**Johnson & Johnson Pharmaceutical Research & Development, L.L.C.**

**920 U. S. Highway 202, P.O. Box 300, Raritan, NJ 08869-0602**

**Background Information Regarding Accelerated Approval of DOXIL** **in
Ovarian Cancer**

**Phase IV Commitments**

**DOXIL** **(doxorubicin HCl liposome injection)**

**NDA** **No. 50-718**

Oncologic Drugs Advisory Committee Meeting

March 12-13, 2003

Bethesda, MD

**[available for public disclosure without redaction]{.smallcaps}**

#  {#section .TOC-1 .unnumbered}

#  {#section-1 .TOC-1 .unnumbered}

#  {#section-2 .TOC-1 .unnumbered}

# Table of Contents {#table-of-contents .TOC-1 .unnumbered}

#  {#section-3 .TOC-1 .unnumbered}

#  {#section-4 .TOC-1 .unnumbered}

# [Background Information Regarding Accelerated Approval of DOXIL in Ovarian Cancer 1](#section-5) {#background-information-regarding-accelerated-approval-of-doxil-in-ovarian-cancer-1 .TOC-1 .unnumbered}

# [Phase IV Commitments 1](#phase-iv-commitments) {#phase-iv-commitments-1 .TOC-1 .unnumbered}

## [1. Summary 1](#summary) {#summary-1 .TOC-2 .unnumbered}

## [2. General Information 1](#general-information) {#general-information-1 .TOC-2 .unnumbered}

## [3. Introduction 1](#introduction) {#introduction-1 .TOC-2 .unnumbered}

### [3.1. Overview of Ovarian Cancer 1](#overview-of-ovarian-cancer) {#overview-of-ovarian-cancer-1 .TOC-3 .unnumbered}

### [3.2. History of Doxorubicin and DOXIL in Ovarian Cancer Treatment 3](#history-of-doxorubicin-and-doxil-in-ovarian-cancer-treatment) {#history-of-doxorubicin-and-doxil-in-ovarian-cancer-treatment-3 .TOC-3 .unnumbered}

## [4. Regulatory History of DOXIL in Ovarian cancer Indication 6](#regulatory-history-of-doxil-in-ovarian-cancer-indication) {#regulatory-history-of-doxil-in-ovarian-cancer-indication-6 .TOC-2 .unnumbered}

## [5. Description of Commitment Studies 7](#description-of-commitment-studies) {#description-of-commitment-studies-7 .TOC-2 .unnumbered}

### [5.1. Sequus / ALZA Study 30-49 7](#sequus-alza-study-30-49) {#sequus-alza-study-30-49-7 .TOC-3 .unnumbered}

### [5.2. SWOG Study SO200 (OBI Study No.: DO01-20-003) 10](#swog-study-so200-obi-study-no.-do01-20-003) {#swog-study-so200-obi-study-no.-do01-20-003-10 .TOC-3 .unnumbered}

## [6. Difficulties Encountered in Conduct, Accrual, or Completion of Trials 13](#difficulties-encountered-in-conduct-accrual-or-completion-of-trials) {#difficulties-encountered-in-conduct-accrual-or-completion-of-trials-13 .TOC-2 .unnumbered}

## [7. References 14](#references) {#references-14 .TOC-2 .unnumbered}

#  {#section-5 .unnumbered}

# Background Information Regarding Accelerated Approval of DOXIL in Ovarian Cancer

# Phase IV Commitments

## Summary

DOXIL (doxorubicin HCl liposome injection) received accelerated approval
28 June 1999 for the treatment of patients with refractory metastatic
carcinoma of the ovary. This approval was based on objective tumor
response rates observed in three non-randomized phase II trials. Study
30-49 was ongoing at the time of the approval of the ovarian cancer
indication and is currently in its follow up phase for an ITT survival
analysis. A subsequent phase IV commitment trial conducted by the
Southwest Oncology Group is ongoing.

To date, more than 17,000 women in the United States with relapsed or
recurrent ovarian cancer have received treatment with this drug product
(doxorubicin HCl liposome injection). More than 45 manuscripts have been
published regarding the use of doxorubicin HCl liposome injection in the
treatment of ovarian carcinoma.

## General Information

**Drug Name:** DOXIL (doxorubicin HCl liposome injection)

**Indication:** DOXIL is indicated for the treatment of metastatic
carcinoma of the ovary in patients with disease that is refractory to
both paclitaxel- and platinum-based chemotherapy regimens. Refractory
disease is defined as disease that has progressed while on treatment, or
within 6 months of completing treatment.

This indication is based on objective tumor response rates. No results
are available from controlled trials that demonstrate a clinical benefit
resulting from this treatment, such as improvement in disease-related
symptoms or increased survival.

**Accelerated Approval Date:** 28 June 1999

## Introduction

### Overview of Ovarian Cancer

Epithelial ovarian cancer is the most frequent cause of death due to
gynecologic malignancies and the fifth most common cause of cancer death
in women. More than 23,100 new cases are diagnosed in the US annually,
with approximately 14,000 deaths due to ovarian cancer each year.
Ovarian cancer is primarily a disease of post-menopausal women; most
cases occur in women between 50 and 75 years of age. The incidence of
ovarian cancer increases with age and peaks at a rate of 54 per 100,000
in the 75- to 79‑year-old age group. Survival strongly correlates with
surgical staging, with 5-year survival rates for stages I, II, III, and
IV of 74%, 58%, 30%, and 19%, respectively.^1^

The extent of disease in ovarian cancer patients is generally described
as either "early-stage" or "late-stage." Because early-stage ovarian
cancer is generally asymptomatic, 75% to 85% of women are first
diagnosed with advanced-stage (Stage III and IV) disease.^2,3^ For the
initial presentation of advanced-stage disease, the standard of care is
combined modality therapy, consisting of aggressive surgical debulking
followed by platinum-based combination chemotherapy.^4^ Response rates
of 60%-80% are reported with carboplatin- or cisplatin-based therapy,
with complete responses in 30%-50% of patients.^5^ As a result of recent
Gynecological Oncology Group (GOG) studies, paclitaxel and
platinum-containing therapy is considered to be the current standard of
care for advanced-stage ovarian cancer.^6^ Median survival with current
front-line therapy is 38 months and 5-year survival for patients with
Stage III and IV disease is 27%.^7^ Despite improvements in both
response rates and survival with current combination chemotherapies,
first-line therapy with platinum and paclitaxel fails in up to 30% of
patients. In addition, 55%-75% of responding patients will relapse
within 2 years and a subset of these patients will relapse within 6
months. Consequently, there is an unmet medical need for safe and
effective drugs after failure of first-line platinum-based chemotherapy.

Platinum-sensitivity, which is defined by response to first-line
platinum-based therapy, is predictive of response to subsequent
treatment with a platinum-containing regimen. Disease progression during
treatment or relapse within 6 months after the last dose of
platinum-based treatment denotes "platinum-refractory" disease.
Recurrent disease is potentially "platinum-sensitive" if there is a
progression-free interval of greater than 6 months after response to
first-line platinum-based chemotherapy. With platinum-sensitive disease,
there is a 20%-30% chance of responding to retreatment with
platinum-based chemotherapy and similar response to non-platinum
regimens is likely. In general, a worse prognosis is associated with
disease progression during initial chemotherapy, residual bulky disease
after initial therapy, or recurrent disease within 6 months of the last
dose of treatment. Moreover, such tumors are much less likely to respond
to subsequent cytotoxic chemotherapy regimens.^8,9^

### History of Doxorubicin and DOXIL in Ovarian Cancer Treatment

Doxorubicin has played an important role in the front-line treatment of
epithelial ovarian cancer.^10,11^ However, doxorubicin has not had a
role as a salvage agent for ovarian cancer after platinum-based
chemotherapy; response rates have been low and in this setting, toxicity
has been substantial. Myelosuppression is a frequent dose-limiting
toxicity, and high cumulative doses of doxorubicin are potentially
cardiotoxic. Severe acute nausea and vomiting, stomatitis, and
esophagitis associated with doxorubicin also may be dose-limiting. In
addition, alopecia typically develops and persists throughout treatment.

In an attempt to improve the anti-tumor activity of doxorubicin and to
reduce its toxicity, a new formulation of doxorubicin was developed.
DOXIL is a formulation of doxorubicin hydrochloride encapsulated in
long-circulating STEALTH^®^ liposomes for intravenous administration.
DOXIL was designed to enhance the efficacy and reduce the dose-limiting
toxicities of doxorubicin by altering the plasma pharmacokinetics and
tissue distribution of the drug. Because of the slower plasma clearance
of DOXIL relative to conventional doxorubicin, the AUC achieved with
DOXIL is 2-3 orders of magnitude larger than the AUC for a similar dose
of conventional doxorubicin. In contrast to the triphasic pattern of
clearance of conventional doxorubicin (approximate mean half-lives of 12
minutes, 3.3 hours, and 30-40 hours), the biphasic disposition of DOXIL
has a short first phase (approximately 5 hours) and a prolonged second
phase (approximately 55 hours).^12^ Several company-sponsored studies
have evaluated the safety and efficacy of DOXIL in patients with ovarian
cancer: three non-comparative studies (30‑22, 30-47 and 30-47E) and two
randomized open-label studies (30-49, comparing DOXIL and topotecan, and
30-57, comparing DOXIL and paclitaxel). The final survival analysis for
study 30-49 is ongoing. Table 1 lists the DOXIL ovarian cancer studies
that have been completed.

+-------+---------------------+------------------+------+-------------+
| **    |                     |                  |      |             |
| Table |                     |                  |      |             |
| 1**:  |                     |                  |      |             |
| DOXI  |                     |                  |      |             |
| L/Cae |                     |                  |      |             |
| lyx\* |                     |                  |      |             |
| Cli   |                     |                  |      |             |
| nical |                     |                  |      |             |
| T     |                     |                  |      |             |
| rials |                     |                  |      |             |
| in    |                     |                  |      |             |
| Ov    |                     |                  |      |             |
| arian |                     |                  |      |             |
| C     |                     |                  |      |             |
| ancer |                     |                  |      |             |
+-------+---------------------+------------------+------+-------------+
| Study | Design              | Treatment, Dose  | No.  | Study       |
| No.   |                     | in mg/m^2^,      | of   | Endpoints   |
|       |                     | Frequency        | pts  |             |
+-------+---------------------+------------------+------+-------------+
| 30-22 | Phase II, open      | 50, every 3      | 35   | Response    |
|       | label study of      | weeks, up to     |      | rates,      |
|       | efficacy and PK in  | 550 mg/m^2^      |      |             |
|       | ovarian cancer      |                  |      | time to and |
|       |                     |                  |      | duration of |
|       |                     |                  |      | response,   |
|       |                     |                  |      | TTP,        |
|       |                     |                  |      | survival    |
+-------+---------------------+------------------+------+-------------+
| 30-47 | Phase II,           | 50, every 4      | 122  | Response    |
|       | noncomparative,     | weeks for 6      |      | rates, time |
|       | multicenter study   | cycles           |      | to and      |
|       | of DOXIL/Caelyx for |                  |      | duration of |
|       | advanced epithelial |                  |      | response,   |
|       | ovarian carcinoma   |                  |      | TTP,        |
|       |                     |                  |      | survival    |
+-------+---------------------+------------------+------+-------------+
| 3     | Phase II,           | 50, every 4      | 62   | Response    |
| 0-47E | noncomparative,     | weeks for 6      |      | rates,      |
|       | multicenter study   | cycles           |      |             |
|       | of DOXIL/ Caelyx    |                  |      | time to and |
|       | for advanced        |                  |      | duration of |
|       | epithelial ovarian  |                  |      | response,   |
|       | carcinoma (European |                  |      | TTP,        |
|       | study sites)        |                  |      | survival    |
+-------+---------------------+------------------+------+-------------+
| 30-49 | Phase III,          | 50, every 4      | 474  | TTP,        |
|       | randomized,         | weeks vs.        |      | response    |
|       | open-label, DOXIL/  | topotecan 1.5    |      | rates, time |
|       | Caelyx versus       | mg/m^2^/day x 5  |      | to and      |
|       | topotecan HCl for   | days, every      |      | duration of |
|       | epithelial ovarian  | 3 weeks          |      | response,   |
|       | carcinoma after     |                  |      | QOL,        |
|       | failure of          |                  |      | survival    |
|       | first-line,         |                  |      |             |
|       | platinum-based      |                  |      |             |
|       | chemotherapy        |                  |      |             |
+-------+---------------------+------------------+------+-------------+
| 30-57 | Phase III, open,    | 50, every 4      | 214  | TTP,        |
|       | DOXIL/ Caelyx vs.   | weeks; Taxol^®^  |      | response    |
|       | Taxol^®^ for        | 175, every 3     |      | rates, time |
|       | epithelial ovarian  | weeks            |      | to and      |
|       | carcinoma           |                  |      | duration of |
|       |                     |                  |      | response,   |
|       |                     |                  |      | QOL,        |
|       |                     |                  |      | survival    |
+-------+---------------------+------------------+------+-------------+
| *\*   |                     |                  |      |             |
| C     |                     |                  |      |             |
| AELYX |                     |                  |      |             |
| is a  |                     |                  |      |             |
| regis |                     |                  |      |             |
| tered |                     |                  |      |             |
| trade |                     |                  |      |             |
| name  |                     |                  |      |             |
| for*  |                     |                  |      |             |
| *d    |                     |                  |      |             |
| oxoru |                     |                  |      |             |
| bicin |                     |                  |      |             |
| HCl   |                     |                  |      |             |
| lip   |                     |                  |      |             |
| osome |                     |                  |      |             |
| injec |                     |                  |      |             |
| tion* |                     |                  |      |             |
| *in   |                     |                  |      |             |
| ce    |                     |                  |      |             |
| rtain |                     |                  |      |             |
| coun  |                     |                  |      |             |
| tries |                     |                  |      |             |
| ou    |                     |                  |      |             |
| tside |                     |                  |      |             |
| the   |                     |                  |      |             |
| US    |                     |                  |      |             |
| but   |                     |                  |      |             |
| is    |                     |                  |      |             |
| ma    |                     |                  |      |             |
| nufac |                     |                  |      |             |
| tured |                     |                  |      |             |
| at    |                     |                  |      |             |
| the   |                     |                  |      |             |
| same  |                     |                  |      |             |
| fac   |                     |                  |      |             |
| ility |                     |                  |      |             |
| as    |                     |                  |      |             |
| DO    |                     |                  |      |             |
| XIL.* |                     |                  |      |             |
+-------+---------------------+------------------+------+-------------+

**Study 30-22**: In this Phase II clinical trial, DOXIL 50 mg/m^2^ was
administered at 3-week intervals to 35 patients with ovarian cancer that
had relapsed after prior treatment with either platinum- or
paclitaxel-based regimens. Objective responses were observed in 9
patients (26%), 7 of which were confirmed by tumor measurements on 2
consecutive computed tomography assessments at least 4 weeks apart. The
dose-limiting toxicity, PPE, was successfully managed by increasing the
dosing interval from 3 to 4 weeks.^13^

**Study 30-47:** The end-of-planned-treatment analysis for this Phase II
study included 122 patients with locally advanced or metastatic
epithelial ovarian carcinoma following failure of at least 2, but not
more than 3, prior cytotoxic chemotherapy regimens. In this study, DOXIL
50 mg/m^2^ was administered at 4-week intervals for 6 cycles or until
disease progression or dose-limiting toxicity occurred. Fifty of the 122
patients were refractory to platinum and paclitaxel (double refractory)
and 67 were refractory to platinum, paclitaxel and topotecan (triple
refractory). One patient was not treated with DOXIL. Objective responses
were reported in 16 patients (1 complete response \[CR\] and 15 partial
responses \[PR\]).

The median time to response was 106 days (15.1 weeks), with a range of
23 to 230 days (3.3 to 32.9 weeks); the median duration of response was
285 days (40.7 weeks), with a range of 45+ to 338 days (6.4+ to 48.3
weeks). The median time to disease progression was 142 days
(20.3 weeks), with a range of 5 to 528+ days (0.7 to 75.4
weeks).^13,\ 14^

**Study 30-47E:** Sixty-two patients with locally advanced or metastatic
epithelial ovarian carcinoma refractory to platinum- and taxane-based
chemotherapy were enrolled in this international Phase II study. DOXIL
50 mg/m^2^ was administered at 4-week intervals for 6 cycles or until
disease progression or dose-limiting toxicity. Thirty-two of the 62
patients were double refractory and 11 were triple refractory. Partial
responses were reported in 4 (6.5%) of the 62 patients. At the time of
study termination, of the remaining 58 patients 5 (8.6%) had unconfirmed
partial responses, 16 (27.6%) had stable disease (SD), 22 (37.9%) had
disease progression, and response data was not available for the
remaining 15 (25.9%) individuals.

The median time to response was 57 days (8.1 weeks), with a range of 53
to 120 days (7.6 to 17.1 weeks); the median duration of response was
124 days (17.7 weeks), with a range of 114+ to 280 days (16.3+ to
40.0 weeks). Median time to disease progression was 81 days
(11.6 weeks), with a range of 1+ day to 399 days (0.1 to 57.0+ weeks).

**Study 30-49:** This Phase III randomized multicenter and multinational
study compared the efficacy and safety of DOXIL and topotecan in 474
patients with ovarian cancer that recurred after or didn't respond to
first-line, platinum-based chemotherapy. Details of this study are
outlined in Section 5.1. Comparable efficacy (overall progression-free
survival, overall response, and median overall survival) was reported
for the two drugs.^15^ Analysis of the platinum-sensitive subset
observed a statistically significant benefit in progression-free
survival for the DOXIL-treated patients (median 28.9 weeks) compared to
those treated with topotecan (median 23.9 weeks), (P = .037). At the
time of publication of the manuscript, overall survival was superior for
the DOXIL-treated patients (median 108 weeks) compared to the
topotecan-treated individuals (median 71.1 weeks) (P = .008).^15^

**Study 30-57:** This Phase III randomized comparative open-label
multicenter study compared DOXIL (50 mg/m^2^ every 4-weeks) and
paclitaxel (175 mg/m^2^ q 3 weeks) in 214 patients with taxane-naive
relapsed ovarian cancer following previous treatment with a
platinum-containing regimen. Comparable efficacy was reported for DOXIL
and paclitaxel-treated patients, with similar overall progression-free
survival rates (DOXIL=21.7 weeks compared to paclitaxel=22.4 weeks); the
overall incidence of response was 17.8% for DOXIL-treated patients
compared to 22.4% for paclitaxel-treated individuals; and median overall
survival was 45.7 weeks for DOXIL-treated patients compared to 56.1
weeks for the paclitaxel-treated patients. ^16^

## Regulatory History of DOXIL in Ovarian cancer Indication

On 28 June 1999, DOXIL was granted accelerated approval under the
accelerated approval regulations, 21 CFR Subpart H, for the treatment of
metastatic carcinoma of the ovary in patients with disease that is
refractory to both paclitaxel- and platinum-based chemotherapy regimens.
Refractory disease is defined as disease that has progressed while on
treatment, or within 6 months of completing treatment. The approval was
based on a supplemental New Drug Application submission that also
contained preliminary data from the ongoing Sequus/ALZA Study 30-49, "A
Phase III Randomized, Open-Label, Comparative Study of DOXIL/CAELYX
versus Topotecan HCl in Patients with Epithelial Ovarian Carcinoma
Following Failure of First-Line, Platinum-Based Chemotherapy."

As part of this accelerated approval, the Sponsor and the FDA agreed
that the Sponsor would provide or perform the following:

1.  Complete Sequus/ALZA Study 30-49.

2.  Following review and discussion of the 30-49 data, if the results
    demonstrated convincing superiority of DOXIL over topotecan HCl in
    either time to progression (TTP) or survival, with a supporting
    trend demonstrated for the other endpoints, this study would likely
    fulfill the Phase IV requirement for demonstration of clinical
    benefit. In this case, it was agreed to submit a supplemental NDA
    within 6 months after discussing the topline results from this
    analysis with FDA.

3.  If the results of study 30-49 do not demonstrate the clinical
    benefit of DOXIL, it was agreed that a protocol would be submitted
    for a study designed to demonstrate the clinical benefit of DOXIL in
    patients with ovarian cancer as well as a proposed timetable for
    completion and submission of the study.

The preliminary results from the first of two planned analyses of Study
30-49 were submitted to the FDA on 13 July 1999. The first analysis,
performed after 241 patients had been enrolled in the study, did not
reveal a statistically significant difference in overall survival and
TTP. The Sponsor agreed to conduct a second analysis (end of planned
treatment) as per the protocol by 31 March 2000. This end of planned
treatment analysis was based on the results from all patients enrolled
as of 3 March 1999 and a database cut-off date of 3 September 1999. On
21 April 2000, the Sponsor submitted a summary of the 30-49 data (end of
treatment analysis), which was provided to the FDA for a 29 June 2000
meeting. While there was no overall difference in TTP, there was a
statistically significant trend in survival favoring DOXIL in the
platinum-sensitive group. It was agreed with the FDA that the Sponsor
would continue follow-up of patients from the 30-49 study and perform
one additional survival analysis. Based upon the FDA's guidance during
the 29 June 2000 meeting, the Sponsor amended the protocol (amendment
#3) to include this additional survival analysis.

Pending final survival data for study 30-49, it was agreed with the FDA
to implement a second commitment study to fulfill the accelerated
approval obligation. The FDA indicated that the new study must
demonstrate superiority in the primary endpoint of survival. Protocol
SO200/OBI No. DO01-20-0003 "A Phase III Randomized Study of Pegylated
Liposomal Doxorubicin Plus Carboplatin Versus Carboplatin in
Platinum-Sensitive Patients with Recurrent Epithelial Ovarian or
Peritoneal Carcinoma After Failure of Initial Platinum-Based
Chemotherapy" was developed with the Southwest Oncology Group (SWOG). On
19 June 2002, the SWOG submitted an Investigational New Drug (IND)
application, with cross-reference to the JJPRD IND, to support the
conduct of protocol SO200 / OBI No. DO01-20‑003. On 30 July 2002, the
SWOG IND was in effect. The first patient was enrolled in this study on
30 September 2002.

## Description of Commitment Studies

### Sequus / ALZA Study 30-49

Study 30-49, "A Phase III Randomized, Open-Label, Comparative Study of
DOXIL/CAELYX versus Topotecan HCl in Patients with Epithelial Ovarian
Carcinoma Following Failure of First-Line, Platinum-Based Chemotherapy"

#### Essentials of Study Design

This Phase III, randomized, multicenter, open-label study compared DOXIL
with topotecan in the treatment of women with histologically proven
recurrent epithelial ovarian carcinoma. Up to 460 protocol-eligible
patients (in order to obtain 370 evaluable patients) with epithelial
ovarian carcinoma following failure of first-line, platinum-based
chemotherapy were to be enrolled in this clinical trial.

Patients entering the trial were stratified prospectively for
platinum-sensitivity and bulky disease. Protocol-eligible patients, with
measurable or measurable and evaluable disease, who had been treated
with no more than one prior platinum-based regimen, were randomized to
treatment with either a one-hour intravenous infusion of DOXIL 50
mg/m^2^ every 4 weeks, or topotecan, 1.5 mg/m^2^/day as a 30 minute
infusion for 5 consecutive days every 3 weeks. Patients were to be
treated for up to one year, and patients with ongoing clinical benefit
could continue study drug upon approval by the Sponsor.

##### Summary of Study Sites

The study was conducted in 104 study centers in the United States and
Europe (47 US and 57 Europe)

##### Patient Population (Eligibility / Exclusion Criteria)

Patients were to satisfy the following key criteria before entering the
study:

-   Histologically proven epithelial ovarian carcinoma. Each patient was
    staged at diagnosis according to FIGO Classification.

-   Measurable disease or measurable and evaluable disease.

-   Recurrence of disease or disease progression indicating failure of
    first-line, platinum-based chemotherapy.

-   Karnofsky performance status (KPS) 60%.

##### Endpoints

[Primary efficacy endpoint]{.underline}

The primary efficacy analysis was comparison of time to progression
between the two treatment regimens.

[Secondary efficacy endpoint]{.underline}

The secondary efficacy analyses included response rates, time to
response, duration of response, health-related quality of life, and
survival.

##### Treatment Schema

Patients were randomized to treatment with either DOXIL (50 mg/m^2^
IV infusion over 1 hour every 28 days) or Topotecan (1.5 mg/m^2^ IV
infusion over 30 minutes daily, Days 1-5, 21-day cycle).

##### Efficacy and Safety Monitoring

Individual sites were monitored at appropriate intervals to assure a
satisfactory rate of enrollment, recording of data, and adherence to the
protocol. The frequency of monitoring varied depending on enrollment
rate and the quality of data collected.

Two planned analyses and a final analysis were specified in the protocol
or its amendments. The initial two analyses were to be conducted to
evaluate time to progression after 200 and 280 of the evaluable patients
were enrolled and all such patients had either experienced disease
progression or had been on study for at least 6 months. Enrollment was
not discontinued while the analyses were being conducted.

##### Statistical Design

It was estimated that enrollment of up to 460 patients would be required
in order to obtain 370 evaluable patients. Patients entering the trial
were stratified prospectively for platinum-sensitivity and bulky
disease.

The primary efficacy analysis was comparison of time to progression
between the two treatment regimens. The FDA and the Sponsor agreed on 29
June 2000 that the final analysis should focus on survival and the
protocol was amended (amendment #3) accordingly. Prior to amendment #3,
all patients had been enrolled in the study. The FDA requested that this
analysis be performed not at a pre-specified time point, but when a
predefined percentage of study subjects had expired or were lost to
follow-up. The Sponsor determined that this analysis would be performed
when 90% of study subjects reached this endpoint as specified in
amendment #3. This final analysis for survival is currently ongoing.

Secondary efficacy analyses included response rates, time to response,
duration of response, health-related quality of life, and survival.
Statistical analyses were performed on the secondary efficacy parameters
for the intent-to-treat (ITT) and the evaluable patient populations.

All statistical tests in these analyses were 2-sided for all variables
except the time to progression variable. For all variables, an overall
5% level of significance was used for treatment difference, and 10%
level for interaction, with adjustments for the two planned analyses.

The ITT Patient Population was defined as all patients who were
randomized and received at least a partial dose of study drug.

The evaluable patient population was defined as all patients who were
randomized, met the enrollment criteria, and received at least two
cycles of study drug.

#### Date of Initiation

Study 30-49 was initiated May 1997.

#### Accrual

Enrollment of 481 patients was reached on 3 March 1999. Of the
481 enrolled patients, 474 patients were treated (239 were randomized to
treatment with DOXIL and 235 were randomized to treatment with
topotecan).

#### Estimated Timeline for Study Completion

The Sponsor submitted Amendment #3 to the IND and indicated that the
Sponsor would conduct an additional set of survival and progression-free
survival analyses when 90% of the 474 patients had either expired or
were lost to follow-up. These analyses were to assess whether the
survival advantage in the platinum-sensitive group was sustained and to
examine the overall survival differences between the two treatment arms.
As of December 2002, more than 90% of patients had either expired or
were lost to follow-up.

#### Estimated Timeline for Submission of Study Results

As noted above, the target number of events was reached in December
2002, and it is expected that results of the final set of survival and
progression free survival analyses will be available 1Q 03. The sNDA may
be submitted 6 months after the survival endpoint is met but will be
dependant on the study results and further discussions with the FDA.

### SWOG Study SO200 (OBI Study No.: DO01-20-003)

Study SO200 / OBI No. DO01-20-003, "A Phase III Randomized Study of
Pegylated Liposomal Doxorubicin Plus Carboplatin Versus Carboplatin in
Platinum-Sensitive Patients with Recurrent Epithelial Ovarian or
Peritoneal Carcinoma After Failure of Initial Platinum-Base
Chemotherapy"

#### Essentials of Study Design

This Phase III, randomized, multicenter, open-label study compares the
combination of DOXIL and carboplatin with single agent carboplatin in
patients with platinum-sensitive recurrent epithelial ovarian or
peritoneal carcinoma.

##### Summary of Study Sites

The study is being conducted as an intergroup study with participation
from the following Cooperative Groups or organizations, including:

> Southwestern Oncology Group (SWOG)
>
> Gynecologic Oncology Group (GOG)
>
> Cancer and Leukemia Group B (CALGB)
>
> Eastern Cooperative Oncology Group (ECOG)
>
> North Central Cancer Treatment Group (NCCTG)
>
> NCI / Cancer Trials Support Unit (CTSU)

##### Patient Population (Eligibility / Exclusion Criteria)

Patients must satisfy the following key criteria before entering the
study:

-   Histologically diagnosed disease consistent with epithelial ovarian
    carcinoma. Primary peritoneal and mixed mullerian tumors are
    allowed. Borderline ovarian tumors are not allowed.

-   Patient must have undergone initial staging laparotomy and must have
    been surgically staged as FIGO Stage III (A, B, or C) or IV at that
    time.

-   Patient must have recurrence or disease progression with a
    progression-free and platinum-free interval of 6-24 months after
    completion of first-line platinum-based chemotherapy (either single
    agent or combination therapy). Recurrent/progressive disease based
    solely on CA-125 elevation is allowed, provided it meets the CA-125
    progression definition.

##### Endpoints

[Primary efficacy endpoint]{.underline}

The primary efficacy endpoint will be a comparison of overall survival
between the two treatment groups.

[Secondary efficacy endpoint]{.underline}

The secondary efficacy endpoint will be progression-free survival and
the incidence of confirmed complete response.

[Tertiary efficacy endpoint]{.underline}

The tertiary efficacy endpoint will be time to treatment failure.

##### Treatment Schema

Patients will be randomized to treatment with either the combination of
carboplatin and DOXIL or single agent carboplatin until disease
progression or systematic deterioration, unacceptable toxicity or delay
in dose of more than 4 weeks. The maximum cumulative dose of DOXIL on
this protocol is limited to 600mg/m^2^.

The treatment arms are as follows:

[ARM 1 (carboplatin and DOXIL)]{.underline}

Carboplatin is to be dosed at AUC = 5 mg/mL IV d 1 every 4 weeks
administered over a minimum of 15 minutes prior to infusion of pegylated
liposomal doxorubicin, followed by administration of pegylated liposomal
doxorubicin at a dose of 30 mg/m^2^ IV d 1 every 4 weeks administered
over 1 hour.

[ARM 2 (Single agent carboplatin)]{.underline}

Carboplatin is to be dosed at AUC = 5 mg/mL IV d 1 every 4 weeks.

##### Efficacy and Safety Monitoring

The study will be conducted under the supervision of SWOG's Data and
Safety Monitoring Committee (DSMC). The DSMC will monitor all endpoint
data. Toxicity and study summary data will be reported every six months
to the SWOG DSMC.

1.  An interim analysis will be conducted when one third (125) of the
    374 anticipated deaths have been observed on the carboplatin-only
    arm. The second interim analysis will be performed when
    approximately two thirds (250) of the anticipated deaths have been
    observed on the control arm.

2.  The Quality Assurance Departments from each Cooperative Group or
    participating organization will perform audits of their groups' data
    per NCI and GCP guidelines

##### Statistical Design

Patients will be randomized equally to the two treatment arms while
stratified by disease measurability, number of disease sites and serous
histology.

Overall survival (OS) will be analyzed primarily by the stratified log
rank test with stratification factors. Progression Free Survival (PFS)
will be analyzed by the stratified logrank test in the same manner as
for the overall survival. The complete response rates between the two
treatment arms will be compared by the Fisher's exact test. To ensure an
overall one-sided 0.025 significance level for these two secondary
measures, the Holm simultaneous testing procedure will be used.

The other comparison will then be regarded as statistically significant
if the corresponding one-sided P value is \<0.025. Time to treatment
failure (TTF) will be a tertiary endpoint.

According to the intent-to-treat principle, all eligible patients will
be included in the analyses for OS, PFS, TTF, and complete response rate
according to the randomized treatment assignment regardless of the
actual treatments received.

#### Date of Initiation

SWOG activated the study on 15 August 2002. The first IRB approval was
obtained in September 2002.

#### Accrual

The first patient was enrolled on 30 September 2002.

#### Estimated Timeline for Study Completion

Nine hundred eligible patients are targeted for accrual over a period of
four and a half years at an accrual rate of 200 patients per year.
Patients will be followed for an additional two years until 374 deaths
have occurred in the carboplatin single agent arm. This study is
estimated to complete accrual in early 2007.

## Difficulties Encountered in Conduct, Accrual, or Completion of Trials

As DOXIL is approved for use in the treatment of patients with ovarian
cancer, it is challenging to expeditiously conduct clinical trials in
this patient population since patients can receive commercially
available drug outside of the clinical trial setting. In addition, as of
Jan 2003 the NCI PDQ lists 45 studies competing for patients in this
limited patient population.

SWOG study SO200 was first proposed to the FDA as a second commitment
study on 27 July 2000. Due to the intricacies of working within the
cooperative group and NCI/CTSU structure, coupled with the transfer of
clinical responsibilities for DOXIL from ALZA Corporation to Ortho
Biotech Products, L.P., there was an unavoidable delay in finalizing the
protocol between the SWOG, NCI, FDA and Ortho Biotech.

## References

1.  Averette HE, Janicek MF, Menck HR. The National Cancer Data Base
    report on ovarian cancer. American College of Surgeons Commission on
    Cancer and the American Cancer Society. Cancer. 76(6):1096-1103,
    1995.

2.  Greenberg P, et al. Breast Cancer and Gynecologic Malignancies in
    Pazdur R (ed): [Medical Oncology, A Comprehensive
    Review]{.underline}, New York, PRR, Inc., 1993.

3.  Sharpless NE, Seiden MV: Advanced ovarian cancer: Recent progress
    and current challenges. Contemp Ob/Gyn 43:123-137, 1998

4.  Richardson GS, Scully RE, Nikrui N, Nelson JH Jr. Common epithelial
    cancer of the ovary (first of two parts). N Engl J Med, 312:474-483,
    1985

5.  Ten Bokkel Huinink W, et al. Studies with carboplatin in ovarian
    cancer: Experiences of the Netherlands Cancer Institute and GCCG of
    the European Organization for Research and Treatment of Cancer, in
    Bunn PA, Canetta R, Ozols, RFD et al (eds): Carboplatin (JM-8):
    Current Perspectives and Future Directions, Philadelphia, WB
    Saunderse, 165-173, 1990.

6.  McGuire WP, Hoskins WJ, Brady MF, et al. Cyclophosphamide and
    cisplastin versus paclitaxel and cisplastin: a phase III randomized
    trial in patients with suboptimal stage III/IV ovarian cancer (from
    the Gynecologic Oncology Group). Semin Oncol. 23(5 Suppl 12):40-7,
    1996.

7.  Kalil N, McGuire W. Chemotherapy for advanced epithelial ovarian
    carcinoma. *Best Pract Res Clin Obstet Gynaecol*;16(4):553-571,
    2002.

8.  McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS,
    Armstrong DK, Donehower RC. Taxol: a unique antineoplastic agent
    with significant activity in advanced ovarian epithelial neoplasms.
    Ann Intern Med, 111:273-9, 1989.

9.  Christian MC and Trimble EL. Salvage Chemotherapy for Epithelial
    Ovarian Carcinoma in [Gynecologic Oncology]{.underline},
    55:S143-S150, 1994..

10. Omura GA, Bundy BN, Berek JS, Curry S, Delgado G, Mortel R.
    Randomized trial of cyclophosphamide plus cisplatin with or without
    doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group
    study. J Clin Oncol. 7:457-465, 1989.

11. A'Hern RP, Gore ME. Impact of doxorubicin on survival in advanced
    ovarian cancer. J Clin Oncol, 13:726-32, 1995.

12. Drug Facts and Comparisons, Cada DJ (editor), St. Louis, MO, updated
    August 2002.

13. Muggia FM, Hainsworth JD, Jeffers S, et al. Phase II study of
    liposomal doxorubicin in refractory ovarian cancer: Antitumor
    activity and toxicity modification by liposomal encapsulation*. J
    Clin Oncol.* 1997;15:987-993.

    14: Gordon AN, Granai CO, Rose PG, et al, Phase II Study of
    Liposomal Doxorubicin in Platinum- and Paclitaxel-Refractory
    Epithelial Ovarian Cancer, J Clin Oncol 18:3093-3100, 2000

    15\. Gordon AN, Fleagle JT, Guthrie D et al: Recurrent Epithelial
    Ovarian Carcinoma: A Randomized Phase III Study of Pegylated
    Liposomal Doxorubicin versus Topotecan, J Clin Oncol 19:3312-3322,
    2001

14. 

15. 

16. 

17. 

18. 

19. 

20. 

21. 

22. 

23. 16\. KJ O'Byrne, P Bliss, JD Graham et al: A Phase III study of
    Doxil/Caelyx versus paclitaxel in platinum-treated, taxane-naïve
    relapsed ovarian cancer Proceedings of ASCO Vol 21, abstract 808,
    page 203a