients
received either:

-   DTIC 1000 mg/m^2^ administered by IV infusion over 60 minutes on Day
    1, or

-   G3139 7 mg/kg/day administered by continuous IV infusion (delivered
    via computerized ambulatory infusion pump with central venous
    access) for 5 days and DTIC 1000 mg/m^2^ administered by IV infusion
    over 60 minutes immediately upon completion of the G3139 infusion

Treatment continued for a maximum of 8 cycles, but was stopped if
disease progression was documented or if the patient incurred
intolerable drug-related side effects that did not respond to dose
modification. Protocol therapy and related testing were to be completed
in the outpatient setting, but inpatient treatment and testing were
permitted at the discretion of the investigator.

All randomized patients (including those who never initiated protocol
therapy, those who discontinued protocol therapy prematurely, and those
who completed protocol therapy) were followed every 2 months after
discontinuation of protocol therapy up to 2 years from the date of
randomization to determine clinical status and to document duration of
survival. Patients in the G3139 plus DTIC group who completed 8 cycles
of treatment and showed response or stable disease after 8 cycles could
enroll in Protocol GM214, an open-label continuation study, if they met
eligibility requirements for that study. No patient who received DTIC
alone in Protocol GM301 was allowed to cross over and receive G3139 plus
DTIC.

### Entry Criteria

Key inclusion criteria included the following:

1.  Histologically confirmed diagnosis of malignant melanoma

2.  Progressive local disease that was not surgically 27espectable, or
    metastatic Stage IV disease

3.  Measurable disease, defined as at least 1 malignant lesion that
    could be accurately and serially measured in at least 1 dimension
    and for which the greatest diameter was ≥ 20 mm as measured by
    contrast-enhanced or spiral computed tomography (CT) scan for
    visceral or nodal/soft tissue disease, or ≥ 10 mm as measured by
    caliper for superficial cutaneous metastases

4.  ECOG Performance Status of 0, 1, or 2

5.  Adequate organ function determined within 2 weeks prior to
    randomization

Key exclusion criteria included the following:

1.  Prior cytotoxic chemotherapy, including regional perfusion

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```
6.  History of brain metastasis or leptomeningeal disease

7.  Significant medical disease other than cancer

8.  History of second cancer (except for adequately treated basal cell
    or squamous cell skin cancer, in situ cervical cancer, or other
    cancer for which the patient had been disease-free for 5 or more
    years)

9.  Bone-only metastatic disease

10. Primary ocular or mucosal melanoma

11. Concomitant anticoagulant therapy (other than warfarin 1 mg/day for
    central line prophylaxis)

### Efficacy Assessments

Efficacy assessment was based on tumor measurement by physical
measurement; photographs of superficial target lesions; radiographs of
target lesions; and assessment of nontarget lesions. Patients in the
G3139 plus DTIC group and the DTIC group were assessed at the same
21-day intervals during the treatment phase and the same 2-month
intervals during the follow-up phase.

**Measurable Disease**

Measurable disease was defined by the presence of at least 1 measurable
lesion, as adapted from RECIST.(Error: Reference source not found)
Specifically, measurable lesions were defined as lesions that could be
accurately and serially measured in at least 1 dimension and for which
the greatest diameter was ≥ 20 mm as measured by contrast-enhanced or
spiral CT scan for visceral or nodal/soft tissue disease, or ≥ 10 mm as
measured by caliper for superficial cutaneous metastases.

Nonmeasurable lesions were those that did not meet the definition of
measurable lesions. All bone lesions, ascites, pleural/pericardial
effusions, abdominal masses that were not confirmed and were followed by
imaging techniques, and tumors treated by irradiation or by intratumor
injection therapy (unless progression outside the treated area had
occurred) were considered to be nonmeasurable.

A total of no more than 10 measurable lesions with the longest diameter
were selected as target lesions. All lesions not identified as target
lesions were considered nontarget lesions. The sum of the longest
diameters (sum LD) was defined as the sum of the longest diameters of
the target lesions.

**Antitumor Response**

For target lesions, complete response was defined as the disappearance
of all target lesions, and partial response was defined as at least a
30% reduction in the sum LD of target lesions taking as a reference the
baseline sum LD. For nontarget lesions, complete response was defined as
the disappearance of all nontarget lesions.

If progression was suggested by increased size of 1 or more target
lesions without evidence of clearly defined new metastases, then all
target lesions were measured and progression was confirmed by
determination of the sum LD. If progression was indicated by the
well-defined development of new metastatic disease, repeat evaluation of
all target lesions was not required, but could be performed at the
investigator's discretion. Based on RECIST, progressive disease was
defined as at least a 20% increase from the minimum in the sum LD of the
target lesions, the appearance of 1 or more new lesions, or unequivocal
progression of existing nontarget lesions.

Stable disease was defined as any measurement not meeting the criteria
for either response or progressive disease.

**Overall Response**

Assessments of response of target and nontarget lesions and appearance
of new lesions were used to determine overall response as shown in Table
1.(Error: Reference source not found)

[]{#__RefHeading___Toc68561773 .anchor}Table 1: Determination of overall
response

  ------------------ -------------------- ------------ -------------------
  **Presence of:**                                     

  **Target lesions** Nontarget lesions    **New        **Overall
                                          lesions**    response**

  Complete response  Complete response    No           Complete response

  Complete response  Stable disease       No           Partial response

  Partial response   Stable disease       No           Partial response

  Stable disease     Stable disease       No           Stable disease

  Progressive        Any                  Yes or No    Progressive disease
  disease                                              

  Any                Progressive disease  Yes or No    Progressive disease
  ------------------ -------------------- ------------ -------------------

If it was difficult to distinguish residual disease from normal tissue,
the residual lesion was to be biopsied, especially if the response was
believed to be complete. In cases where biopsy was not appropriate,
positron emission tomography (PET) scans were used to document absence
of residual disease.

**Confirmation of Objective Response**

A patient was assigned a response of confirmed complete response or
confirmed partial response if this response was confirmed by a repeat
evaluation done no less than 3 weeks after response was first noted. The
confirmatory evaluation after a 3-week interval reflects a modification
from the 4-week interval specified by RECIST. The 3-week interval was
chosen in order to coincide with the schedule of study visits specified
by protocol.

**Independent, Blinded Assessment of Response**

RadPharm (Princeton, NJ) conducted a blinded assessment of response in
responding patients. They independently reviewed the data of patients
who were identified as having a response on the basis of lesion
measurements. Study sites were instructed to remove all markings on
x-rays, and no clinical information was provided to RadPharm.

### Statistical Considerations

It was assumed that median survival time for patients treated with DTIC
would be 6 months and median survival for patients treated with G3139
plus DTIC would be 8 months. Using the log-rank test, 750 patients (375
patients per treatment group) followed until 508 events (ie, deaths)
occurred would provide a power of 90% to detect a significant difference
between the 2 treatment groups in the survival distribution at a 2-sided
significance level of 0.05.

The protocol was amended twice to increase the sample size from 270 to
450 (change of power from 80% to 90%; amended protocol approved by the
FDA in Jan 2002) and from 450 to 750 (change in the assumption of hazard
ratio from 1.50 to 1.33; amended protocol approved by the FDA in Jun
2002). The final statistical analysis plan was approved by the FDA prior
to unblinding of the study. The increases in sample size were determined
without performing any interim analyses, and the Sponsor remained
blinded until unblinding of the study in September 2003.

The Intent-to-Treat Population was defined as all patients randomized.
The Safety Population was defined as all Intent-to-Treat subjects who
received any protocol therapy.

The following endpoints were analyzed:

-   **Survival:** Survival was calculated as the number of days from
    randomization to the date of death.

-   **Antitumor Response Rate:** For each patient, response was
    independently calculated based on the totals of the individual
    lesion measurements recorded on the case report form and included
    evaluation of nonmeasurable lesions, as well as the presence or
    absence of new lesions. The antitumor response rate was calculated
    as the percentage of patients with complete response or partial
    response for the Intent-to-Treat Population.

-   **Duration of Response:** The duration of response was measured from
    the first date that criteria for complete response or partial
    response (whichever was recorded first) were met, until the first
    date that recurrent or progressive disease was objectively
    documented.

-   **Durable Response:** A durable response was defined as a complete
    or partial response lasting ≥ 6 months from the date the response
    was first recorded. No anticancer therapy other than protocol
    therapy was to be administered during the 4 months after the
    response was initially determined.

-   **Progression-Free Survival:** Progression-free survival was defined
    as the time from the date of randomization to the first date when
    criteria for progression were met or when the patient died,
    whichever occurred first. Only deaths occurring within 60 days from
    the last lesion measurement were considered as events in the
    progression-free survival analyses. For patients who died more than
    60 days after the last lesion measurement, the progression-free
    survival was censored at the date of the last lesion measurement.

## Study Population

A total of 771 patients were randomized at 139 study sites in 9
countries (G3139 plus DTIC group, 386 patients; DTIC group, 385
patients). Subjects were enrolled during a 2.5-year period. The first
patient was enrolled in July 2000, and the last patient was enrolled in
February 2003. Notably, 251 (32.6%) patients were enrolled during the
last 6 months of the study and 160 (20.8%) were enrolled during the last
3 months of the study. Overall, all 771 patients randomized comprised
the Intent-to-Treat Population.

A total of 15 (3.9%) patients in the G3139 plus DTIC group and 25 (6.5%)
patients in the DTIC group were randomized but did not initiate protocol
therapy (see Table 2). The most frequently reported reason for
discontinuing prior to initiation of protocol therapy differed between
the 2 treatment groups and included patient ineligibility in the G3139
plus DTIC group and patient choice in the DTIC group.

[]{#__RefHeading___Toc68561774 .anchor}Table 2: Disposition of patients
not treated

  ------------------------- ----------------------- ----------------------
  Reason for                G3139 plus DTIC\        DTIC\
  discontinuation           (n = 15)                (n = 25)

  Disease progression or    3                       4
  relapse                                           

  Patient choice            4                       15

  Patient ineligible        5                       3

  Death                     2                       2

  Other                     1                       1

                                                    
  ------------------------- ----------------------- ----------------------

A total of 731 (94.8%) patients initiated protocol therapy. Overall,
most patients in each treatment group who initiated protocol therapy
discontinued from the study early (ie, before completion of 8 cycles of
protocol therapy). In both treatment groups, disease progression was the
most frequently reported reason for discontinuation (239 \[64.4%\]
patients in the G3139 plus DTIC group and 262 \[72.8%\] patients in the
DTIC group).

Patients were evenly distributed in the 2 treatment groups with respect
to age, gender, and race (see Table 3). The mean age in both groups was
59 years; females represented a little more than one third of the
patients randomized to each group. More than 95% of patients in both
treatment groups were white. Patients ≥ 65 years of age represented
approximately 38% of those randomized in both treatment groups and
approximately 15% were ≥ 75 years of age. Overall, this patient
population was older than those historically included in other melanoma
studies.(Error: Reference source not found)

[]{#__RefHeading___Toc68561775 .anchor}Table 3: Demographic
characteristics by treatment group: Intent-to-Treat Population

+---------------------+---------------+---------------+---------------+
| Demographic\        | G3139 plus    | DTIC\         | Overall\      |
| characteristic      | DTIC\         | (N = 385)     | (N = 771)     |
|                     | (N = 386)     |               |               |
+=====================+===============+===============+===============+
| Age, years          |               |               | []{.mark}     |
+---------------------+---------------+---------------+---------------+
| > n                 | 386           | 385           | 771           |
+---------------------+---------------+---------------+---------------+
| > Mean (SD)         | 58.6 (13.94)  | 58.7 (13.87)  | 58.7 (13.90)  |
+---------------------+---------------+---------------+---------------+
| > Median            | 59.0          | 60.0          | 59.0          |
+---------------------+---------------+---------------+---------------+
| > Minimum, maximum  | 17, 93        | 16, 89        | 16, 93        |
+---------------------+---------------+---------------+---------------+
| Age group, n (%)^a^ |               |               |               |
+---------------------+---------------+---------------+---------------+
| > \< 65 years       | 239 (61.9)    | 241 (62.6)    | 480 (62.3)    |
+---------------------+---------------+---------------+---------------+
| > ≥ 65 years        | 147 (38.1)    | 144 (37.4)    | 291 (37.7)    |
+---------------------+---------------+---------------+---------------+
| > ≥ 75 years        | 47 (12.2)     | 54 (14.0)     | 101 (13.1)    |
+---------------------+---------------+---------------+---------------+
| Gender, n (%)^a^    |               |               |               |
+---------------------+---------------+---------------+---------------+
| > Female            | 150 (38.9)    | 132 (34.3)    | 282 (36.6)    |
+---------------------+---------------+---------------+---------------+
| > Male              | 236 (61.1)    | 253 (65.7)    | 489 (63.4)    |
+---------------------+---------------+---------------+---------------+
| Race, n (%)^a,b^    |               |               |               |
+---------------------+---------------+---------------+---------------+
| > Caucasian/White   | 375 (97.2)    | 371 (96.4)    | 746 (96.8)    |
+---------------------+---------------+---------------+---------------+
| > All other         | 10 ( 2.6)     | 12 ( 3.1)     | 22 ( 2.9)     |
+---------------------+---------------+---------------+---------------+
| > Unknown^c^        | 1 ( 0.3)      | 2 ( 0.5)      | 3 ( 0.4)      |
+---------------------+---------------+---------------+---------------+
| SD = standard       |               |               |               |
| deviation           |               |               |               |
|                     |               |               |               |
| ^a^ Percentages     |               |               |               |
| were calculated by  |               |               |               |
| using N, the total  |               |               |               |
| number of patients  |               |               |               |
| in the group, as    |               |               |               |
| the denominator.    |               |               |               |
|                     |               |               |               |
| ^b^ Racial          |               |               |               |
| categories on the   |               |               |               |
| case report form    |               |               |               |
| included            |               |               |               |
| Caucasian/White,    |               |               |               |
| Hispanic, Asian,    |               |               |               |
| Black, and Other.   |               |               |               |
|                     |               |               |               |
| ^c^ Recording of    |               |               |               |
| race was not        |               |               |               |
| permitted at the    |               |               |               |
| study site.         |               |               |               |
+---------------------+---------------+---------------+---------------+

The median time from initial diagnosis to randomization was similar in
the 2 treatment groups: 29.5 months in the G3139 plus DTIC group and
26.4 months in the DTIC group (see Table 4).

Unlike other studies in which subjects with an ECOG Performance Status
\> 1 were excluded,(Error: Reference source not found) approximately 7%
of subjects in both groups had an ECOG Performance Status of 2. In
addition, 1 patient in the G3139 plus DTIC group and 2 patients in the
DTIC group who had a performance status of 2 at the time of
randomization had a deterioration in clinical status prior to initiation
of protocol therapy with a resultant ECOG Performance Status of 3 at the
time of first dosing.

The distribution of patients in the 2 treatment groups was similar based
on classification according to American Joint Committee on Cancer (AJCC)
criteria.([^38]) These criteria, which were published in 2002 after the
protocol had been prepared and the study initiated, were not used as
stratification factors. There was a small difference between treatment
groups in the percentage of patients in the M1c category, with a greater
percentage of patients in the DTIC group falling in this category. The
potential impact of this observed difference on efficacy parameters was
rigorously examined using the Cox Proportional Hazard model and logistic
regression analysis and was determined to have no effect on any efficacy
parameter measured.

[]{#__RefHeading___Toc68561776 .anchor}Table 4: Melanoma history and
disease characteristics at baseline by treatment group: Intent-to-Treat
Population

+---------------------------------------+--------------+---------------+
| Characteristic                        | G3139 plus   | DTIC\         |
|                                       | DTIC\        | (N = 385)     |
|                                       | (N = 386)    |               |
+---------------------------------------+--------------+---------------+
| Time from initial diagnosis to        |              |               |
| randomization, months                 |              |               |
+---------------------------------------+--------------+---------------+
| > n                                   | 386          | 384           |
+---------------------------------------+--------------+---------------+
| > Median                              | 29.5         | 26.4          |
+---------------------------------------+--------------+---------------+
| Metastasis^a^, n (%)^b^               |              |               |
+---------------------------------------+--------------+---------------+
| > Local regional disease only         | 34 ( 8.8)    | 22 ( 5.7)     |
+---------------------------------------+--------------+---------------+
| > Distant metastatic disease          | 352 ( 91.2)  | 363 ( 94.3)   |
+---------------------------------------+--------------+---------------+
| AJCC LDH-disease site distribution, n |              |               |
| (%)^b,\ c^                            |              |               |
+---------------------------------------+--------------+---------------+
| > Nonvisceral and nonelevated LDH     | 61 ( 15.8)   | 50 ( 13.0)    |
| > (M1a)                               |              |               |
+---------------------------------------+--------------+---------------+
| > Lung and nonelevated LDH (M1b)      | 93 ( 24.1)   | 75 ( 19.5)    |
+---------------------------------------+--------------+---------------+
| > Visceral other than lung, or        | 226 (58.5)   | 257 (66.8)    |
| > elevated LDH (M1c)                  |              |               |
+---------------------------------------+--------------+---------------+
| > Unknown                             | 6 ( 1.6)     | 3 ( 0.8)      |
+---------------------------------------+--------------+---------------+
| ECOG Performance Status, n (%)^d^     |              |               |
+---------------------------------------+--------------+---------------+
| > 0                                   | 207 (54.8)   | 220 (57.4)    |
+---------------------------------------+--------------+---------------+
| > 1                                   | 146 (38.6)   | 132 (34.5)    |
+---------------------------------------+--------------+---------------+
| > 2                                   | 24 ( 6.3)    | 29 ( 7.6)     |
+---------------------------------------+--------------+---------------+
| > 3                                   | 1 ( 0.3)     | 2 ( 0.5)      |
+---------------------------------------+--------------+---------------+
| AJCC = American Joint Committee on    |              |               |
| Cancer; LDH = lactate dehydrogenase;  |              |               |
| SD = standard deviation               |              |               |
|                                       |              |               |
| ^a^ Referred to as "general           |              |               |
| metastasis" on the case report form.  |              |               |
| Patients with both local regional     |              |               |
| disease and distant metastatic        |              |               |
| disease counted in distant metastatic |              |               |
| disease category.                     |              |               |
|                                       |              |               |
| ^b^ Percentages were calculated by    |              |               |
| using N, the total number of patients |              |               |
| in the group, as the denominator.     |              |               |
|                                       |              |               |
| ^c^ Based on the AJCC classification. |              |               |
| A baseline LDH value was not          |              |               |
| available for 6 patients in the G3139 |              |               |
| plus DTIC group and for 3 patients in |              |               |
| the DTIC group.                       |              |               |
|                                       |              |               |
| ^d^ Percentages were calculated based |              |               |
| on the number of patients with ECOG   |              |               |
| Performance Status data at baseline.  |              |               |
+---------------------------------------+--------------+---------------+

The percentage of patients who had received previous cancer treatment by
type of treatment was similar in the 2 treatment groups (see Table 5).
Most patients in each treatment group had received previous surgical
intervention. Previous immunotherapy (primarily interferon-alpha) was
also frequently reported in both treatment groups.

[]{#__RefHeading___Toc68561777 .anchor}Table 5: Previous cancer
treatment by treatment group: Intent-to-Treat Population

+--------------------------+---------------+--------------+------------+
| Characteristic           | G3139 plus    | DTIC\        | Overall\   |
|                          | DTIC\         | (N = 385)    | (N = 771)  |
|                          | (N = 386)     |              |            |
+==========================+===============+==============+============+
| Prior surgery, n         | 369 (95.6)    | 372 (96.6)   | 741 (96.1) |
| (%)^a,\ b^               |               |              |            |
+--------------------------+---------------+--------------+------------+
| Prior radiation therapy, | 73 (18.9)     | 65 (16.9)    | 138 (17.9) |
| n (%)^a^                 |               |              |            |
+--------------------------+---------------+--------------+------------+
| Prior                    | 156 (40.4)    | 142 (36.9)   | 298 (38.7) |
| immunotherapy/cytokine   |               |              |            |
| therapy, n (%)^a^        |               |              |            |
+--------------------------+---------------+--------------+------------+
| ^a^ Percentages were     |               |              |            |
| calculated by using N,   |               |              |            |
| the total number of      |               |              |            |
| patients in the group,   |               |              |            |
| as the denominator.      |               |              |            |
|                          |               |              |            |
| ^b^ Includes diagnostic  |               |              |            |
| procedures               |               |              |            |
+--------------------------+---------------+--------------+------------+

Patients were evenly distributed between treatment groups in each of the
6 randomization strata (see Table 6).

[]{#__RefHeading___Toc68561778 .anchor}Table 6: Stratification
information by treatment group: Intent-to-Treat Population

  -----------------------------------------------------------------------------------------
  Stratum         ECOG    Liver        Disease             G3139 plus DTIC\      Overall\
                  score   metastases   distribution and    DTIC\      (N = 385)\ (N = 771)\
                                       LDH status          (N = 386)\ n (%)^a^   n (%)^a^
                                                           n (%)^a^              
  --------------- ------- ------------ ------------------- ---------- ---------- ----------
  1               0       Present      Not considered if   70 (18.1)  63 (16.4)  133 (17.3)
                                       liver metastasis                          
                                       was present                               

  2               1 or 2  Present      Not considered if   58 (15.0)  73 (19.0)  131 (17.0)
                                       liver metastasis                          
                                       was present                               

  3               0       Absent       Disease in visceral 113 (29.3) 120 (31.2) 233 (30.2)
                                       organ other than                          
                                       liver, or elevated                        
                                       LDH                                       

  4               1 or 2  Absent       Disease in visceral 82 (21.2)  78 (20.3)  160 (20.8)
                                       organ other than                          
                                       liver, or elevated                        
                                       LDH                                       

  5               0       Absent       Disease in skin,    36 ( 9.3)  32 ( 8.3)  68 ( 8.8)
                                       subcutaneous                              
                                       tissue, and/or                            
                                       lymph nodes without                       
                                       visceral                                  
                                       metastases, and LDH                       
                                       not elevated                              

  6               1 or 2  Absent       Disease in skin,    25 ( 6.5)  18 ( 4.7)  43 ( 5.6)
                                       subcutaneous                              
                                       tissue, and/or                            
                                       lymph nodes without                       
                                       visceral                                  
                                       metastases, and LDH                       
                                       not elevated                              

  ^a^ Percentages                                                                
  were calculated                                                                
  by using N, the                                                                
  total number of                                                                
  patients in the                                                                
  group, as the                                                                  
  denominator.                                                                   
  Due to missing                                                                 
  information, 2                                                                 
  patients in the                                                                
  G3139 plus DTIC                                                                
  group and 1                                                                    
  patient in the                                                                 
  DTIC group                                                                     
  could not be                                                                   
  categorized by                                                                 
  randomization                                                                  
  stratum.                                                                       
  -----------------------------------------------------------------------------------------

In both groups, most patients initiated ≤ 2 cycles of protocol therapy
(see Table 7). Since the first disease restaging was required at the
conclusion of Cycle 2, many patients had demonstrable disease
progression and were removed from the study at that time. At the time of
the cutoff date for the NDA (01 Aug 2003), 11 subjects (including 10 in
the G3139 plus DTIC group and 1 in the DTIC group) were in the treatment
phase of the study.

[]{#__RefHeading___Toc68561779 .anchor}Table 7: Number (%) of patients
by maximum number of cycles initiated by treatment group:
Intent-to-Treat Population

+--------------+------------------+------------------+-----------------+
| Maximum      | G3139 plus DTIC\ | DTIC\            | Overall\        |
| number of    | (N = 386)\       | (N = 385)\       | (N = 771)\      |
| cycles       | n (%)^a^         | n (%)^a^         | n (%)^a^        |
| initiated    |                  |                  |                 |
+==============+==================+==================+=================+
| 0 (not       | 15 ( 3.9)        | 25 ( 6.5)        | 40 ( 5.2)       |
| treated)     |                  |                  |                 |
+--------------+------------------+------------------+-----------------+
| 1            | 38 ( 9.8)        | 45 (11.7)        | 83 (10.8)       |
+--------------+------------------+------------------+-----------------+
| 2            | 147 (38.1)       | 164 (42.6)       | 311 (40.3)      |
+--------------+------------------+------------------+-----------------+
| 3            | 36 ( 9.3)        | 23 ( 6.0)        | 59 ( 7.7)       |
+--------------+------------------+------------------+-----------------+
| 4            | 40 (10.4)        | 33 ( 8.6)        | 73 ( 9.5)       |
+--------------+------------------+------------------+-----------------+
| 5            | 18 ( 4.7)        | 9 ( 2.3)         | 27 ( 3.5)       |
+--------------+------------------+------------------+-----------------+
| 6            | 20 ( 5.2)^b^     | 24 ( 6.2)        | 44 ( 5.7)       |
+--------------+------------------+------------------+-----------------+
| 7            | 13 ( 3.4)        | 5 ( 1.3)         | 18 ( 2.3)       |
+--------------+------------------+------------------+-----------------+
| ≥ 8          | 59 (15.3)        | 57 (14.8)        | 116 (15.0)      |
+--------------+------------------+------------------+-----------------+
| > ^a^        |                  |                  |                 |
| >            |                  |                  |                 |
|  Percentages |                  |                  |                 |
| > were       |                  |                  |                 |
| > calculated |                  |                  |                 |
| > by using   |                  |                  |                 |
| > N, the     |                  |                  |                 |
| > total      |                  |                  |                 |
| > number of  |                  |                  |                 |
| > patients   |                  |                  |                 |
| > in the     |                  |                  |                 |
| > group, as  |                  |                  |                 |
| > the        |                  |                  |                 |
| >            |                  |                  |                 |
| denominator. |                  |                  |                 |
| >            |                  |                  |                 |
| > ^b^ One    |                  |                  |                 |
| > patient    |                  |                  |                 |
| > had        |                  |                  |                 |
| > completed  |                  |                  |                 |
| > Cycle 6    |                  |                  |                 |
| > but not    |                  |                  |                 |
| > yet        |                  |                  |                 |
| > initiated  |                  |                  |                 |
| > Cycle 7 as |                  |                  |                 |
| > of the     |                  |                  |                 |
| > data       |                  |                  |                 |
| > cut-off    |                  |                  |                 |
| > date of 01 |                  |                  |                 |
| > Aug 2003.  |                  |                  |                 |
| > This       |                  |                  |                 |
| > patient is |                  |                  |                 |
| > reported   |                  |                  |                 |
| > in this    |                  |                  |                 |
| > table as   |                  |                  |                 |
| > initiating |                  |                  |                 |
| > a maximum  |                  |                  |                 |
| > of 6       |                  |                  |                 |
| > cycles at  |                  |                  |                 |
| > the time   |                  |                  |                 |
| > of the     |                  |                  |                 |
| > data       |                  |                  |                 |
| > cut-off    |                  |                  |                 |
| > date.      |                  |                  |                 |
+--------------+------------------+------------------+-----------------+

The relatively similar number of treatment cycles received by subjects
in both treatment groups reflects the lack of important differences
between the treatment groups in dose-limiting toxicities.

Both the mean and median normalized doses of DTIC were similar in the 2
treatment groups, confirming that the usual dosing with DTIC was
maintained in patients who received G3139 (see Table 8).

[]{#__RefHeading___Toc68561780 .anchor}Table 8: Descriptive statistics
for cumulative (total) dose of study drug across all cycles: Safety
Population

+-----------------+---------------+-----------------+---+-----------------+
| Study drug      | G3139 plus    |                 |   | DTIC\           |
| (units)         | DTIC\         |                 |   | (N = 360)       |
|                 | (N = 371)     |                 |   |                 |
+=================+===============+=================+===+=================+
|                 | G3139 (mg/kg) | DTIC (mg/m^2^)  | m |                 |
|                 |               |                 | g |                 |
|                 |               |                 | / |                 |
|                 |               |                 | m |                 |
|                 |               |                 | ^ |                 |
|                 |               |                 | 2 |                 |
|                 |               |                 | ^ |                 |
+-----------------+---------------+-----------------+---+-----------------+
| n               | 371           | 365^a^          | 3 |                 |
|                 |               |                 | 6 |                 |
|                 |               |                 | 0 |                 |
+-----------------+---------------+-----------------+---+-----------------+
| Mean (SD)       | 126.1 (85.30) | 3417.9          | 3 |                 |
|                 |               | (2191.40)       | 3 |                 |
|                 |               |                 | 7 |                 |
|                 |               |                 | 1 |                 |
|                 |               |                 | . |                 |
|                 |               |                 | 9 |                 |
|                 |               |                 | ( |                 |
|                 |               |                 | 2 |                 |
|                 |               |                 | 3 |                 |
|                 |               |                 | 0 |                 |
|                 |               |                 | 0 |                 |
|                 |               |                 | . |                 |
|                 |               |                 | 8 |                 |
|                 |               |                 | 2 |                 |
|                 |               |                 | ) |                 |
+-----------------+---------------+-----------------+---+-----------------+
| Median          | 76.9          | 2054.9          | 2 |                 |
|                 |               |                 | 0 |                 |
|                 |               |                 | 0 |                 |
|                 |               |                 | 8 |                 |
|                 |               |                 | . |                 |
|                 |               |                 | 1 |                 |
+-----------------+---------------+-----------------+---+-----------------+
| 25^th^          | 68            | 1944            | 1 |                 |
| percentile      |               |                 | 9 |                 |
|                 |               |                 | 5 |                 |
|                 |               |                 | 7 |                 |
+-----------------+---------------+-----------------+---+-----------------+
| 75^th^          | 177           | 4795            | 4 |                 |
| percentile      |               |                 | 8 |                 |
|                 |               |                 | 6 |                 |
|                 |               |                 | 2 |                 |
+-----------------+---------------+-----------------+---+-----------------+
| Minimum,        | 9, 608        | 873, 9000       | 9 |                 |
| maximum         |               |                 | 0 |                 |
|                 |               |                 | 1 |                 |
|                 |               |                 | , |                 |
|                 |               |                 | 9 |                 |
|                 |               |                 | 8 |                 |
|                 |               |                 | 4 |                 |
|                 |               |                 | 5 |                 |
+-----------------+---------------+-----------------+---+-----------------+
| SD = standard   |               |                 |   |                 |
| deviation       |               |                 |   |                 |
|                 |               |                 |   |                 |
| ^a^ A total of  |               |                 |   |                 |
| 6 patients      |               |                 |   |                 |
| initiated Cycle |               |                 |   |                 |
| 1 but           |               |                 |   |                 |
| discontinued    |               |                 |   |                 |
| from the study  |               |                 |   |                 |
| prior to        |               |                 |   |                 |
| receiving the   |               |                 |   |                 |
| scheduled dose  |               |                 |   |                 |
| of DTIC.        |               |                 |   |                 |
+-----------------+---------------+-----------------+---+-----------------+

## Efficacy Results

### Overall Survival

In accordance with the statistical analysis plan, unblinding was event
driven. It was to occur after at least 508 events (ie, deaths) had been
reported. Unblinding of the study was performed when 537 events had
occurred. Two deaths occurred after 2 years of follow-up (Subjects 90201
and 92602, both in the G3139 plus DTIC group), and, as specified in the
analysis plan, the survival times for these 2 patients were censored at
2 years (730 days). Therefore, a total of 535 events were included in
the survival analysis.

Table 9 provides the results of the survival time analysis for the
Intent-to-Treat Population. In the Intent-to-Treat Population, 68.9%
(266 of 386) of patients in the G3139 plus DTIC group and 69.9% (269 of
385) of patients in the DTIC group had died by the time of analysis or
at the end of the 2-year follow-up, whichever came first. The median
survival time was 274 days in the G3139 plus DTIC group and 238 days in
the DTIC group. The hazard ratio was 0.89. The difference between groups
in survival distribution was not statistically significant (log-rank
test, P = 0.18).

[]{#__RefHeading___Toc68561781 .anchor}Table 9: Survival time analysis:
Intent-to-Treat Population

+-------------------------+--------------+---------+----------+------+
| Parameter               | G3139 plus   | DTIC\   | Hazard   | Log- |
|                         | DTIC\        | (N =    | ratio^b^ | rank |
|                         | (N = 386)    | 385)    |          | P    |
|                         |              |         |          | v    |
|                         |              |         |          | alue |
+=========================+==============+=========+==========+======+
| Number (%)^a^ of        | 266 (68.9)   | 269     |          |      |
| patients who died       |              | (69.9)  |          |      |
+-------------------------+--------------+---------+----------+------+
| Median survival time    | 274          | 238     | 0.89     | 0.18 |
| (days)                  |              |         |          |      |
+-------------------------+--------------+---------+----------+------+
| 95% confidence interval | 232 --306    | 219 --  | 0        |      |
|                         |              | 271     | .75-1.06 |      |
+-------------------------+--------------+---------+----------+------+
| Survival time was       |              |         |          |      |
| defined as the time     |              |         |          |      |
| from the date of        |              |         |          |      |
| randomization to the    |              |         |          |      |
| date of death.          |              |         |          |      |
|                         |              |         |          |      |
| ^a^ Percentages were    |              |         |          |      |
| calculated by using N,  |              |         |          |      |
| the total number of     |              |         |          |      |
| patients in the group,  |              |         |          |      |
| as the denominator.     |              |         |          |      |
|                         |              |         |          |      |
| ^b^ Hazard ratio and    |              |         |          |      |
| 95% confidence interval |              |         |          |      |
| from the unadjusted Cox |              |         |          |      |
| Proportional Hazards    |              |         |          |      |
| Model                   |              |         |          |      |
+-------------------------+--------------+---------+----------+------+

Kaplan-Meier survival curves by treatment group for the Intent-to-Treat
Population are shown in Figure 2. The curves are nearly superimposable
for the first 6 months and then begin to separate before the median. The
separation is most pronounced around the 75^th^ percentile, at which
time a greater than 3-month difference is apparent (G3139 plus DTIC
group, 522 days; DTIC group, 421 days; see Figure 2 and Table 10). It is
noteworthy that more than 20% (160) of the 771 patients randomized were
enrolled during the last 3 months of recruitment.

[]{#__RefHeading___Toc68561794 .anchor}Figure 2: Kaplan-Meier survival
curves by treatment group: Intent-to-Treat Population (N = 771)

![](media/image3.wmf){width="5.979861111111111in"
height="5.188194444444444in"}

[]{#__RefHeading___Toc68561782 .anchor}Table 10: Survival time (in days)
by percentile: Intent-to-Treat Population

  --------------------------------------------------------------------------
  Percentile   **G3139 plus     **DTIC**         **Treatment difference\
               DTIC**                            (G3139 plus DTIC -- DTIC)**
  ------------ ---------------- ---------------- ---------------------------
  25^th^       128              127              1

  50^th^       274              238              36

  75^th^       522              421              101
  --------------------------------------------------------------------------

At the time of analysis, the median follow-up time was 7.1 months (212
days) in the Intent-to-Treat Population. The data for 236 (30.6%)
patients included in the survival analysis were censored, including 189
(24.5%) patients who were in follow-up at the time of the data cut-off
date (01 Aug 2003). Of the remaining 47 censored patients, 24 (3.1%)
patients had reached their 2-year follow-up and 23 (3.0%) patients were
lost to follow-up or withdrew consent.

### Progression-Free Survival

As shown in Table 11 and Figure 3 for the Intent-to-Treat Population,
progression-free survival time was statistically significantly longer in
the G3139 plus DTIC group than in the DTIC group (median of 74 days
versus 49 days), and the hazard ratio was 0.73 (log-rank test, P =
0.0003), representing a 27% reduction of risk of disease progression and
a 37% improvement in progression-free survival.

[]{#__RefHeading___Toc68561783 .anchor}Table 11: Progression-free
survival analysis: Intent-to-Treat Population

+----------------------------+-----------+-----------+----------+-----+
| Parameter                  | G3139     | DTIC\     | **Hazard | Log |
|                            | plus      | (N = 385) | ra       | -ra |
|                            | DTIC\     |           | tio^b^** | nk\ |
|                            | (N = 386) |           |          | P   |
|                            |           |           |          | va  |
|                            |           |           |          | lue |
+============================+===========+===========+==========+=====+
| Number (%)^a^ of patients  | 263       | 260       |          |     |
| with disease progression   | (68.1)    | (67.5)    |          |     |
| or death                   |           |           |          |     |
+----------------------------+-----------+-----------+----------+-----+
| > Disease progression      | 257       | 255       |          |     |
|                            | (66.6)    | (66.2)    |          |     |
+----------------------------+-----------+-----------+----------+-----+
| > Death within 60 days of  | 6 ( 1.6)  | 5 ( 1.3)  |          |     |
| > last lesion measurement  |           |           |          |     |
+----------------------------+-----------+-----------+----------+-----+
| Median progression-free    | 74\       | 49\       | 0.73\    | 0.0 |
| survival, days\            | 62-91     | 48-55     | 0        | 003 |
| 95% confidence interval    |           |           | .62-0.87 |     |
+----------------------------+-----------+-----------+----------+-----+
| Time to progression was    |           |           |          |     |
| calculated from the date   |           |           |          |     |
| of randomization to the    |           |           |          |     |
| date progression was first |           |           |          |     |
| documented or the patient  |           |           |          |     |
| died within 60 days of     |           |           |          |     |
| last lesion measurement.   |           |           |          |     |
|                            |           |           |          |     |
| ^a^ Percentages were       |           |           |          |     |
| calculated by using N, the |           |           |          |     |
| total number of patients   |           |           |          |     |
| in the group, as the       |           |           |          |     |
| denominator.               |           |           |          |     |
|                            |           |           |          |     |
| ^b^ Hazard ratio and 95%   |           |           |          |     |
| confidence interval from   |           |           |          |     |
| the unadjusted Cox         |           |           |          |     |
| Proportional Hazards Model |           |           |          |     |
+----------------------------+-----------+-----------+----------+-----+

The differences between treatment groups increased with time. There was
a 25-day difference at the median and a 40-day difference at the 75^th^
percentile.

[]{#__RefHeading___Toc68561784 .anchor}Table 12: Progression-free
survival (in days) by percentile: Intent-to-Treat Population

  --------------------------------------------------------------------------
  Percentile   **G3139 plus     **DTIC**         **Treatment difference\
               DTIC**                            (G3139 plus DTIC -- DTIC)**
  ------------ ---------------- ---------------- ---------------------------
  25^th^       48               42               6

  50^th^       74               49               25

  75^th^       158              118              40
  --------------------------------------------------------------------------

[]{#__RefHeading___Toc68561795 .anchor}Figure 3: Kaplan-Meier
progression-free survival curves by treatment group: Intent-to-Treat
Population (N = 771)

![](media/image4.wmf){width="6.375694444444444in"
height="4.134722222222222in"}

The data for 248 (32.2%) patients included in the Intent-to-Treat
progression-free survival analysis were censored. Of these patients, 139
had no lesion measurements or had lesion measurements at baseline only,
primarily due to rapid disease progression or death. Progression-free
survival time for those patients was censored on Day 1. For the
remaining 109 patients, progression-free survival time was censored at
the last lesion assessment because the patient had either a response
(complete or partial) or stable disease. Of these patients, 58 were in
follow-up at the time of the analysis.

To examine the robustness of the results, several sensitivity analyses
were performed. Results of all sensitivity analyses yielded findings
supportive of the original results in progression-free survival:
progression-free survival was statistically significantly longer in the
G3139 plus DTIC group than in the DTIC group (median of 74 days versus
49 days; hazard ratio = 0.73; log-rank test, P = 0.0003).

Among the sensitivity analyses performed, time to progression between
the 2 treatment groups was compared. The difference between
progression-free survival and time to progression was limited to 11
patients who died within 60 days of their last lesion measurement. The
results of the time-to-progression analysis were the same as the results
of the analysis performed for progression-free survival and showed a
significant difference between treatment groups in favor of the G3139
plus DTIC group (median, 74 days versus 49 days; hazard ratio = 0.73;
log-rank test, P = 0.0003).

An additional sensitivity analysis was performed and included expansion
of "progression" to include additional events, thereby reducing the
percentage of censored data. Based on the investigator's evaluation,
reasons for discontinuation of study treatment due to "progression or
relapse," "intercurrent illness," "adverse drug toxicity," or "death"
were considered "events" in this sensitivity analysis. Other sensitivity
analyses were performed for various scenarios that might impact
progression-free survival; the hazard ratio ranged from 0.73 to 0.78 for
these sensitivity analyses (see Table 13). The results show consistent
statistically significant improvement in favor of the G3139 plus DTIC
group and support the robustness of the observation. Table 13 provides
details for all sensitivity analyses performed for progression-free
survival.

[]{#__RefHeading___Toc68561785 .anchor}Table 13: Sensitivity analyses
performed for time to progression and progression-free survival:
Intent-to-Treat Population

+-----------------------+------------------+---------+-----+----+----+
| Method                | Parameter        | G3139   | DT  | ** | Lo |
|                       |                  | plus    | IC\ | Ha | g- |
|                       |                  | DTIC\   | N = | za | ra |
|                       |                  | N = 386 | 385 | rd | nk |
|                       |                  |         |     | ra | P  |
|                       |                  |         |     | ti | v  |
|                       |                  |         |     | o^ | al |
|                       |                  |         |     | b^ | ue |
|                       |                  |         |     | ** |    |
+=======================+==================+=========+=====+====+====+
| ***Time to            | Number (%)^a^ of | 257     | 255 |    |    |
| progression***        | patients with    | (66.6)  | (66 |    |    |
|                       | events           |         | .2) |    |    |
+-----------------------+------------------+---------+-----+----+----+
|                       | Median           | 74\     | 49\ | 0  | 0. |
|                       | progression-free | 62-90   | 48  | .7 | 00 |
|                       | survival, days\  |         | -55 | 3\ | 03 |
|                       | 95% confidence   |         |     | 0  |    |
|                       | interval         |         |     | .6 |    |
|                       |                  |         |     | 1- |    |
|                       |                  |         |     | 0. |    |
|                       |                  |         |     | 87 |    |
+-----------------------+------------------+---------+-----+----+----+
| Average of prior and  | Number (%)^a^ of | 263     | 260 |    |    |
| postobservation       | patients with    | (68.1)  | (67 |    |    |
| measurements used for | disease          |         | .5) |    |    |
| missing target lesion | progression or   |         |     |    |    |
| data                  | death            |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+
|                       | Median           | 72\     | 49\ | 0  | 0. |
|                       | progression-free | 61-91   | 48  | .7 | 00 |
|                       | survival, days\  |         | -55 | 4\ | 04 |
|                       | 95% confidence   |         |     | 0  |    |
|                       | interval         |         |     | .6 |    |
|                       |                  |         |     | 2- |    |
|                       |                  |         |     | 0. |    |
|                       |                  |         |     | 87 |    |
+-----------------------+------------------+---------+-----+----+----+
| Progression-free      | Number (%)^a^ of | 343     | 332 |    |    |
| survival or           | patients with    | (88.9)  | (86 |    |    |
| discontinuation due   | events           |         | .2) |    |    |
| to progressive        |                  |         |     |    |    |
| disease, intercurrent |                  |         |     |    |    |
| illness, adverse drug |                  |         |     |    |    |
| toxicity, or death    |                  |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+
|                       | Median           | 59\     | 48\ | 0  | 0. |
|                       | progression-free | 54-67   | 46  | .7 | 00 |
|                       | survival, days\  |         | -50 | 8\ | 08 |
|                       | 95% confidence   |         |     | 0  |    |
|                       | interval         |         |     | .6 |    |
|                       |                  |         |     | 7- |    |
|                       |                  |         |     | 0. |    |
|                       |                  |         |     | 90 |    |
+-----------------------+------------------+---------+-----+----+----+
| Progression free      | Number (%)^a^ of | 263     | 260 |    |    |
| survival censored at  | patients with    | (68.1)  | (67 |    |    |
| 60 days after last    | disease          |         | .5) |    |    |
| lesion measurement    | progression or   |         |     |    |    |
| date                  | death            |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+
|                       | Median           | 85\     | 50\ | 0  | 0  |
|                       | progression-free | 64-93   | 48  | .7 | .0 |
|                       | survival, days\  |         | -56 | 5\ | 01 |
|                       | 95% confidence   |         |     | 0  |    |
|                       | interval         |         |     | .6 |    |
|                       |                  |         |     | 4- |    |
|                       |                  |         |     | 0. |    |
|                       |                  |         |     | 90 |    |
+-----------------------+------------------+---------+-----+----+----+
| Earliest lesion       | Number (%)^a^ of | 262     | 260 |    |    |
| measurement date used | patients with    | (67.9)  | (67 |    |    |
| for a given cycle to  | disease          |         | .5) |    |    |
| determine date of     | progression or   |         |     |    |    |
| disease progression   | death            |         |     |    |    |
| or censoring date     |                  |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+
|                       | Median           | 69\     | 48\ | 0  | 0. |
|                       | progression-free | 58-89   | 45  | .7 | 00 |
|                       | survival, days\  |         | -50 | 3\ | 02 |
|                       | 95% confidence   |         |     | 0  |    |
|                       | interval         |         |     | .6 |    |
|                       |                  |         |     | 1- |    |
|                       |                  |         |     | 0. |    |
|                       |                  |         |     | 86 |    |
+-----------------------+------------------+---------+-----+----+----+
|                       |                  |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+
| Progression-free      | Number (%)^a^ of | 232     | 247 |    |    |
| survival censored at  | patients with    | (60.1)  | (64 |    |    |
| end of treatment      | disease          |         | .2) |    |    |
| phase                 | progression or   |         |     |    |    |
|                       | death            |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+
|                       | Median           | 69\     | 49\ | 0  | 0. |
|                       | progression-free | 59-87   | 48  | .7 | 00 |
|                       | survival, days\  |         | -55 | 3\ | 05 |
|                       | 95% confidence   |         |     | 0  |    |
|                       | interval         |         |     | .6 |    |
|                       |                  |         |     | 1- |    |
|                       |                  |         |     | 0. |    |
|                       |                  |         |     | 87 |    |
+-----------------------+------------------+---------+-----+----+----+
| Nontarget lesion      | Number (%)^a^ of | 289     | 287 |    |    |
| measurements used to  | patients with    | (74.9)  | (74 |    |    |
| determine progression | disease          |         | .5) |    |    |
| of disease status     | progression or   |         |     |    |    |
| when target lesion is | death            |         |     |    |    |
| absent or indicating  |                  |         |     |    |    |
| stable disease or     |                  |         |     |    |    |
| responding status     |                  |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+
|                       | Median           | 67\     | 49\ | 0  | 0. |
|                       | progression-free | 57-84   | 48  | .7 | 00 |
|                       | survival, days\  |         | -54 | 5\ | 06 |
|                       | 95% confidence   |         |     | 0  |    |
|                       | interval         |         |     | .6 |    |
|                       |                  |         |     | 4- |    |
|                       |                  |         |     | 0. |    |
|                       |                  |         |     | 89 |    |
+-----------------------+------------------+---------+-----+----+----+
| ^a^ Percentages were  |                  |         |     |    |    |
| calculated by using   |                  |         |     |    |    |
| N, the total number   |                  |         |     |    |    |
| of patients in the    |                  |         |     |    |    |
| group, as the         |                  |         |     |    |    |
| denominator.          |                  |         |     |    |    |
|                       |                  |         |     |    |    |
| ^b^ Hazard ratio and  |                  |         |     |    |    |
| 95% confidence        |                  |         |     |    |    |
| interval from         |                  |         |     |    |    |
| unadjusted Cox        |                  |         |     |    |    |
| Proportional Hazards  |                  |         |     |    |    |
| Model                 |                  |         |     |    |    |
+-----------------------+------------------+---------+-----+----+----+

To evaluate the consistency of results for progression-free survival,
the protocol specified that analyses would be performed on several
subgroups of potential clinical relevance (eg, age, gender). Analyses of
progression-free survival showed a consistent treatment effect across
subgroups based on age, gender, and AJCC criteria (see Figure 4),
demonstrating that the treatment effect was not driven by any specific
subgroup(s): the effect was seen across the entire study population.

[]{#__RefHeading___Toc68561796 .anchor}Figure 4: Plots of hazard ratios
and 95% confidence intervals for progression-free survival:
Intent-to-Treat Population

![](media/image5.jpeg){width="5.9944444444444445in"
height="4.368055555555555in"}

### Antitumor Response Rate

A response was defined as either complete or partial regression of
disease. Only response confirmed by a repeat measurement performed no
less than 3 weeks after the response was first noted was called a
confirmed response. Responses were calculated by determining
computerized lesion measurements (using the information recorded on the
case report form) based on RECIST, including confirmation measurements
at least 3 weeks after the initial response and the presence of new
lesions or unequivocal increase or decrease in existing nonmeasurable
lesions.

The confirmed response rate was 11.7% in the G3139 plus DTIC group and
6.8% in the DTIC group (chi-square test, P = 0.019; see Table 14).

[]{#__RefHeading___Toc68561786 .anchor}Table 14: Antitumor response
rates during the treatment phase by treatment group: Intent-to-Treat
Population

+-------------------------+----------------+------------+-------------+
|                         | G3139 plus     | DTIC\      | P value     |
|                         | DTIC\          | (N = 385)\ |             |
|                         | (N = 386)\     | n (%)      |             |
|                         | n (%)          |            |             |
+-------------------------+----------------+------------+-------------+
| 30% reduction at ≥ 2    |                |            |             |
| assessments (RECIST)    |                |            |             |
+-------------------------+----------------+------------+-------------+
| > Objective response    | 45 (11.7)      | 26 ( 6.8)  | 0.019       |
+-------------------------+----------------+------------+-------------+
| > Complete              | 5^a^ ( 1.3)    | 2 ( 0.5)   |             |
+-------------------------+----------------+------------+-------------+
| > Partial               | 40 (10.4)      | 24 ( 6.2)  |             |
+-------------------------+----------------+------------+-------------+
| > Stable disease        | 116 (30.1)     | 106 (27.5) |             |
+-------------------------+----------------+------------+-------------+
| > Progressive disease   | 152 (39.4)     | 178 (46.2) |             |
+-------------------------+----------------+------------+-------------+
| > Inevaluable^b^        | 73 (18.9)      | 75 (19.5)  |             |
+-------------------------+----------------+------------+-------------+
| 30% reduction at ≥ 1    |                |            |             |
| assessment              |                |            |             |
+-------------------------+----------------+------------+-------------+
| > Objective response    | 64 (16.6)      | 42 (10.9)  | 0.022       |
+-------------------------+----------------+------------+-------------+
| ^a^ Includes 2 complete |                |            |             |
| responses subsequently  |                |            |             |
| documented by biopsy    |                |            |             |
| and/or PET scan in      |                |            |             |
| follow up               |                |            |             |
|                         |                |            |             |
| ^b^ Includes those      |                |            |             |
| patients for whom no    |                |            |             |
| tumor measurements were |                |            |             |
| available after         |                |            |             |
| baseline due primarily  |                |            |             |
| to disease progression  |                |            |             |
| or death                |                |            |             |
+-------------------------+----------------+------------+-------------+

Findings based on ≥ 1 assessment also showed that a greater percentage
of patients in the G3139 plus DTIC group than in the DTIC group achieved
a complete response or a partial response: 64 (16.6%) patients in the
G3139 plus DTIC group and 42 (10.9%) patients in the DTIC group
(chi-square test, P = 0.022; see Table 14). It should be noted that the
response rate was calculated based on the Intent-to-Treat Population and
included all inevaluable patients, unlike analyses reported in other
published studies.(Error: Reference source not found)

Stable disease was reported for 116 (30.1%) patients in the G3139 plus
DTIC group versus 106 (27.5%) patients in the DTIC group as best
response. The percentage of patients with complete response, partial
response, or stable disease as the best response during treatment was
41.7% in the G3139 plus DTIC group and 34.3% in the DTIC group
(chi-square test, P = 0.034).

Three patients in the G3139 plus DTIC group and 2 patients in the DTIC
group had complete responses during the treatment period and did not
require biopsy or PET scan confirmation. In the follow-up period, 2
complete responses determined by case report form data were further
documented in the G3139 plus DTIC group: Subject 30026 (response
confirmed by biopsy) and Subject 91702 (response confirmed by PET scan).

-   Subject 30026, a 61-year-old male, had subcutaneous and lymph node
    metastases at the time of entry in the study. This patient had
    complete remission of measurable disease with only a solitary skin
    lesion on the chest at the conclusion of Cycle 5 therapy, which was
    thought by the investigator to be nonmalignant. A subsequent biopsy
    confirmed that the lesion was benign, and the patient remains free
    of disease as of 31 Jan 2004. This patient remains in clinical
    remission 1 year following randomization.

-   Subject 91702, a 55-year-old female, had extensive bilateral pelvic
    and inguinal lymph node and soft tissue metastases at study entry,
    which rendered her non-ambulatory, and demonstrated a dramatic
    reduction in all measurable lesions. A CT scan showed a small
    residua in a single site of previous pelvic node involvement, which
    was not amenable to biopsy, at the protocol conclusion visit. A PET
    scan conducted during the follow-up period showed absence of any
    viable signal, consistent with the clinical presentation of complete
    response. As of 31 Jan 2004, this patient remains in complete
    clinical remission approximately 3 years following randomization.

Neither of these 2 patients received any surgical, chemotherapeutic, or
biologic intervention after completing treatment with G3139 plus DTIC.

Responses to treatment with G3139 plus DTIC were seen across subgroups
based on age, gender, and AJCC criteria (see Table 15), demonstrating
that the treatment effect was not driven by any specific subgroup(s):
the effect was seen across the entire study population.

[]{#__RefHeading___Toc68561787 .anchor}Table 15: Response rates by
subgroup: Intent-to-Treat Population

+----------------------+-----------------+--------------+--------------+
|                      |                 | **% of       |              |
|                      |                 | responding   |              |
|                      |                 | p            |              |
|                      |                 | atients^a^** |              |
+----------------------+-----------------+--------------+--------------+
|                      |                 | **G3139 plus | **DTIC**     |
|                      |                 | DTIC**       |              |
+----------------------+-----------------+--------------+--------------+
| Age group            | \< 65 years (n  | 13.8         | 6.6          |
|                      | = 480)          |              |              |
+----------------------+-----------------+--------------+--------------+
|                      | [               | 8.2          | 6.9          |
|                      | \>]{.underline} |              |              |
|                      | 65 years (n =   |              |              |
|                      | 291)            |              |              |
+----------------------+-----------------+--------------+--------------+
| Gender               | Male (n = 489)  | 11.4         | 5.1          |
+----------------------+-----------------+--------------+--------------+
|                      | Female (n =     | 12.0         | 9.8          |
|                      | 282)            |              |              |
+----------------------+-----------------+--------------+--------------+
| AJCC LDH -- disease  | M1a (n = 111)   | 21.3         | 12.0         |
| site distribution    |                 |              |              |
+----------------------+-----------------+--------------+--------------+
|                      | M1b (n = 168)   | 17.2         | 12.0         |
+----------------------+-----------------+--------------+--------------+
|                      | M1c (n = 483)   | 7.1          | 4.3          |
+----------------------+-----------------+--------------+--------------+
| AJCC = American      |                 |              |              |
| Joint Committee on   |                 |              |              |
| Cancer; LDH =        |                 |              |              |
| lactate              |                 |              |              |
| dehydrogenase        |                 |              |              |
|                      |                 |              |              |
| ^a^ Percentages were |                 |              |              |
| calculated by using  |                 |              |              |
| the total number of  |                 |              |              |
| patients in the      |                 |              |              |
| subgroup as the      |                 |              |              |
| denominator.         |                 |              |              |
+----------------------+-----------------+--------------+--------------+

###  Duration of Antitumor Response 

The duration of antitumor response was calculated from the date the
response was first documented until disease progression or the date of
the last lesion measurement.

Among the 71 responding subjects included in the analysis of duration of
response at the data cutoff date (ie, 45 in the G3139 plus DTIC group
and 26 in the DTIC group), the median duration of antitumor response was
similar between the 2 treatment groups (126 days for the G3139 plus DTIC
group and 128 days for the DTIC group; see Table 16). Duration of
response at the 75^th^ percentile differed in the 2 treatment groups by
more than 3 months (238 days in the G3139 plus DTIC group versus 142
days in the DTIC group).

[]{#__RefHeading___Toc68561788 .anchor}Table 16: Duration of antitumor
response in responding patients by treatment group: Intent-to-Treat
Population

+-------------------------------------+---------------+---------------+
| Days                                | G3139 plus    | DTIC\         |
|                                     | DTIC\         | (N = 385)     |
|                                     | (N = 386)     |               |
+=====================================+===============+===============+
| n^a^                                | 45            | 26            |
+-------------------------------------+---------------+---------------+
| Mean (SD)                           | 175.7 (136.0) | 153.5 (99.2)  |
+-------------------------------------+---------------+---------------+
| Median                              | 126           | 128           |
+-------------------------------------+---------------+---------------+
| 25^th^ percentile                   | 86            | 84            |
+-------------------------------------+---------------+---------------+
| 75^th^ percentile                   | 238           | 142           |
+-------------------------------------+---------------+---------------+
| Minimum, maximum                    | 41, 565       | 42, 390       |
+-------------------------------------+---------------+---------------+
| > SD = standard deviation           |               |               |
| >                                   |               |               |
| > ^a^ Calculated only for those     |               |               |
| > patients who responded (ie, those |               |               |
| > who had a complete response or a  |               |               |
| > partial response) by RECIST       |               |               |
| > criteria                          |               |               |
+-------------------------------------+---------------+---------------+

### Durable Response Rate

Durable response was defined as a complete or partial response lasting ≥
6 months from the date the response was first documented; no type of
anticancer therapy was to be administered during the 4 months after the
response was initially determined.

A total of 13 (3.4%) patients in the G3139 plus DTIC group and 5 (1.3%)
patients in the DTIC group had a durable response (P = 0.057; see Figure
5).

Although not included as a durable responder, 1 patient with multiple
liver metastases at baseline was randomized to receive G3139 plus DTIC
in July 2001 and had a complete remission by the end of Cycle 8
treatment in January 2002. Despite continued complete regression of
liver metastases, the subject required excison of new subcutaneous
lesions in March 2002 and has been maintained in surgical remission
without receiving further systemic treatment for melanoma as of 31 Jan
2004.

[]{#__RefHeading___Toc68561797 .anchor}Figure 5: Durable responses:
Intent-to-Treat Population

![](media/image6.jpeg){width="6.372916666666667in"
height="3.4166666666666665in"}

### ECOG Performance Status

Shifts from baseline in ECOG Performance Status to a less favorable
category were apparent in both treatment groups overall; there were no
clinically meaningful differences between treatment groups.

## Efficacy Conclusions

The proposed mechanism of Bcl-2 downregulation suggested that the
addition of G3139 would enhance the activity of DTIC in patients with
malignant melanoma. Although the primary efficacy endpoint of overall
survival for the Intent-to-Treat Population was not statistically
significant by the time of study unblinding, the results favored the
G3139 plus DTIC group. All secondary endpoints significantly supported
the response benefit achievable with G3139 plus DTIC. At the time of
analysis, the median follow-up time was only 7.1 months.

Progression-free survival time was statistically significantly longer in
the G3139 plus DTIC group than in the DTIC group (median of 74 days
versus 49 days; hazard ratio = 0.73; log-rank test, P = 0.0003). The
results of multiple sensitivity analyses of progression-free survival,
including time to progression, which evaluated a variety of scenarios,
consistently favored the G3139 plus DTIC group, indicating that this
finding was robust. Analyses of progression-free survival in a number of
prespecified subgroups (including those based on baseline LDH-disease
distribution \[ie, AJCC classification\], age, gender) provided
consistent results showing longer progression-free survival in the G3139
plus DTIC group.

The confirmed antitumor response rate for G3139 plus DTIC was 11.7%
versus 6.8% for DTIC (odds ratio = 1.82; P = 0.019). This response rate
for single-agent DTIC was consistent with that reported in a recent
study that utilized RECIST measurement criteria, in which a response
rate of 7% has been reported.(Error: Reference source not found) The low
response rate probably more accurately reflects single-agent DTIC
activity than reported in previous studies. The observed mean duration
of response was greater in the G3139 plus DTIC group than in the DTIC
group, and more patients in the G3139 plus DTIC group had a durable
response (≥ 180 days) than in the DTIC group (13 and 5 patients,
respectively).

Overall, the G3139 plus DTIC regimen provided a 27% reduction of risk of
disease progression (ie, a 37% improvement in progression-free survival
time) and an 82% improvement in response rate.

The robust and statistically significant benefit shown for
progression-free survival and confirmed antitumor response rate in the
Intent-to-Treat Population, as well as the consistency of efficacy
results across endpoints and subgroups provides compelling evidence of
the benefit of G3139 plus DTIC when compared to DTIC alone. This
treatment regimen is a promising alternative to existing therapies for
patients with advanced melanoma.

# Safety results

A total of 1052 patients were treated in 14 completed studies (including
the single randomized study, Protocol GM301, as well as 13 nonrandomized
studies) reported in the NDA, as follows:

-   692 patients received G3139 only or G3139 in combination with
    chemotherapy (371 \[53.6%\] of these patients were treated in the
    randomized, Phase III study in advanced malignant melanoma
    \[Protocol GM301\])

-   360 patients received a comparative agent (Protocol GM301, DTIC
    only)

These 14 completed studies were conducted in patients with advanced
malignant melanoma, in patients with other solid tumors (breast cancer,
prostate cancer, and other cancers), and in patients with various
hematologic malignancies (chronic lymphocytic leukemia and lymphoma).

In addition, a total of 555 patients were treated in ongoing studies
reported in the NDA, including:

-   307 patients who received G3139 only or G3139 in combination with
    chemotherapy

-   248 patients who received chemotherapy only

## Randomized Phase III Study in Advanced Malignant Melanoma

### Safety Assessments

Safety assessments included adverse events and changes in clinical
laboratory findings, vital signs, and physical examination findings.
Adverse events were categorized based on the Medical Dictionary for
Regulatory Activities (MedDRA, Version 4.0). The severity of adverse
events and laboratory changes was assessed according to the National
Cancer Institute Common Toxicity Criteria (Version 2.0). A Data Safety
Monitoring Board reviewed safety data periodically to alert the Sponsor
to possible safety concerns for patients in the study.

Some differences between treatment groups in the incidence of adverse
events were anticipated because of the 5-day continuous intravenous
infusion required for G3139 therapy. In particular, patients in the
G3139 plus DTIC group had more opportunities for observation due to the
need for line placement and maintenance and were at increased risk of
developing events associated with the central line. Additionally, the
investigator and study site personnel were aware of the treatment group
to which a patient had been randomized and may have been more likely to
report adverse events for the investigational treatment.

Treatment-emergent adverse events were defined as adverse events with an
onset date on or after the start date of the first study drug infusion
and within 30 days of the last study drug infusion. Events that were
present at baseline and worsened during the treatment phase of the study
also were considered treatment-emergent adverse events.

Treatment-related treatment-emergent adverse events included those
treatment-emergent adverse events considered by the investigator to be
probably or definitely related and possibly related, as well as events
for which this information was not recorded. When assessing the
relationship of an adverse event to study drug, the investigator could
assign relationship to G3139 only, to DTIC only, or to both G3139 and
DTIC separately for the specific event. In the event that relationship
was assigned to G3139 as well as DTIC, then the event was counted as
being related to the G3139/DTIC combination. Among patients in the G3139
plus DTIC group, an event was considered treatment related regardless of
whether the investigator considered the event to be related to G3139
only, DTIC only, or the G3139/DTIC combination.

A serious adverse event was defined as any adverse event occurring at
any dose that resulted in any of the following outcomes: death; a
life-threatening adverse drug experience (defined as any adverse drug
experience that placed the patient, in the view of the investigator, at
immediate risk of death from the reaction as it occurred, ie, not
including a reaction that, had it occurred in a more severe form, might
have caused death); inpatient hospitalization or prolongation of
existing hospitalization; a persistent or significant disability
(defined as a substantial disruption of a person's ability to conduct
normal life functions)/incapacity; congenital anomaly/birth defect; or a
significant medical event that may not have resulted in death, been
considered life-threatening, or required hospitalization. An event also
could be reported as a serious adverse drug experience when, based upon
appropriate medical judgment, the event required medical or surgical
intervention to prevent one of the outcomes listed in this definition.

### Overview of Treatment-Emergent Adverse Events

Most patients in both treatment groups had at least 1 treatment-emergent
adverse event (see Table 17). This was not unexpected given the advanced
disease in this patient population.

A total of 69 (18.6%) subjects in the G3139 plus DTIC group and 39
(10.8%) of subjects in the DTIC group discontinued protocol therapy due
to at least 1 treatment-emergent adverse event. In the G3139 plus DTIC
group, 42 (60.9%) of the 69 patients had adverse events clearly
associated with or reported as disease progression that led to
discontinuation. In the DTIC group, 30 (76.9%) of the 39 patients had
adverse events clearly associated with or reported as disease
progression that led to discontinuation. Additionally, 5 patients in the
G3139 plus DTIC group had injection site infections or catheter-related
thromboses that were not fatal and resulted in discontinuation. The
remaining subjects in both groups had diverse adverse events that
occurred in 1 or 2 patients each and resulted in discontinuation.

Notably, the percentage of patients who discontinued protocol therapy
due to a treatment-related treatment-emergent adverse event was low in
both groups: G3139 plus DTIC group, 6.2% and DTIC group, 2.2%.

The percentage of patients who had an adverse event with an outcome of
death (regardless of relationship to treatment) was low and similar in
both treatment groups: G3139 plus DTIC group, 8.6% and DTIC group,
9.2%.[]{#_Ref67816011 .anchor}

Table 17: Overview of treatment-emergent adverse events by treatment
group: Safety Population

  ---------------------- -------------------- ------------- -------- ------------------- -------------
                         All                                         Treatment-related   
                         treatment-emergent                          treatment- emergent 

  **Treatment-emergent   G3139 plus DTIC\     DTIC\         G3139                        DTIC\
  adverse event**        (N = 371)\           (N = 360)\    plus                         (N = 360)\
                         n (%)                n (%)         DTIC\                        n (%)
                                                            (N =                         
                                                            371)\                        
                                                            n (%)                        

  Any                    365 (98.4)           342 (95.0)    347                          287 (79.7)
                                                            (93.5)                       

  Grade 3 or 4           249 (67.1)           154 (42.8)    182                          80 (22.2)
                                                            (49.1)                       

  Serious                149 (40.2)           97 (26.9)     65                           27 ( 7.5)
                                                            (17.5)                       

  Leading to             69 (18.6)            39 (10.8)     23 (                         8 ( 2.2)
  discontinuation                                           6.2)                         

  With outcome of        32 ( 8.6)            33 ( 9.2)     3 ( 0.8)                     2 ( 0.6)
  death^a^                                                                               

  Death ≤ 30 days from   29 ( 7.8)            25 ( 6.9)     3 ( 0.8)                     1 ( 0.3)
  last dose of study                                                                     
  drug                                                                                   

  ^a^ Deaths occurring ≤                                                                 
  30 days and \> 30 days                                                                 
  from last dose of                                                                      
  study drug are                                                                         
  included.                                                                              
  ---------------------- -------------------- ------------- -------- ------------------- -------------

It is noteworthy that patients in the G3139 plus DTIC group had more
opportunities for observation and intervention due to the need for line
placement and maintenance during the 5-day Genasense infusion than did
patients in the DTIC group who received a 60-minute infusion of DTIC in
each 21-day cycle.

### Treatment-Emergent Adverse Events

More treatment-emergent adverse events were seen with the combination of
G3139 and DTIC than with DTIC alone. However, the types of events
reported were similar in the 2 treatment groups (see Table 18). In large
part, the events observed in both groups were consistent with the known
side-effect profile of single-agent DTIC: myelosuppression, especially
neutropenia and thrombocytopenia, as well as nausea and vomiting, and
flu-like symptoms. Notably, neutropenia was associated with infection in
only a small number of patients in each treatment group. In particular,
12 patients in the G3139 plus DTIC group and 5 patients in the DTIC
group had a Grade 2, 3, or 4 infection in the presence of Grade 4
neutropenia. With respect to thrombocytopenia, there was a greater
incidence of all grades of bleeding events in the G3139 plus DTIC group
than in the DTIC group. However, this was primarily accounted for by
more frequent Grade 1 or Grade 2 epistaxis and hematuria in the G3139
plus DTIC group than in the DTIC group.

The types of treatment-emergent adverse events considered related to
study treatment were similar in the 2 treatment groups. The 2
treatment-emergent adverse events or types of events most clearly
associated with G3139 were pyrexia and catheter-related events (ie,
infection, thrombosis, and pump-related events); the latter were due to
the requirement for an indwelling central catheter for the 5-day
continuous IV administration of G3139.

**Grade 3 and Grade 4 Treatment-Emergent Adverse Events**

A total of 249 (67.1%) patients in the G3139 plus DTIC group and 154
(42.8%) patients in the DTIC group had at least 1 Grade 3 or Grade 4
treatment-emergent adverse event (see Table 17). As shown in Table 18,
neutropenia and thrombocytopenia were the most frequently reported Grade
3 or Grade 4 treatment-emergent adverse events in both treatment groups.
The percentages of patients with Grade 3 or Grade 4 neutropenia and
Grade 3 or Grade 4 thrombocytopenia were greater in the G3139 plus DTIC
group than in the DTIC group. Most serious infections that occurred in
the G3139 plus DTIC group were not neutropenic in nature; injection site
infections due to the central catheter were the most commonly reported
type of serious infection in the G3139 plus DTIC group.

Despite the relatively greater incidence of Grade 3 or Grade 4
thrombocytopenia in the G3139 plus DTIC group, the incidence of Grade 3
or Grade 4 bleeding events was greater in the DTIC group than in the
G3139 plus DTIC group, reflecting more frequent and serious
gastrointestinal bleeding events (ie, gastrointestinal hemorrhage,
hematemesis, and melena).

In an attempt to more clearly delineate the toxicities related to G3139
administration, Grade 3 and Grade 4 events that occurred during the
first 5-day infusion of G3139 prior to administration of DTIC were
assessed. During this period, 34 (9.2%) subjects had at least 1 Grade 3
or Grade 4 treatment-emergent adverse event. The most frequently
occurring Grade 3 or 4 event was pyrexia (10 \[2.7%\] patients). Other
Grade 3 or Grade 4 events that occurred in \> 1 patient in the G3139
plus DTIC group prior to DTIC dosing included headache (3 \[0.8%\]
patients), thrombocytopenia (3 \[0.8%\] patients), anemia (2 \[0.5%\]
patients), fatigue (2 \[0.5%\] patients), accidental overdose (2
\[0.5%\] patients), and night sweats (2 \[0.5%\] patients).

**Serious Treatment-Emergent Adverse Events**

A total of 149 (40.2%) patients in the G3139 plus DTIC group and 97
(26.9%) patients in the DTIC group had at least 1 serious
treatment-emergent adverse event (see Table 17). As shown in Table 18,
serious treatment-emergent adverse events that occurred in \> 1% more
subjects in the G3139 plus DTIC group than in the DTIC group included
pyrexia, thrombocytopenia, nausea, vomiting, and neutropenia. Notably,
pyrexia was the only serious adverse event that occurred in \> 5% of
patients in the G3139 plus DTIC group.

A detailed review of certain serious treatment-emergent adverse events
was performed and events were categorized based on clinical findings.
Review of these events usually confirmed the presence of multiple
underlying factors related to metastatic melanoma that contributed to
the occurrence and outcome of a majority of these events. Several of
these serious treatment-emergent adverse events are briefly discussed:

-   The incidence of serious treatment-emergent adverse events
    associated with bleeding was lower in the G3139 plus DTIC group
    (0.5%) than in the DTIC group (2.8%). This is noteworthy given the
    increased incidence of thrombocytopenia and all grades of bleeding
    events in the G3139 plus DTIC group compared with findings in the
    DTIC group.

-   Most serious infections that occurred in the G3139 plus DTIC group
    were not neutropenic in nature; injection site infections due to the
    central catheter were the most commonly reported type of serious
    infection in the G3139 plus DTIC group.

-   Catheter-related complications occurred at an incidence consistent
    with that reported in the literature,([^39]) and did not impede
    patients from receiving protocol therapy. A total of 8 (2.2%)
    patients in the G3139 plus DTIC group had a serious thrombotic event
    related to central venous catheters and 15 (4.0%) patients had a
    serious injection site infection.

-   Misprogramming of the infusion pump with resulting overdose occurred
    in 2 (0.5%) patients, both of whom received the entire Cycle 1 dose
    of G3139 in 5 hours instead of 5 days:

```{=html}
<!-- -->
```
-   In 1 patient, adverse events reported in the 5-day period following
    the overdose of G3139 included Grade 1 tachycardia, hypomagnesemia,
    rash, and hematuria; Grade 2 vomiting, abdominal pain, fatigue, and
    pyrexia; and Grade 3 nausea and thrombocytopenia. All of these
    events resolved. This patient subsequently completed 4 cycles of
    protocol therapy and then discontinued from the study due to
    progressive disease.

-   In the remaining patient, adverse events reported in the 5-day
    period following the overdose of G3139 included Grade 1 hypokalemia,
    nausea, decreased blood magnesium, facial edema, tumor pain, and
    anemia; Grade 2 pyrexia, anemia, malaise, rigors, and nausea; and
    Grade 3 hypophosphatemia. All of these events except the tumor pain
    resolved (tumor pain continued). This patient subsequently completed
    7 cycles of protocol therapy and had a confirmed partial response.

[]{#__RefHeading___Toc68561790 .anchor}Table 18: Treatment-emergent
adverse events that occurred in ≥ 20% of patients in either treatment
group by preferred term: Safety Population

+----------+---------+---------+---------+---------+---------+---------+
| Tr       | All     |         | Grade 3 |         | Serious |         |
| eatment- | grades  |         | or      |         | ^a^\    |         |
| emergent |         |         | 4^a^\   |         | n       |         |
| adverse  | n       |         | n       |         | (%)^b^  |         |
| event    | (%)^b^  |         | (%)^b^  |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
|          | G3139   | DTIC    | G3139   | DTIC    | G3139   | DTIC    |
|          | plus    |         | plus    |         | plus    |         |
|          | DTIC    | (N =    | DTIC    | (N =    | DTIC    | (N =    |
|          |         | 360)    |         | 360)    |         | 360)    |
|          | (N =    |         | (N =    |         | (N =    |         |
|          | 371)    |         | 371)    |         | 371)    |         |
+----------+---------+---------+---------+---------+---------+---------+
| Nausea   | 231     | 169     | 26 (    | 9 (     | 14      | 5 (1.4) |
|          | (62.3)  | (46.9)  | 7.0)    | 2.5)    | (3.8)   |         |
+----------+---------+---------+---------+---------+---------+---------+
| Pyrexia  | 197     | 63      | 16 (    | 7 (     | 22      | 11      |
|          | (53.1)  | (17.5)  | 4.3)    | 1.9)    | (5.9)   | (3.1)   |
+----------+---------+---------+---------+---------+---------+---------+
| Fatigue  | 170     | 142     | 17 (    | 11 (    | 1 (0.3) | 3 (0.8) |
|          | (45.8)  | (39.4)  | 4.6)    | 3.1)    |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Vomiting | 139     | 75      | 17 (    | 7 (     | 13      | 6 (1.7) |
|          | (37.5)  | (20.8)  | 4.6)    | 1.9)    | (3.5)   |         |
+----------+---------+---------+---------+---------+---------+---------+
| Anorexia | 114     | 56      | 9 (     | 1 (     | 4 (1.1) | 1 (0.3) |
|          | (30.7)  | (15.6)  | 2.4)    | 0.3)    |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Thromboc | 107     | 40      | 58      | 23 (    | 15      | 4 (1.1) |
| ytopenia | (28.8)  | (11.1)  | (15.6)  | 6.4)    | (4.0)   |         |
+----------+---------+---------+---------+---------+---------+---------+
| Cons     | 103     | 93      | 8 (     | 3 (     | 5 (1.3) | 1 (0.3) |
| tipation | (27.8)  | (25.8)  | 2.2)    | 0.8)    |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Neu      | 103     | 56      | 79      | 45      | 8 (2.2) | 1 (0.3) |
| tropenia | (27.8)  | (15.6)  | (21.3)  | (12.5)  |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Diarrhea | 100     | 63      | 6 (     | 3 (     | 1 (0.3) | 2 (0.6) |
|          | (27.0)  | (17.5)  | 1.6)    | 0.8)    |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Headache | 97      | 47      | 10 (    | 1 (     | 3 (0.8) | 0 (0.0) |
|          | (26.1)  | (13.1)  | 2.7)    | 0.3)    |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Anemia   | 86      | 61      | 26 (    | 17      | 9 (2.4) | 8 (2.2) |
|          | (23.2)  | (16.9)  | 7.0)    | (4.7)   |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| Rigors   | 76      | 16 (    | 3 (     | 0 (0.0) | 2 (0.5) | 0 (0.0) |
|          | (20.5)  | 4.4)    | 0.8)    |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+
| n = the  |         |         |         |         |         |         |
| number   |         |         |         |         |         |         |
| of       |         |         |         |         |         |         |
| patients |         |         |         |         |         |         |
| with at  |         |         |         |         |         |         |
| least 1  |         |         |         |         |         |         |
| oc       |         |         |         |         |         |         |
| currence |         |         |         |         |         |         |
| of the   |         |         |         |         |         |         |
| event in |         |         |         |         |         |         |
| the      |         |         |         |         |         |         |
| s        |         |         |         |         |         |         |
| pecified |         |         |         |         |         |         |
| category |         |         |         |         |         |         |
|          |         |         |         |         |         |         |
| ^a^      |         |         |         |         |         |         |
| Shown    |         |         |         |         |         |         |
| only for |         |         |         |         |         |         |
| those    |         |         |         |         |         |         |
| tr       |         |         |         |         |         |         |
| eatment- |         |         |         |         |         |         |
| emergent |         |         |         |         |         |         |
| adverse  |         |         |         |         |         |         |
| events   |         |         |         |         |         |         |
| that     |         |         |         |         |         |         |
| occurred |         |         |         |         |         |         |
| in ≥ 20% |         |         |         |         |         |         |
| of       |         |         |         |         |         |         |
| subjects |         |         |         |         |         |         |
| in       |         |         |         |         |         |         |
| either   |         |         |         |         |         |         |
| t        |         |         |         |         |         |         |
| reatment |         |         |         |         |         |         |
| group    |         |         |         |         |         |         |
|          |         |         |         |         |         |         |
| ^b^      |         |         |         |         |         |         |
| Per      |         |         |         |         |         |         |
| centages |         |         |         |         |         |         |
| were     |         |         |         |         |         |         |
| ca       |         |         |         |         |         |         |
| lculated |         |         |         |         |         |         |
| using N, |         |         |         |         |         |         |
| the      |         |         |         |         |         |         |
| total    |         |         |         |         |         |         |
| number   |         |         |         |         |         |         |
| of       |         |         |         |         |         |         |
| subjects |         |         |         |         |         |         |
| in the   |         |         |         |         |         |         |
| group,   |         |         |         |         |         |         |
| as the   |         |         |         |         |         |         |
| deno     |         |         |         |         |         |         |
| minator. |         |         |         |         |         |         |
+----------+---------+---------+---------+---------+---------+---------+

**Discontinuations due to Treatment-Emergent Adverse Events**

A total of 69 (18.6%) patients in the G3139 plus DTIC group and 39
(10.8%) patients in the DTIC group discontinued protocol therapy due to
a treatment-emergent adverse event (see Table 17), including 15.6% of
patients in the G3139 plus DTIC group and 9.2% of patients in the DTIC
group who discontinued due to a Grade 3 or Grade 4 event. In both
treatment groups, disease progression was the most frequently reported
Grade 3 or Grade 4 treatment-emergent adverse event that resulted in
discontinuation of protocol therapy (see Table 19).

[]{#__RefHeading___Toc68561791 .anchor}Table 19: Grade 3 and Grade 4
adverse events resulting in discontinuation: Safety Population

+----------------------------+----------------------+-----------------+
| Preferred term^a,b^        | G3139 plus DTIC\     | DTIC\           |
|                            | (N = 371)\           | (N = 360)\      |
|                            | n (%)^c^             | n (%)^c^        |
+============================+======================+=================+
| Disease progression        | 10 (2.7)             | 5 (1.4)         |
+----------------------------+----------------------+-----------------+
| Neutropenia                | 5 (1.3)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Metastases to brain        | 4 (1.1)              | 2 (0.6)         |
+----------------------------+----------------------+-----------------+
| Thrombocytopenia           | 4 (1.1)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Cardiorespiratory arrest   | 3 (0.8)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Injection site infection   | 3 (0.8)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Sepsis                     | 2 (0.5)              | 2 (0.6)         |
+----------------------------+----------------------+-----------------+
| Abdominal pain             | 2 (0.5)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Pneumonia                  | 2 (0.5)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Pulmonary embolism         | 2 (0.5)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Cardiac arrest             | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Convulsions                | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Hyperglycemia              | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Hypotension                | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Leukopenia                 | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Multiorgan failure         | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Muscle weakness            | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Renal failure              | 2 (0.5)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Deep venous thrombosis     | 1 (0.3)              | 2 (0.6)         |
+----------------------------+----------------------+-----------------+
| General physical health    | 1 (0.3)              | 2 (0.6)         |
| deterioration              |                      |                 |
+----------------------------+----------------------+-----------------+
| Pain                       | 1 (0.3)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Pyrexia                    | 1 (0.3)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Small intestinal           | 1 (0.3)              | 1 (0.3)         |
| obstruction                |                      |                 |
+----------------------------+----------------------+-----------------+
| *Table continued on next   |                      |                 |
| page*                      |                      |                 |
+----------------------------+----------------------+-----------------+
| Akathisia                  | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Alanine aminotransferase   | 1 (0.3)              | 0 (0.0)         |
| increased                  |                      |                 |
+----------------------------+----------------------+-----------------+
| Anorexia                   | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Ascites                    | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Aspartate aminotransferase | 1 (0.3)              | 0 (0.0)         |
| increased                  |                      |                 |
+----------------------------+----------------------+-----------------+
| Atrial fibrillation        | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Bacteremia                 | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Cerebral hemorrhage        | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Depression                 | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Difficulty in walking      | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Febrile neutropenia        | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Hepatic failure            | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Hypoglycaemia              | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Infection                  | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Loss of consciousness      | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Metastases to spine        | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Musculoskeletal pain       | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Myalgia                    | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Neutropenic sepsis         | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Edema lower limb           | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Edema                      | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Pleuritic pain             | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Respiratory distress       | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Respiratory failure (excl  | 1 (0.3)              | 0 (0.0)         |
| neonatal)                  |                      |                 |
+----------------------------+----------------------+-----------------+
| Spinal cord compression    | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Subclavian vein thrombosis | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Thrombosis                 | 1 (0.3)              | 0 (0.0)         |
+----------------------------+----------------------+-----------------+
| Dyspnea                    | 0 (0.0)              | 3 (0.8)         |
+----------------------------+----------------------+-----------------+
| Gastrointestinal           | 0 (0.0)              | 3 (0.8)         |
| hemorrhage                 |                      |                 |
+----------------------------+----------------------+-----------------+
| Fatigue                    | 0 (0.0)              | 2 (0.6)         |
+----------------------------+----------------------+-----------------+
| Hypoxia                    | 0 (0.0)              | 2 (0.6)         |
+----------------------------+----------------------+-----------------+
| Nausea                     | 0 (0.0)              | 2 (0.6)         |
+----------------------------+----------------------+-----------------+
| Weakness                   | 0 (0.0)              | 2 (0.6)         |
+----------------------------+----------------------+-----------------+
| Abdominal distension       | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| *Table continued on next   |                      |                 |
| page*                      |                      |                 |
+----------------------------+----------------------+-----------------+
| Cardiac failure congestive | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Cardiac failure            | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Coma                       | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Hemothorax                 | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Intestinal perforation     | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Jaundice                   | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Malaise                    | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Metastases                 | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Myocardial infarction      | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Obstructive airways        | 0 (0.0)              | 1 (0.3)         |
| disorder                   |                      |                 |
+----------------------------+----------------------+-----------------+
| Pain in limb               | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Pancytopenia               | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Paraparesis                | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Tachycardia                | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Tumor pain                 | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Urinary retention          | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| Vomiting                   | 0 (0.0)              | 1 (0.3)         |
+----------------------------+----------------------+-----------------+
| n = the number of patients |                      |                 |
| with at least 1 occurrence |                      |                 |
| of the event in the        |                      |                 |
| specified category         |                      |                 |
|                            |                      |                 |
| excl = excluding           |                      |                 |
|                            |                      |                 |
| ^a^ Preferred terms are    |                      |                 |
| presented in descending    |                      |                 |
| order of incidence based   |                      |                 |
| on findings in the G3139   |                      |                 |
| plus DTIC group.           |                      |                 |
|                            |                      |                 |
| ^b^ If a patient had more  |                      |                 |
| than 1 occurrence of the   |                      |                 |
| same adverse event, the    |                      |                 |
| patient was counted in the |                      |                 |
| category of greatest known |                      |                 |
| intensity for that event.  |                      |                 |
|                            |                      |                 |
| ^c^ Percentages were       |                      |                 |
| calculated by using N, the |                      |                 |
| total number of patients   |                      |                 |
| in the group, as the       |                      |                 |
| denominator.               |                      |                 |
+----------------------------+----------------------+-----------------+

**Deaths**

In the G3139 plus DTIC group, 29 (7.8%) of the 371 patients treated died
during treatment or within 30 days of the last dose of protocol therapy
(see Table 17). Death more than 30 days after the last dose of study
drug was reported for an additional 229 patients (61.7%). The majority
of these deaths were due to malignant melanoma.

In the DTIC group, 25 (6.9%) of the 360 patients treated died during
treatment or within 30 days of the last dose of protocol therapy. Death
more than 30 days after the last dose of study drug was reported for an
additional 230 patients (63.9%). The majority of these deaths were due
to malignant melanoma.

### Other Safety Evaluations

Shifts in laboratory parameters to Grade 3 or Grade 4 generally were
transient (Table 20). Hematology assessments showed an increase in the
incidence of Grade 3 or Grade 4 neutropenia and thrombocytopenia when
G3139 was added to DTIC. However, the majority of patients recovered
fully. The addition of G3139 to DTIC had little impact on hepatic and
renal function. Most changes were transient, with patients recovering to
Grade 0 or Grade 1 by the end of the treatment phase of the study.

[]{#__RefHeading___Toc68561792 .anchor}Table 20: Shifts in laboratory
parameters: Safety Population

+----------+--------+---------+----------+------+--------+----------+
| La       | G3139  |         |          | DTIC |        |          |
| boratory | plus   |         |          |      |        |          |
| p        | DTIC   |         |          | \%   |        |          |
| arameter |        |         |          | of   |        |          |
|          | \% of  |         |          | pati |        |          |
|          | pa     |         |          | ents |        |          |
|          | tients |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+
|          | To     | Rec     | (Dif     | To   | Rec    | (Dif     |
|          | Grade  | overy:\ | ference) | G    | overy\ | ference) |
|          | 3-4    | Grade 3 |          | rade | Grade  |          |
|          | post   | or 4 to |          | 3-4  | 3 or 4 |          |
|          | ba     | Grade 0 |          |      | to     |          |
|          | seline | or 1    |          |      | Grade  |          |
|          |        |         |          |      | 0 or 1 |          |
+----------+--------+---------+----------+------+--------+----------+
| Absolute | 29.5   | 23.0    | 6.5      | 14.4 | 9.2    | 5.2      |
| ne       |        |         |          |      |        |          |
| utrophil |        |         |          |      |        |          |
| count    |        |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+
| Platelet | 19.2   | 13.6    | 5.6      | 7.4  | 5.1    | 2.3      |
| count    |        |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+
| He       | 4.4    | 0.8     | 3.6      | 4.6  | 0.6    | 4.0      |
| moglobin |        |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+
| Alkaline | 2.2    | 0.3     | 1.9      | 2.0  | 0.0    | 2.0      |
| pho      |        |         |          |      |        |          |
| sphatase |        |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+
| AST      | 3.9    | 1.7     | 2.2      | 0.9  | 0.0    | 0.9      |
+----------+--------+---------+----------+------+--------+----------+
| ALT      | 4.8    | 2.7     | 2.1      | 0.6  | 0.3    | 0.3      |
+----------+--------+---------+----------+------+--------+----------+
| B        | 1.1    | 0.3     | 0.8      | 0.3  | 0.0    | 0.3      |
| ilirubin |        |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+
| Cr       | 0.6    | 0.0     | 0.6      | 0.0  | 0.0    | 0.0      |
| eatinine |        |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+
| BUN      | 0.3    | 0.0     | 0.3      | 0.0  | 0.0    | 0.0      |
+----------+--------+---------+----------+------+--------+----------+
| ALT =    |        |         |          |      |        |          |
| alanine  |        |         |          |      |        |          |
| a        |        |         |          |      |        |          |
| minotran |        |         |          |      |        |          |
| sferase; |        |         |          |      |        |          |
| AST =    |        |         |          |      |        |          |
| a        |        |         |          |      |        |          |
| spartate |        |         |          |      |        |          |
| a        |        |         |          |      |        |          |
| minotran |        |         |          |      |        |          |
| sferase; |        |         |          |      |        |          |
| BUN =    |        |         |          |      |        |          |
| blood    |        |         |          |      |        |          |
| urea     |        |         |          |      |        |          |
| nitrogen |        |         |          |      |        |          |
+----------+--------+---------+----------+------+--------+----------+

## Other Completed Studies

The remaining completed studies were nonrandomized studies conducted in
patients with solid tumors and various hematologic malignancies. In
these studies, G3139 was well tolerated when administered as monotherapy
or when administered with chemotherapies as part of a combination
treatment. The type and severity of adverse events among patients
receiving combination therapy was determined by the specific
chemotherapeutic agents used. No unexpected or new toxicity was
identified.

## 120-Day Safety Update

The 120-Day Safety Update included data for the remaining 10 patients in
Protocol GM301 who completed treatment with G3139 plus DTIC subsequent
to the NDA cutoff date and data for an additional 118 patients treated
with G3139 alone or in combination with chemotherapy in ongoing studies.

Review of these data demonstrates that safety findings are consistent
with those reported in the NDA. No new or unique adverse event was
observed.

## Overall Safety Conclusions

The safety of G3139 has been evaluated in approximately 1000 patients
who received G3139 only or G3139 in combination with chemotherapy in
completed and ongoing clinical studies. A total of 692 patients received
G3139 in completed studies, including 371 patients randomized to receive
G3139 plus DTIC in the controlled completed study in advanced malignant
melanoma (Protocol GM301). As of 30 Nov 2003, a total of 425 patients
had received G3139 in ongoing studies.

Analyses of safety data for G3139 support the following conclusions:

-   Adding G3139 to full-dose chemotherapy is practical and safe for use
    in the outpatient setting. Full doses of chemotherapy can be
    administered on time and without unexpected toxicity.

-   The types of adverse events seen were usually those associated with
    chemotherapy, such as cytopenias, nausea, vomiting, etc. No new or
    unique adverse event was observed.

-   Two distinct adverse events were apparent with the G3139 plus DTIC
    regimen  pyrexia and catheter-related events. In general, fever
    occurred most frequently during the first 3 days of the treatment
    cycle in the G3139 plus DTIC group. Since G3139 administration
    required an indwelling central catheter for continuous intravenous
    infusion, the incidence of complications related to central venous
    catheters was within expected limits and did not impede patients
    from receiving full protocol therapy.

-   The incidence of neutropenia and thrombocytopenia was increased when
    G3139 was added to DTIC. Mild neutropenia and thrombocytopenia have
    been demonstrated in single-agent studies with G3139 in a variety of
    tumors. However, these laboratory changes were, for the most part,
    transient, and the majority of patients recovered fully. Moreover,
    neutropenia was associated with infection in only a small number of
    patients, with serious infections in the G3139 plus DTIC group most
    frequently related to the indwelling catheter. Thrombocytopenia was
    not associated with an increase in Grade 3 or Grade 4 bleeding
    events in patients treated with G3139 plus DTIC.

-   There was a low rate of discontinuation due to a treatment-related
    safety finding, and most events were tolerable and self-limiting in
    nature. The percentage of patients who died while on protocol
    therapy was similar and low in both treatment groups.

-   Most of the very common adverse events can be effectively managed
    with specific concomitant medications, such as antipyretics, colony
    stimulating factors and antiemetics/antinauseants.

-   On the whole, treatment with G3139 was well tolerated for use in the
    outpatient setting.

# Conclusions

The role of Bcl-2 in the survival of cancer cells has been well
documented. In particular, this protein prevents or substantially
retards the onset of cell death, thus enabling cancer cells to withstand
the cytotoxic effects of chemotherapy. Antisense represents a
pharmacologic approach to selectively reduce the production of specific
proteins. Genasense, a novel Bcl-2 antisense agent, may function as a
chemosensitizing agent and thus enable conventional anticancer drugs to
function more effectively.

More than 90% of patients with advanced melanoma have been reported to
express Bcl-2.(Error: Reference source not found) Thus, Genasense was
administered in combination with a conventional cytotoxic agent (DTIC)
in a Phase I-II study in patients with Stage IV melanoma.(Error:
Reference source not found) Promising results were achieved based on
both response and survival.(Error: Reference source not found)
Accordingly, a randomized Phase III study (Protocol GM301) was conducted
to assess the efficacy of Genasense in combination with DTIC in this
patient population. A 5-day continuous IV infusion of G3139 7 mg/kg/day
plus DTIC 1000 mg/m^2^ was compared with DTIC 1000 mg/m^2^ alone. A
total of 771 patients were randomized at 139 study sites in 9 countries,
and patients were stratified prior to randomization based on documented
prognostic factors. Notably, this study was the largest randomized,
controlled study conducted to date in patients with malignant melanoma.

The primary endpoint of overall survival was not achieved in this study.
However, the results of the primary analysis clearly favored the
Genasense plus DTIC treatment. In addition, Genasense in combination
with DTIC provided highly significant benefit based on progression-free
survival, including time to progression, and confirmed response rate: a
27% reduction of risk of disease progression (ie, a 37% improvement in
progression-free survival time) and an 82% improvement in response rate
were documented. Results of multiple sensitivity analyses of
progression-free survival, including time to progression, were robust
and showed a consistent difference between treatment groups that favored
the Genasense plus DTIC regimen. Progression-free survival time was
significantly longer in the Genasense plus DTIC group than in the DTIC
group for patients with lung and non-visceral disease, as well as for
patients with liver metastases. Analyses of progression-free survival in
a number of additional subgroups (age, gender, US and non-US study
sites, prior immunotherapy, and time since initial diagnosis) yielded
similarly favorable and significant results. Objective responses were
documented among patients with metastatic melanoma of the skin,
subcutaneous tissue, lung, and liver. More patients treated with
Genasense plus DTIC than with DTIC alone had a durable response (13 and
5 patients, respectively).

Pyrexia and catheter-related events were associated with administration
of Genasense. In addition, Genasense increased the incidence of adverse
events commonly reported with administration of DTIC, particularly
neutropenia and thrombocytopenia. Nevertheless, treatment with the
conventional dose of DTIC was maintained throughout Genasense
administration, most adverse events were tolerable and self-limiting in
nature, and the rate of discontinuation due to a treatment-related
safety finding was low (6.2%). Notably, the percentage of patients who
received Genasense plus DTIC and had an adverse event with an outcome of
death was low (8.6%) and similar to that reported for patients treated
with DTIC alone (9.2%).

Given the pressing need for improved therapy for patients with advanced
malignant melanoma, Genasense 7 mg/kg/day administered by continuous
intravenous infusion for 5 days in combination with DTIC 1000 mg/m^2^ is
a promising alternative as a first-line treatment for this patient
population.

-   The strong internal consistency of efficacy results across endpoints
    and subgroups provides compelling evidence of the benefit of G3139
    plus DTIC when compared to DTIC alone.

-   The adverse events observed with the Genasense plus DTIC regimen are
    predictable and clearly manageable in a routine practice setting by
    a qualified oncologist.

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