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

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

**Background Information**

**Regarding Accelerated Approval of DOXIL® in Kaposi's Sarcoma**

# 

**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**

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

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

# TABLE OF CONTENTS {#table-of-contents .TOC-1 .unnumbered}

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

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

## [1. Summary 1](#__RefHeading___Toc32293581) {#summary-1 .TOC-2 .unnumbered}

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

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

### [3.1. Overview of AIDS-Kaposi's Sarcoma 2](#overview-of-aids-kaposis-sarcoma) {#overview-of-aids-kaposis-sarcoma-2 .TOC-3 .unnumbered}

### [3.2. History of DOXIL Clinical Development In AIDS-KS 6](#history-of-doxil-clinical-development-in-aids-ks) {#history-of-doxil-clinical-development-in-aids-ks-6 .TOC-3 .unnumbered}

## [4. Regulatory History of DOXIL in Kaposi's Sarcoma Indication 22](#__RefHeading___Toc32293586) {#regulatory-history-of-doxil-in-kaposis-sarcoma-indication-22 .TOC-2 .unnumbered}

## [5. Description of Commitment Studies 23](#description-of-commitment-studies) {#description-of-commitment-studies-23 .TOC-2 .unnumbered}

### [5.1. Original Commitment Study: Sequus/Alza Study 30-38 23](#original-commitment-study-sequusalza-study-30-38) {#original-commitment-study-sequusalza-study-30-38-23 .TOC-3 .unnumbered}

### [5.2. Proposed New Commitment Study 25](#proposed-new-commitment-study) {#proposed-new-commitment-study-25 .TOC-3 .unnumbered}

## [6. Difficulties Encountered in Conduct, Accrual or Completion of Trials 26](#__RefHeading___Toc32293590) {#difficulties-encountered-in-conduct-accrual-or-completion-of-trials-26 .TOC-2 .unnumbered}

### [6.1. Study 30-38 26](#study-30-38-1) {#study-30-38-26 .TOC-3 .unnumbered}

### [6.2. Proposed New Phase IV Commitment Trial 26](#proposed-new-phase-iv-commitment-trial) {#proposed-new-phase-iv-commitment-trial-26 .TOC-3 .unnumbered}

## [7. References 27](#references) {#references-27 .TOC-2 .unnumbered}

**Background Information Regarding Accelerated Approval of DOXIL^®^ in
Kaposi's Sarcoma**

# 

# Phase IV commitments

## Summary

DOXIL (doxorubicin HCl liposome injection) received accelerated approval
on 17 November 1995 for the treatment of chemotherapy refractory
AIDS-related Kaposi's sarcoma (AIDS-KS). This approval was based on
objective tumor response rates from an interim analysis of an
open-label, single-arm, multicenter study. The original phase IV
commitment trial (study 30-38) entitled "A Double-Blind, Randomized
Evaluation of Clinical Benefits of DOXIL in Patients with AIDS-Related
Kaposi's Sarcoma Treated with DOXIL or DaunoXome^®"^ was designed in
close collaboration with the FDA. On 31 July 2002, the FDA communicated
to the Sponsor that the introduction of highly active antiretroviral
therapy for the treatment of HIV infection during the conduct of the
trial made it difficult for the FDA to interpret the clinical benefit of
DOXIL. This resulted in the non-approval of the supplemental New Drug
Application. Discussions are underway between the Sponsor and the FDA to
design another phase IV commitment study that will allow for the
conversion from accelerated approval to full approval for this
indication.

To date, it is estimated that more than 7000 patients with AIDS-KS in
the United States have received treatment with this drug product
(doxorubicin HCl liposome injection). DOXIL is considered the standard
of care for US patients with AIDS-KS for whom systemic chemotherapy is
indicated. More than 20 manuscripts have been published regarding the
use of doxorubicin HCl liposome injection (DOXIL^®^) in the treatment of
patients with AIDS-KS.

## General Information

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

**Indication:** DOXIL is indicated for the treatment of AIDS-related
Kaposi's sarcoma in patients with disease that has progressed on prior
combination chemotherapy or in patients who are intolerant to such
therapy.

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:** 17 November 1995

## Introduction

### Overview of AIDS-Kaposi's Sarcoma

Kaposi's sarcoma (KS) is an acquired immunodeficiency syndrome
(AIDS)-defining illness and despite its declining incidence since the
introduction of highly active antiretroviral therapy (HAART), KS remains
one of the most common neoplasms reported in patients with AIDS. It is
associated with significant morbidity and mortality, especially in
patients with systemic disease.^1^

KS produces a wide spectrum of clinical manifestations, ranging from
asymptomatic cutaneous papules to extensive skin disease with ulcerative
plaques and associated edema. Extracutaneous spread of KS is common,
especially in the oral cavity, most commonly affecting the palate and
gingival areas that are easily traumatized during mastication, with
subsequent pain, ulceration, bleeding and secondary infection. Nutrition
and speech may be affected, impacting the patient's overall quality of
life. Gastrointestinal involvement has been noted in approximately 40%
of patients at initial diagnosis of AIDS-KS and in up to 80% of patients
with AIDS at autopsy. KS gastrointestinal lesions may be associated with
weight loss, abdominal pain, nausea and vomiting, gastrointestinal
bleeding, and diarrhea. Pulmonary involvement is also common, and may
present with shortness of breath, fever, cough, hemoptysis, or chest
pain, or it may be an asymptomatic finding on a chest X-ray. KS visceral
lesions may be present in patients who have no cutaneous manifestations.
Palliation of symptoms is a major goal of KS treatment.^2^

The incidence of AIDS-KS in the United States has declined since its
peak in the late 1980's to approximately 0.7 cases per 100,000
population in 1999.^3,4^ This decline was evident before the
introduction of HAART. The frequency of KS as a presenting AIDS illness
among the Multicenter AIDS Cohort Study (MACS) has declined from 25.6
cases per 100 patient-years in the early 1990's to 7.5 cases per
100 patient-years in 1996-1997.^5^ The CDC reported a decline in KS
incidence by 8.8% per year from 1990 through 1998. Nonetheless, new
cases of KS continue to present, even among patients with viral load
suppression resulting from treatment with antiretroviral therapy.^6,7^
Despite the low incidence of KS, considerable morbidity and mortality
still exist in patients with AIDS who develop KS.

Management and treatment options for AIDS-KS depend on the extent of the
disease, the rate of progression, the presence and severity of symptoms
affecting daily activities and quality of life, and the presence of
opportunistic infections. The choice of treatment may also be influenced
by the severity of the underlying HIV infection, immune system status
and by the presence of other co-morbid complications.^2^ Some patients
with AIDS-KS have experienced lesion regression after initiation of
triple-drug antiretroviral therapy. Optimal antiretroviral therapy may
inhibit development or progression of KS in several ways, including
treatment of the underlying immunosuppression.

AIDS-KS treatment can be broadly classified into local or systemic
therapy.

Local therapy directed at control of individual lesions is appropriate
for limited, relatively slowly progressive disease without
life-threatening organ involvement. Local approaches are most
appropriate for individuals with few numbers of small lesions.
Individuals with oral lesions or limited cutaneous disease, e.g. 25 or
fewer small skin lesions that are cosmetically disturbing to the
patient, may benefit from local therapy. Treatment modalities include
surgical excision of the lesions, cryotherapy, photodynamic therapy,
intralesional injections, laser therapy, local radiation therapy, and
topical application of various drugs such as topical retinoids. Because
local treatment does not result in a cure, the most important goals are
to improve the patient's appearance and reduce the suffering and social
isolation AIDS-KS can cause.^2,8,9,10^

Systemic chemotherapy is medically indicated for individuals with
advanced or rapidly progressive AIDS-KS that causes medical or
functional impairment.^10^ This group includes patients with extensive
or symptomatic cutaneous disease, extensive oral disease, symptomatic
tumor-associated edema, or compromised visceral function by pulmonary or
gastrointestinal AIDS-KS. The goals of systemic chemotherapy are to
induce durable regression of widespread, disfiguring, or disabling
lesions, control or reverse life-threatening visceral disease, reduce
functional impairment caused by edema or mucocutaneous disease, and to
achieve these benefits with agents that have an acceptable side effect
profile. Response rates of 10% to 48% have been reported with single
agent cytotoxic agents including doxorubicin, bleomycin, and
vincristine, with higher response rates (56% to 88%) when used in
combination.^10^ (Three cytotoxic drugs have been approved by the FDA
for the treatment of HIV-associated KS. DOXIL received accelerated
approval on 17 November 1995 based on the results of an interim analysis
of a phase II open-label, single-arm, multicenter study (n=77).
DaunoXome (daunorubicin liposomal) received full approval on 8 April
1996 based on the results of a multicenter open-label, randomized,
controlled clinical study (n=227). TAXOL (paclitaxel) received full
approval on 04 August 1997 based on two phase II open-label, single-arm,
non-randomized studies (n=85). Although a wide variety of single and
combination drug regimens are available for treatment of AIDS-KS,
treatment with one of the FDA-approved liposomal anthracyclines is the
current standard of care for first-line therapy of AIDS-KS. ^2,^ ^8,\ 9^

Before the approval of DOXIL for this patient population, combination
cytotoxic chemotherapy with bleomycin and vincristine (BV) or
doxorubicin (Adriamycin), bleomycin and vincristine (ABV) was considered
to be the most effective chemotherapy for AIDS-KS, with reported
response rates of 60 to 80%, but with appreciable toxicity. The initial
clinical studies of ABV in AIDS-KS generally administered doxorubicin at
doses of either 40 mg/m^2^ every 4 weeks or 20 mg/m^2^ every 2 to
3 weeks, with reports of impressive response rates of 84% and 88%,
respectively. However, therapy was frequently limited by neutropenia and
concomitant non-KS opportunistic infections. In addition to
dose-limiting myelosuppression, administration of effective therapeutic
doses for extended periods of time was often limited by cardiac,
pulmonary, and neurologic toxicities.^2,8,9^ While many patients
benefited from such agents and regimens, it was not infrequent for
patients to die with severe, progressive AIDS-KS in spite of optimal
therapy.

DOXIL, a pegylated liposomal formulation of doxorubicin, was developed
to circumvent the short *in vivo* half-life of standard doxorubicin and
has been investigated extensively in patients with AIDS-KS (see Table
1). The pegylated liposomes contain segments of polyethylene glycol
attached to the surface, thus delaying uptake by the monocyte macrophage
system and thereby increasing plasma residence time. 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).^11^ Such prolonged
plasma residence time may allow for greater exposure of the tumor to
drug. In a study conducted to assess pharmacokinetics and tissue
distribution of DOXIL after intravenous administration, biopsies of KS
lesions and normal skin were obtained from 11 patients at 48 and 96
hours following infusion of DOXIL at a dose of 20 mg/m^2^. The
doxorubicin concentration was 3- to 53-times (median 19) higher in the
AIDS-KS lesions than in normal skin at 48 hours after the infusion.^12^

> Superiority of single agent DOXIL has been reported in several studies
> comparing DOXIL monotherapy (20 mg/m^2^ every 2 weeks) with
> combination chemotherapy regimens such as BV and ABV.^2,10^

DOXIL is generally well tolerated compared to other cytotoxic
chemotherapy, with myelosuppression as the most common dose-limiting
adverse event in patients with AIDS-KS. While neutropenia occurs most
often, anemia and thrombocytopenia occur less frequently, as do nausea
and vomiting and stomatitis. Palmar-plantar erythrodysesthesia may occur
in some patients, most commonly after 6 to 8 weeks of chemotherapy.
Although symptoms may occasionally be severe, adverse events rarely
necessitate discontinuation of therapy. Primarily because of a superior
safety profile and concomitant improvement in quality of life, single
agent DOXIL has largely replaced combination regimens (ABV and BV) as
the first-line systemic treatments of choice. In the period between
September 2001 and August 2002, 61% of patients with AIDS-KS were
treated with DOXIL monotherapy as their initial treatment. In that same
time period, no other cytotoxic chemotherapy drug was used in more than
7% of this patient population.^13^

DaunoXome is a liposomal formulation of daunorubicin that has also
demonstrated activity in AIDS-KS and was approved in 1996. In the
pivotal trial, DaunoXome treatment resulted in an objective response
rate that was similar to the control ABV arm (25% vs. 28%).^14^ IMS
Health 2002 year- to- date data identifies only limited usage of
liposomal daunorubicin.^15^ Paclitaxel was approved in 1997 for the
treatment of chemotherapy refractory AIDS-KS. The side effect profile of
paclitaxel is well known and includes significant myelosuppression and
alopecia. Prolonged paclitaxel therapy can also cause peripheral
neuropathy. In the period between September 2001 and August 2002, 6.6%
of patients with AIDS-KS were treated with single agent paclitaxel as
their initial treatment. Paclitaxel in combination with etoposide (7.4%)
or DOXIL (5.9%) also was reported as first-line therapy in patients with
AIDS-KS.^15^

Since the introduction of HAART, few studies have been conducted to
demonstrate a therapeutic benefit of cytotoxic chemotherapy in patients
with AIDS-KS, even though the use of cytotoxic chemotherapy is the
standard of care in this patient population with presentation of KS.
Study 30-38 was a randomized trial of DOXIL vs. DaunoXome designed to
demonstrate the clinical benefits of DOXIL in patients with AIDS-KS and
was intended to convert the accelerated approval of DOXIL to full
approval. This study was conducted between September 1996 and September
2000, during the timeframe of the introduction of HAART. The
introduction of HAART confounded the ability to assess the clinical
benefit of DOXIL on AIDS-KS. The number of patients for which HAART
therapy did not confound the assessment of the clinical benefit of DOXIL
was small and did not allow for an adequate FDA assessment for
conversion of DOXIL to full approval for AIDS-KS.

Even with the low incidence of AIDS-KS, KS remains one of the most
common neoplasms reported in patients with AIDS. New cases of KS
continue to be diagnosed, even among patients with HIV viral load
suppression, and KS remains a cause of considerable morbidity and
mortality in HIV-infected individuals. Treatment remains palliative,
with treatment decisions determined on a case-by-case basis, balancing
anti-tumor efficacy and toxicity with quality of life considerations.
For patients with rapidly progressing and disseminated KS, especially
those with symptomatic visceral disease, the rapid tumor reduction
achieved with systemic chemotherapy, even in the face of a stable
regimen of HAART, can be a lifesaving intervention.

### History of DOXIL Clinical Development In AIDS-KS

DOXIL was granted accelerated approval on 17 November 1995 for the
treatment of AIDS-related Kaposi's sarcoma in patients with disease that
has progressed on prior combination therapy or in patients who are
intolerant to such therapy.

Eleven studies have been conducted that evaluate the use of DOXIL in
patients with AIDS-KS. These studies include two open-label efficacy and
safety studies (30-03, 30-12), three randomized comparative studies
(30-10, 30-11, 30-38), one study in which cardiac biopsies were obtained
(30-21), and 3 studies of long-term treatment with DOXIL (30-24, 30-25,
30-26). Additional safety data were obtained also from two
pharmacokinetic studies (30-05, 30-14).

More than 1700 patients with AIDS-KS were enrolled in 7 primary studies
(30-03, 30-05, 30-10, 30-11, 30-12, 30-14 and 30-38) and in 3 long-term
follow-up studies (30-24, 30-25 and 30-26). The majority of the patients
were male, with patient ages ranging from 21-77 years (median + 38
years).

Table 1 lists the DOXIL AIDS-KS studies that have been completed.

+-----+-----------------------+--------------+------+-----------------+
| *   |                       |              |      |                 |
| *Ta |                       |              |      |                 |
| ble |                       |              |      |                 |
| 1   |                       |              |      |                 |
| :** |                       |              |      |                 |
| DOX |                       |              |      |                 |
| IL/ |                       |              |      |                 |
| Cae |                       |              |      |                 |
| lyx |                       |              |      |                 |
| Cl  |                       |              |      |                 |
| ini |                       |              |      |                 |
| cal |                       |              |      |                 |
| Tri |                       |              |      |                 |
| als |                       |              |      |                 |
| in  |                       |              |      |                 |
| A   |                       |              |      |                 |
| IDS |                       |              |      |                 |
| -KS |                       |              |      |                 |
| Pa  |                       |              |      |                 |
| tie |                       |              |      |                 |
| nts |                       |              |      |                 |
+-----+-----------------------+--------------+------+-----------------+
| St  | Design                | Treatment,   | No.  | Study Endpoints |
| udy |                       | DOXIL Dose   | of   |                 |
| No. |                       | (mg/m2);     | pts. |                 |
|     |                       | Frequency    |      |                 |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase II/III, open,   | 10, 20, 30,  | 250  | Objective       |
| -03 | noncomparative; dose  | or 40; every |      | response, QOL,  |
|     | escalation and        | 2 weeks      |      | safety, plasma  |
|     | efficacy; multicenter |              |      | and tissue drug |
|     |                       |              |      | levels          |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase I, randomized,  | 10, 20, or   | 18   | PK, comparison  |
| -05 | single dose,          | 40; single   |      | of PK           |
|     | crossover in PK       | dose         |      | variables,      |
|     | comparison with CD    |              |      | objective       |
|     |                       |              |      | response,       |
|     |                       |              |      | tissue drug     |
|     |                       |              |      | levels, safety  |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase III,            | 20; every 2  | 258  | Compare         |
| -10 | randomized, parallel, | weeks for up |      | objective       |
|     | multicenter;          | to 6 cycles  |      | response and    |
|     | comparison to ABV     |              |      | safety          |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase III,            | 20; every 3  | 241  | Compare         |
| -11 | randomized, parallel, | weeks for up |      | objective       |
|     | multicenter;          | to 6 cycles  |      | response and    |
|     | comparison to BV      |              |      | safety          |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase III, open,      | 20; every 3  | 871  | Tolerability    |
| -12 | noncomparative,       | weeks (or 2  |      | and efficacy    |
|     | multicenter; efficacy | weeks)       |      | (objective      |
|     | in pts who failed     |              |      | response) of    |
|     | prior therapy,        |              |      | long-term DOXIL |
|     | long-term safety and  |              |      | treatment       |
|     | efficacy              |              |      |                 |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase I, randomized,  | 10 and 20;   | 43   | PK variables,   |
| -14 | crossover             | every 3      |      | efficacy        |
|     | DOXIL/Caelyx dose     | weeks for    |      | (objective      |
|     | comparison; PK and    | 1‑2 doses    |      | response), and  |
|     | tissue distribution   |              |      | of 2 dose       |
|     |                       |              |      | levels of DOXIL |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase I/II, open,     | cumulative,  | 10   | Cardiac biopsy  |
| -21 | blinded reading of    | \>400; every |      | scores compared |
|     | cardiac biopsy data;  | 3 weeks      |      | for DOXIL- and  |
|     | retrospective         | until        |      | (historical)    |
|     | comparison to CD      | cumulative   |      | doxo            |
|     |                       | dose reached |      | rubicin-treated |
|     |                       |              |      | patients        |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase III, long-term, | 20; every 3  | 94   | Tolerability of |
| -24 | multicenter (Europe); | weeks for up |      | long-term DOXIL |
|     | continuation for      | to 30 cycles |      | treatment       |
|     | patients in other     |              |      |                 |
|     | studies or patients   |              |      |                 |
|     | having failed         |              |      |                 |
|     | combination           |              |      |                 |
|     | chemotherapy          |              |      |                 |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase III, long-term, | 20; every 3  | 635  | Tolerability of |
| -25 | multicenter (US);     | weeks for up |      | long-term DOXIL |
|     | continuation for      | to 30 cycles |      | treatment       |
|     | patients in other     |              |      |                 |
|     | studies or patients   |              |      |                 |
|     | having failed         |              |      |                 |
|     | combination           |              |      |                 |
|     | chemotherapy          |              |      |                 |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Phase III, long-term  | 20; every 3  | 67   | Tolerability of |
| -26 | multicenter (Europe); | weeks for up |      | long-term DOXIL |
|     | compassionate use by  | to 30 cycles |      | treatment       |
|     | patients for whom no  |              |      |                 |
|     | other therapy is      |              |      |                 |
|     | available             |              |      |                 |
+-----+-----------------------+--------------+------+-----------------+
| 30  | Double-blind          | 20 every 2   | 79   | Clinical        |
| -38 | randomized evaluation | weeks for 6  |      | benefit,        |
|     | of DOXIL/Caelyx vs.   | cycles vs.   |      | objective tumor |
|     | DaunoXome® in         | DaunoXome®   |      | response, and   |
|     | patients whose        | 40 every 2   |      | safety          |
|     | AIDS-related KS       | weeks for 6  |      |                 |
|     | progressed on prior   | cycles       |      |                 |
|     | systemic combination  |              |      |                 |
|     | chemotherapy          |              |      |                 |
+-----+-----------------------+--------------+------+-----------------+
| NOT |                       |              |      |                 |
| ES: |                       |              |      |                 |
| A   |                       |              |      |                 |
| BV= |                       |              |      |                 |
| Ad  |                       |              |      |                 |
| ria |                       |              |      |                 |
| myc |                       |              |      |                 |
| in® |                       |              |      |                 |
| (   |                       |              |      |                 |
| con |                       |              |      |                 |
| ven |                       |              |      |                 |
| tio |                       |              |      |                 |
| nal |                       |              |      |                 |
| d   |                       |              |      |                 |
| oxo |                       |              |      |                 |
| rub |                       |              |      |                 |
| ici |                       |              |      |                 |
| n), |                       |              |      |                 |
| b   |                       |              |      |                 |
| leo |                       |              |      |                 |
| myc |                       |              |      |                 |
| in, |                       |              |      |                 |
| and |                       |              |      |                 |
| vin |                       |              |      |                 |
| cri |                       |              |      |                 |
| sti |                       |              |      |                 |
| ne; |                       |              |      |                 |
| BV= |                       |              |      |                 |
| ble |                       |              |      |                 |
| omy |                       |              |      |                 |
| cin |                       |              |      |                 |
| and |                       |              |      |                 |
| vin |                       |              |      |                 |
| cri |                       |              |      |                 |
| sti |                       |              |      |                 |
| ne; |                       |              |      |                 |
| Da  |                       |              |      |                 |
| uno |                       |              |      |                 |
| Xom |                       |              |      |                 |
| e®= |                       |              |      |                 |
| dau |                       |              |      |                 |
| nor |                       |              |      |                 |
| ubi |                       |              |      |                 |
| cin |                       |              |      |                 |
| c   |                       |              |      |                 |
| itr |                       |              |      |                 |
| ate |                       |              |      |                 |
| li  |                       |              |      |                 |
| pos |                       |              |      |                 |
| ome |                       |              |      |                 |
| i   |                       |              |      |                 |
| nje |                       |              |      |                 |
| cti |                       |              |      |                 |
| on; |                       |              |      |                 |
| CD= |                       |              |      |                 |
| con |                       |              |      |                 |
| ven |                       |              |      |                 |
| tio |                       |              |      |                 |
| nal |                       |              |      |                 |
| do  |                       |              |      |                 |
| xor |                       |              |      |                 |
| ubi |                       |              |      |                 |
| cin |                       |              |      |                 |
|     |                       |              |      |                 |
| ^a^ |                       |              |      |                 |
| E   |                       |              |      |                 |
| nro |                       |              |      |                 |
| llm |                       |              |      |                 |
| ent |                       |              |      |                 |
| for |                       |              |      |                 |
| pa  |                       |              |      |                 |
| tie |                       |              |      |                 |
| nts |                       |              |      |                 |
| who |                       |              |      |                 |
| re  |                       |              |      |                 |
| cei |                       |              |      |                 |
| ved |                       |              |      |                 |
| at  |                       |              |      |                 |
| le  |                       |              |      |                 |
| ast |                       |              |      |                 |
| 1   |                       |              |      |                 |
| d   |                       |              |      |                 |
| ose |                       |              |      |                 |
| of  |                       |              |      |                 |
| st  |                       |              |      |                 |
| udy |                       |              |      |                 |
| dr  |                       |              |      |                 |
| ug. |                       |              |      |                 |
| N   |                       |              |      |                 |
| umb |                       |              |      |                 |
| ers |                       |              |      |                 |
| i   |                       |              |      |                 |
| ncl |                       |              |      |                 |
| ude |                       |              |      |                 |
| pa  |                       |              |      |                 |
| tie |                       |              |      |                 |
| nts |                       |              |      |                 |
| rol |                       |              |      |                 |
| led |                       |              |      |                 |
| o   |                       |              |      |                 |
| ver |                       |              |      |                 |
| f   |                       |              |      |                 |
| rom |                       |              |      |                 |
| s   |                       |              |      |                 |
| ome |                       |              |      |                 |
| s   |                       |              |      |                 |
| tud |                       |              |      |                 |
| ies |                       |              |      |                 |
| i   |                       |              |      |                 |
| nto |                       |              |      |                 |
| lar |                       |              |      |                 |
| ger |                       |              |      |                 |
| fol |                       |              |      |                 |
| low |                       |              |      |                 |
| -up |                       |              |      |                 |
| st  |                       |              |      |                 |
| udi |                       |              |      |                 |
| es. |                       |              |      |                 |
+-----+-----------------------+--------------+------+-----------------+

####  {#section-5 .unnumbered}

#### Study 30-03 {#study-30-03 .unnumbered}

Study 30-03, a Phase II/III study of pegylated liposomal doxorubicin for
the treatment of AIDS-related KS, was initiated in October 1991 and
conducted by 23 investigators in seven countries ex-U.S. (Australia,
England, Germany, Italy, Portugal, Switzerland, and the Netherlands).
The objectives of this study were to determine the incidence of
objective response of cutaneous AIDS-KS to treatment with DOXIL, to
evaluate the patients' quality of life during DOXIL therapy, to
determine the incidence of acute and chronic toxicity in DOXIL-treated
patients, and to determine doxorubicin levels in KS lesions, normal
skin, and serum following treatment with DOXIL.

A total of 247 patients with AIDS-KS (and 1 non-AIDS-KS patient) were
treated with DOXIL in cumulative doses ranging from 10‑520 mg/m^2^ in
this open-label, multicenter, dose escalation study. DOXIL was to be
administered every 2 weeks, initially at a dose of 10 mg/m^2^, and if no
response was noted after the first two cycles, the dose was doubled for
two additional cycles, with continued dose escalation until response was
observed. Maintenance treatment continued at every 2-week intervals at
the same dose at which response occurred. Protocol amendments increased
the initial dose of DOXIL up to 40 mg/m^2^, with maintenance doses
ranging from 10 to 40 mg/m^2^.

This study demonstrated the safety and efficacy of DOXIL at doses of
10 and 20 mg/m^2^ administered at 2-week intervals. Objective response
(complete or partial) response was reported in 81% of patients.
Responses occurred rapidly, with a mean time to response of 57 days (or
three cycles). Response was maintained for an average of 17 weeks,
ranging up to 65 weeks. When compared to baseline, an overall reduction
in lesion size as well as clinically and statistically significant
reduction in nodularity and edema was reported along with the patients'
best response to DOXIL. In addition, statistically significant numbers
of patients experienced improvement in quality of life within the first
six weeks of study, at the time of best KS response, and for the
duration of the response.

#### Study 30-05 {#study-30-05 .unnumbered}

Study 30-05 investigated the pharmacokinetics of DOXIL and conventional
doxorubicin in patients with AIDS-KS. Other objectives of the trial
included comparison of concentrations of doxorubicin within AIDS-KS
lesions following intravenous administration of each drug and to assess
safety and tolerability of DOXIL. This randomized, single dose,
crossover study, with optional long-term DOXIL maintenance therapy,
enrolled 18 patients. Both DOXIL and conventional doxorubicin were
administered in doses of 10, 20, and 40 mg/m^2^. Patients were treated
for 2 cycles, with a 3-week interval between each cycle. Either DOXIL or
conventional doxorubicin was administered in the first cycle, followed
by the alternate drug in the second cycle, with a 4-week follow-up
period. This study was conducted between January 1992 and June 1993.

Plasma samples for PK analyses were collected for 4 days following
administration of the first dose of study drug. At 72 hours
post-infusion, a representative KS lesion was excised from each patient
and tissue drug levels were measured. Disposition kinetics for the two
drugs were markedly different. Disposition of doxorubicin after DOXIL
administration occurred in two phases: a relatively short first phase of
doxorubicin disposition accounted for only a small percentage of the
area under the curve (AUC), with a long second-phase representing nearly
88% of the AUC. The second disposition half-life of DOXIL was 43.7,
35.8, and 38 hours in the 10, 20, and 40 mg/m^2^ dose groups,
respectively. Due to the rapid clearance of doxorubicin from plasma in
patients treated with conventional doxorubicin, plasma concentrations of
doxorubicin were below the limit of quantitation of the HPLC assay at
all but the first time point after drug administration, and data could
not be fitted to a pharmacokinetic model. The first disposition
half-life of administration of conventional doxorubicin, representing
the majority of the AUC, is reported to be less than 10 minutes. The
volume of distribution of DOXIL (3.2-3.5 L/m^2^) was near the estimated
plasma volume, indicating disposition of pegylated
liposomal-encapsulated doxorubicin is controlled by the distribution of
the liposome carrier. The volume of distribution of conventional
doxorubicin is reported to be more than 500‑times the plasma volume.

DOXIL disposition kinetics were reported to be independent of dose, and
dose-dependent linear increases were observed in the initial plasma drug
level (C~max~) and in AUC. Doxorubicinol, the major metabolite of
doxorubicin, was not detected in plasma after DOXIL administration.
Doxorubicin levels in biopsies of KS lesions from patients who received
the same dose of DOXIL or conventional doxorubicin were 5 to11-fold
higher in the DOXIL-treated patients 72-hours after drug administration.

#### Study 30-10 {#study-30-10 .unnumbered}

Study 30-10 was a Phase III prospectively randomized, parallel
multicenter comparative trial of DOXIL vs. Adriamycin, Bleomycin, and
Vincristine (ABV) in the treatment of severe AIDS-KS conducted at 25
U.S. sites between April 1993 and December 1994. In this study, 258
patients with moderate-to-severe AIDS-KS were randomized to treatment
with either DOXIL (133 patients) or ABV (125 patients). Patients were
treated with either DOXIL 20 mg/m^2^ or ABV (20 mg/m^2^ Adriamycin, 10
U/m^2^ bleomycin, and 1.0 mg/m^2^ vincristine) at every 2-week
intervals. All but 3 patients were male, and the median age was 38
years.

Objective responses (complete and partial) responses were reported in
46.2% of DOXIL-treated patients, compared to 25.6% of ABV-treated
individuals (P\<0.001). In addition, DOXIL-treated patients improved in
all nine domains of a self-administered Quality of Life questionnaire,
and DOXIL-treated patients recorded significantly better scores in five
domains (general health, pain, social functioning, energy level, and
health distress).

Dose delays and dose modifications were more frequent in the ABV-treated
group, with 46 (36.8%) of the 125 ABV patients terminating treatment
prematurely due to an adverse event, compared to adverse event-related
early termination in 14 (10.5%) of the 133 DOXIL-treated patients.
Neuropathy, nausea and vomiting, and alopecia occurred more frequently
with ABV treatment (28.0% vs. 12.0%, 57.6% vs. 33.8%, and 42.4 vs. 11.3%
respectively). Mucositis was more common in the DOXIL-treated patients
(18.0% vs. 8.0%). While neutropenia occurred in both treatment groups,
ANC \< 500/mm^3^ was more common in the ABV-treated patients (13.6% vs.
6.0%).

More DOXIL-treated patients (68.0% vs. 34.0%) completed the six cycles
of therapy. Difference in attrition was thought to be due to improved
tolerance and efficacy of DOXIL over ABV.

#### Study 30-11 {#study-30-11 .unnumbered}

Study 30-11 was a Phase III prospectively randomized, parallel,
multicenter comparative trial of DOXIL vs. Bleomycin and Vincristine
(BV) in the treatment of AIDS-KS conducted in Europe (17 sites) and the
U.S. (5 sites) between January 1993 and September 1995.

A total of 241 patients with moderate-to-severe AIDS-KS were enrolled in
this study, with 121 patients randomized to treatment with DOXIL and
120 patients randomized to the BV arm. All but 2 of the patients were
male, with a mean age of 38 years. Demographics and baseline disease
characteristics were well balanced between the two treatment groups.

Patients were treated with either DOXIL (20 mg/m^2^) or BV (Bleomycin
15 U/m2 and Vincristine 1.4 mg/m^2^ (maximum dose 2.0 mg) at 3-week
intervals. Objective responses (complete and partial) responses were
reported in 58.7% of DOXIL-treated patients compared to 23.3% of
BV-treated individuals (P\<0.001).

Patients were asked to complete two quality of life questionnaires. With
the Wu instrument, DOXIL-treated patients improved significantly in the
domains of cognitive functioning, overall quality of life, and health
transition, while BV-treated patients were reported to have improvement
in only the health distress domain. With the KS questionnaire,
statistically significant improvement was reported for DOXIL-treated
patients in regards to ease of walking, relief from sleep disturbance,
and social well-being. On the other hand, when compared with baseline
assessments, BV-treated patients reported significant improvement in
social-well being only.

More DOXIL-treated patients (55.4% vs. 30.8%) were able to complete the
six cycles of therapy specified in the protocol. More BV-treated
patients discontinued the study prematurely as a result of adverse
events (26.7% vs. 10.7%). Dose delays due to adverse events were more
common in the DOXIL-treated patients (8.5% vs. 2.7%). Almost all
patients (96.7 % of DOXIL-treated and 95.8% of BV-treated patients)
reported at least one adverse event. More adverse events were thought to
be related to drug in the BV group than in the DOXIL group (21.1% vs.
10.0%), although the majority of adverse events were considered to be
unrelated to study drug (68.1% for DOXIL-treated patients, 52.6% for
BV-treated patients).

Nausea and vomiting (mostly of mild or moderate severity) was noted as
an adverse event for both drugs (15.7% with DOXIL, 25.0% with BV).
Treatment with BV was associated with more peripheral neuropathy (in
26.7% of BV-treated patients vs. 8.3% of those treated with DOXIL).
Significantly more patients discontinued treatment prematurely in the BV
group (69.2%) compared to the DOXIL group (44.6%) (P\<0.001).

#### Study 30-12 {#study-30-12 .unnumbered}

Study 30-12 was a Phase III non-comparative open-label multicenter study
of DOXIL at a dose of 20 mg/m^2^ administered at 3-week intervals to
evaluate the safety and efficacy of long term DOXIL treatment in
patients with moderate-to-severe AIDS-KS. Treatment continued until
disease progression or intolerance occurred. This study was conducted
between March 1993 and December 1995 at 18 sites (12 U.S., 3 U.K., 2
Germany, and 1 The Netherlands). There was no fixed limit on the number
of patients. Patients were eligible for enrollment if they were rolled
over from a completed DOXIL study or if they were a treatment failure
from a non-DOXIL based regimen. A total of 892 patients were enrolled in
this study.

DOXIL was administered at a dose of 20 mg/m^2^ at q 3-week intervals for
a total of up to 20 cycles (the cumulative number of cycles included
previously administered DOXIL in other studies). The 892 patients
remained in the study for a duration ranging from 1 to 791 days (median:
127 days), with cumulative doses of DOXIL ranging from 3.3 to 769.7
mg/m^2^ (median 120.0 mg/m^2^).

The pattern of adverse events noted in this study is similar to that
noted in other DOXIL-KS studies.

Subsequently, a cohort of 77 patients was identified retrospectively as
either having developed disease progression while undergoing systemic
chemotherapy with a non-DOXIL based regimen or being intolerant to such
therapy. The median CD4 counts for these individuals was only 10
cell/mm^3^ and forty-nine of these 77 individuals (64%) had been
previously treated with conventional doxorubicin. Using ACTG staging
criteria, 78% of the patients were considered poor risk due to tumor
burden, 96% were at poor risk due to immune system status, and 58% were
at poor risk for systemic illness at baseline. All 77 patients had
cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% had
pulmonary lesions, and 14% had gastrointestinal lesions as well. The
majority of these individuals had disease progression while undergoing
treatment with prior systemic chemotherapy.

The median time on study for these 77 patients was 155 days (range 1 to
456 days) and the median cumulative dose was 154 mg/m^2^ (range 20 to
620 mg/m^2^).

Two analyses of tumor response were used to evaluate efficacy of DOXIL
in these patients. Investigator assessment of response was based on ACTG
criteria, defining a partial response as no new lesions, sites of
disease, or worsening edema, flattening of [\>]{.underline}50% of
previously raised lesions, or the area of indicator lesions decreasing
by [\>]{.underline}50%, and maintenance of response for at least 21
days. The other method of assessment of response was indicator lesion
assessment of up to 5 prospectively identified representative indicator
lesions, defining a partial response as flattening of 50% of previously
raised indicator lesions or 50% decrease in the area of the indicator
lesions lasting at least 21 days with no prior progression.

Only patients with adequate documentation of baseline and follow-up
assessments were considered evaluable for response. Patients treated
concomitantly for their KS, those who had undergone local radiotherapy
to sites encompassing 1 or more of the indicator lesions within 2 months
prior to study entry, those who had less than 4 indicator lesions, or
those who had less than 3 raised indicator lesions at baseline (for
indicator lesion assessment only) were considered inevaluable for
response.

Of the 77 patients with disease progression while undergoing treatment
with prior systemic non-DOXIL based chemotherapy or those intolerant to
such therapy, 34 were evaluable for investigator assessment of response,
and 42 were evaluable for indicator lesion assessment. By investigator
assessment, partial responses were observed overall in 27% of the
patients (n=34), with a median duration of response of 73 days (range
42-210 days); and in those (n=20) who had been treated previously with
doxorubicin, partial responses were reported in 30%, with a median
duration of response of 89 days (range 42-210 days).

For response by indicator lesion assessment, partial responses were
observed overall in 48% of the patients (n=42), with a median duration
of response of 71 days (range 22-210 days); and in those (n=23) who had
been treated previously with doxorubicin, partial responses were
reported in 52%, with a median duration of response of 79 days (range
35-210 days).

Table 2 summarizes the results of 30-12.

+---------------------+-------------------+---------------------------+
| > **Table 2:**      |                   |                           |
| > Study 30-12:      |                   |                           |
| > Response in       |                   |                           |
| > Refractory^a^     |                   |                           |
| > AIDS-KS Patients  |                   |                           |
+---------------------+-------------------+---------------------------+
| > Investigator      | > All Evaluable   | > Evaluable Patients Who  |
| > Assessment        | > Patients        | > Received Prior          |
|                     | >                 | > Doxorubicin             |
|                     | > (n=34)          | >                         |
|                     |                   | > (n=20)                  |
+---------------------+-------------------+---------------------------+
| > **Response^b^**   |                   |                           |
+---------------------+-------------------+---------------------------+
| > Partial (PR)      | > 27%             | > 30%                     |
+---------------------+-------------------+---------------------------+
| > Stable            | > 29%             | > 40%                     |
+---------------------+-------------------+---------------------------+
| > Progression       | > 44%             | > 30%                     |
+---------------------+-------------------+---------------------------+
|                     |                   |                           |
+---------------------+-------------------+---------------------------+
| > **Duration of PR  |                   |                           |
| > (days)**          |                   |                           |
+---------------------+-------------------+---------------------------+
| > Median            | > 73              | > 89                      |
+---------------------+-------------------+---------------------------+
| > Range             | > 42210           | > 42210                   |
+---------------------+-------------------+---------------------------+
|                     |                   |                           |
+---------------------+-------------------+---------------------------+
| > **Time to PR      |                   |                           |
| > (days)**          |                   |                           |
+---------------------+-------------------+---------------------------+
| > Median            | > 43              | > 53                      |
+---------------------+-------------------+---------------------------+
| > Range             | > 15133           | > 15109                   |
+---------------------+-------------------+---------------------------+
| > Indicator Lesion  | > All Evaluable   | > Evaluable Patients Who  |
| > Assessment        | > Patients        | > Received Prior          |
|                     | >                 | > Doxorubicin             |
|                     | > (n=42)          | >                         |
|                     |                   | > (n=23)                  |
+---------------------+-------------------+---------------------------+
| > **Response^b^**   |                   |                           |
+---------------------+-------------------+---------------------------+
| > Partial (PR)      | > 48%             | > 52%                     |
+---------------------+-------------------+---------------------------+
| > Stable            | > 26%             | > 30%                     |
+---------------------+-------------------+---------------------------+
| > Progression       | > 26%             | > 17%                     |
+---------------------+-------------------+---------------------------+
|                     |                   |                           |
+---------------------+-------------------+---------------------------+
| > **Duration of PR  |                   |                           |
| > (days)**          |                   |                           |
+---------------------+-------------------+---------------------------+
| > Median            | > 71              | > 79                      |
+---------------------+-------------------+---------------------------+
| > Range             | > 22210           | > 35210                   |
+---------------------+-------------------+---------------------------+
|                     |                   |                           |
+---------------------+-------------------+---------------------------+
| > **Time to PR      |                   |                           |
| > (days)**          |                   |                           |
+---------------------+-------------------+---------------------------+
| > Median            | > 22              | > 48                      |
+---------------------+-------------------+---------------------------+
| > Range             | > 15109           | > 15109                   |
+---------------------+-------------------+---------------------------+
| > ^a^ Patients with |                   |                           |
| > disease that      |                   |                           |
| > progressed on     |                   |                           |
| > prior combination |                   |                           |
| > chemotherapy or   |                   |                           |
| > who were          |                   |                           |
| > intolerant to     |                   |                           |
| > such therapy.     |                   |                           |
+---------------------+-------------------+---------------------------+
| > ^b^ There were no |                   |                           |
| > complete          |                   |                           |
| > responses in this |                   |                           |
| > population.       |                   |                           |
+---------------------+-------------------+---------------------------+

#### Study 30-14 {#study-30-14 .unnumbered}

Study 30-14 was a randomized, cross-over, pharmacokinetic and tumor
localization study in which DOXIL was administered as either 10- and
20 mg/m^2^ in order to assess the relationship between dose and
pharmacokinetic variables. In this single center study conducted between
March and December 1993, 43 patients with AIDS-KS were treated with
2 cycles of DOXIL at 3-week intervals. The first 26 patients were
randomized to treatment with either the 10 or 20 mg/m^2^ dose, followed
3 weeks later with crossover to the other dose. Plasma samples for
plasma pharmacokinetic analyses were collected for 4 days following the
first dose. At 48-hours post-infusion, a representative KS lesion was
excised and tissue drug levels were measured. The protocol was amended
in September 1993 to include 16 additional patients who were randomized
to treatment with either the 10 or the 20 mg/m^2^ dose level, followed
by biopsy of KS lesions and normal skin at either 48 or 96 hours
post-infusion. These additional individuals were not crossed over to the
alternate dose and they did not undergo full plasma pharmacokinetic
analyses.

In general, both dose levels of DOXIL were well tolerated. DOXIL
displayed linear pharmacokinetics best described by a two-compartment
model. Plasma concentrations and AUCs were dose-proportional, whereas
DOXIL disposition kinetics were independent of dose. Following DOXIL
administration, disposition occurred in two phases, with a relatively
short first phase (~1~ half-life of 5 hours) and a prolonged second
phase (~2~ half-life of 52 hours) that accounted for the majority of the
AUC. Very low levels of doxorubicinol, the major metabolite of
doxorubicin, were detected in plasma after dosing, representing
approximately 0.1% - 0.5% of the measured doxorubicin plasma levels.
Since only non-liposomal doxorubicin is metabolized, and since
doxorubicinol levels are typically one-half of the doxorubicin levels,
this suggests that the amount of free, non-liposomal doxorubicin in the
plasma is less than 1% of the total.

Forty-eight hours after DOXIL administration, median doxorubicin levels
in biopsies of KS lesions were 2-fold (for the 10 mg/m^2^ dose) and
20-fold higher (for the 20 mg/m^2^ dose) than in normal skin from the
same patient. Doxorubicin levels in the KS lesions 96-hours after
treatment were 3-times (for the 10 mg/m^2^ dose) and 4-times (for the 20
mg/m^2^ dose) greater than in normal skin, demonstrating the selective
accumulation of DOXIL in KS lesions.

#### Study 30-21 {#study-30-21 .unnumbered}

Study 30-21 compared the effects of DOXIL and non-liposomal
(conventional) doxorubicin on myocardial tissues. Between July 1994 and
July 1995 ten patients with AIDS-KS who had been treated with
\>400 mg/m^2^ (469 to 860 mg/m^2^) of DOXIL underwent myocardial biopsy.
For each DOXIL patient, a matched doxorubicin patient who had received a
similar cumulative amount of doxorubicin was identified from a cardiac
biopsy database of 131 patients who had undergone cardiac biopsy while
participating in clinical trials at Stanford University from 1974-1982.

DOXIL was administered at a dose of 20 mg/m^2^ at 2-3 week intervals.
Individuals treated with conventional, non-liposomal doxorubicin were
treated at a dose intensity of 20 mg/m^2^ per week on one of two
schedules: 20 mg/m^2^ every week or 60 mg/m^2^ every 3 weeks.
DOXIL-treated patients had not been treated previously with any other
anthracycline.

The primary criterion for match was cumulative doxorubicin exposure
within 10 mg/m^2^. Using a 7-point morphologic grading system for
cardiotoxicity, the amount of cardiac damage in the DOXIL- and
doxorubicin-treated patients was measured and compared.

The primary criterion for evaluation was the condition of the myocardium
as assessed by the Billingham Morphologic Grading System for
Cardiotoxicity. This scale begins at Grade 0 (cells show no
anthracycline damage) and progresses to Grade 3.0 (specimens exhibit
diffuse cell damage, with more than 35% of cells showing pathologic
change, loss of contractile elements and organelles, and mitochondrial
and nuclear degeneration).

Less myocardial damage was observed in patients treated with DOXIL
compared to their matched doxorubicin controls. The mean (+/-SD) cardiac
biopsy score for the DOXIL treated patients was 0.5 (+/-0.55), (range
0-1.5) compared to a mean of 2.4 (+/-0.70) (range 1.5-3.0) for the
unadjusted conventional doxorubicin patient and a mean of 1.8 (+/-0.78)
(range 0.7-3.0) for the adjusted doxorubicin patient. The difference
between the DOXIL and doxorubicin patients was statistically significant
(P \<0.001) when the biopsy scores for the DOXIL-treated patients were
compared with the unadjusted scores for the doxorubicin patients. The
same test comparing the DOXIL patient scores with the doxorubicin
patient scores adjusted for administered dose also gave a significant
difference (p=0.015).

#### Study 30-24  {#study-30-24 .unnumbered}

Study 30-24 was a Phase III open-label multicenter study of long-term
use of DOXIL in the treatment of moderate-to-severe AIDS-KS that was
conducted in Europe and enrolled 94 patients between February 1994 and
October 1998. Patients treated previously on a DOXIL protocol within the
last 4 months and who had AIDS-KS of a severity requiring systemic
chemotherapy were eligible for enrollment if no other treatment option
was available. DOXIL was administered at a dose of 20 mg/m^2^ at 3-week
intervals for a cumulative total of up to 20 cycles, with an option for
extension of treatment upon Sponsor approval.

Six patients were classified as complete responders.

Overall, a total of 1083 doses of DOXIL were administered to 94
patients, and the median number of days on study drug was 191 (range
1-1,645 days). The median cumulative dose of DOXIL was 146.7 mg/m^2^
(range 20.0 -- 1,060.9 mg/m^2^). Most of the patients (86 of 94, 91.5%)
reported at least one adverse event, and 16 (17%) patients reported
adverse events that were probably related to study drug and 46 (48.9%)
reported adverse events that were possibly related to study drug, and 81
(86.2%) reported adverse events that were unrelated to study drug.
Sixty-one of the 94 patients reported a severe adverse event. The most
frequently reported adverse events were pneumonia (16 patients, 17.0% -
not related to study drug), neutropenia (15 patients, 16.0% - related to
study drug), and leukopenia (14 patients, 14.9% - related to study
drug).

A total of 60 study patients died. Forty-seven of the deaths were on
study and 13 patients died during the follow up period. The majority of
deaths were due to other AIDS-related complications (n=42) and
progression of KS (n=11). The median time to death was 337 days from the
start of study drug (range 6+ to 1,708+ days). Death of one patient from
sepsis was considered possibly related to study drug, and for the
remaining 59 patients, death was considered unrelated to study drug.

#### Study 30-25 {#study-30-25 .unnumbered}

Study 30-25 was a Phase III multicenter non-comparative open-label study
of DOXIL in the treatment of patients with moderate-to-severe AIDS-KS
who had no other treatment options, were intolerant to non-DOXIL based
combination chemotherapy, or who had been enrolled in another DOXIL
protocol and for whom continuation of DOXIL was medically indicated.
This study was conducted between December 1994 and January 1996,
enrolling 635 patients.

DOXIL was administered at a dose of 20 mg/m^2^ at 3-week intervals. The
overall incidence of objective response (complete and partial) was 16.4%
(104/635). Three (0.5%) patients were classified as complete responders,
and 101 (15.9%) were recorded as having a partial response.

The median duration of response was 219.0 days (range 29+ to 327+ days).

In total, 4309 doses of DOXIL were administered to the 635 patients, and
the duration of DOXIL therapy ranged from 1.0 -- 367.0 days, with a
median of 117.0 days. The median cumulative dose of DOXIL was 120.0
mg/m^2^ (range 10.3 to 443.8 mg/m^2^). A total of 437 adverse events
were reported by 255 (43.4%) of the 588 patients with AE forms. Of
these, 112 (19.0%) experienced mild events, 130 (22.1%) experienced
moderate events, and 86 (14.6%) experienced severe adverse events.
Adverse events considered possibly related and probable related to DOXIL
were reported in 192 (32.7%) and 107 (18.2%) patients, respectively. The
Adverse Event form used in this study listed four categories of severity
(mild, moderate, severe, and fatal), and two categories of relationship
of the adverse event to study drug (possibly related and probably
related).

The most common adverse events reported were leukopenia (119 patients,
20.2%), asthenia (32 patients (5.4%), anemia 26 patients (4.4%), and
nausea (25 patients, 4.3%). Leukopenia was the most frequently reported
serious adverse event (62 patients, 10.5%), followed by anemia (9
patients, 1.5%).

A total of 176 (27.7%) of study patients died (156 on study, and 20 died
during the follow-up period). The majority of deaths (n=153) were due to
HIV-related opportunistic disease. The median time to death was 366 days
from the start of study drug (range 1+ to 616+ days). Overall, long-term
use of DOXIL was well tolerated in this patient population.

#### Study 30-26 {#study-30-26 .unnumbered}

Study 30-26 was another long-term Phase III open-label multicenter study
conducted at 5 sites in Germany between April 1995 and February 1996 to
provide DOXIL to patients with KS for whom no other therapy was
available. Administration of up to 20 cycles of DOXIL, 20 mg/m^2^ at
q 3‑week intervals, was permitted. A total of 67 patients with AIDS-KS
were treated with 349 doses of DOXIL, with at least 1 clinical response
recorded. The median number of days on study drug was 95 (range 1.0 to
231.0 days). The median cumulative dose was 99.8 mg/m^2^ (range 10.0 to
241.1 mg/m^2^).

The mean time to death was 177.9 days (range 1+ to 447+ days).

#### Study 30-38 {#study-30-38 .unnumbered}

Study 30-38 was a Phase IV prospective, randomized, double-blind,
multicenter study comparing DOXIL with DaunoXome in the treatment of 80
patients with AIDS-KS. This post-marketing commitment study conducted
between September 1996 and September 2000 was designed to satisfy the
requirements of an Accelerated Approval. The study was not powered to
demonstrate superiority of DOXIL over DaunoXome. Enrollment was limited
to patients with KS-associated symptoms that could be evaluated for
clinical benefit. After two baseline visits to measure disease, patients
with AIDS-KS of a severity requiring systemic chemotherapy were
randomized in a 3:1 fashion to treatment with either DOXIL (20 mg/m^2^
every 2 weeks) or DaunoXome (40 mg/m^2^ every 2 weeks) for up to 6
cycles. At each study visit, patients were evaluated for clinical
benefit (defined as an improvement in functional activity, pulmonary or
gastrointestinal symptoms, KS-associated pain, self image and tumor
response).

The presence of one or more of the following KS-associated manifestation
was a prerequisite for eligibility for this study: KS-associated edema
that impaired the patient's functional activity of the extremities,
groin, or face; bronchoscopy-proven symptomatic and evaluable pulmonary
KS documented within 3 months prior to study entry, provided that an
imaging technique (such as CT scan) could be used for assessment of
response and that was not associated with any other manifestation of HIV
disease; symptomatic and evaluable gastrointestinal KS documented by
endoscopy within 3 months prior to study entry, with symptoms definitely
associated with KS and not another manifestation of HIV disease;
KS-associated pain reported by the patient to be of moderate severity at
a minimum, despite use of analgesics; KS lesions that were disfiguring
and impaired the patient's self image or daily activities; 5 or more
measurable mucocutaneous lesions.

Patients in the DOXIL-treated group were predominately male (97%) and
the median age was 38 years (range 23 to 75 years). Using ACTG staging
criteria, 57% of patients were poor prognosis for tumor burden, 73% were
poor prognosis for immune system, and 58% were poor prognosis for
systemic illness at baseline. Median CD4 count was 131 cells/mm^3^.
Fifty-five percent of patients treated with DOXIL had received no prior
therapy for AIDS-KS and only 9% of patients had been treated previously
with systemic chemotherapy.

At baseline and throughout the course of the study, patients were asked
to assess their status using an eleven item symptom questionnaire that
involved five symptom categories: lymphedema, pulmonary disease,
gastrointestinal disease, disfiguring lesions, and KS-associated pain.
Patients were asked to rate the degree to which symptoms interfered with
their daily activities, using a four point scale from "symptom absent"
to "symptom present and interfered very much with daily activities."

Forty-eight (80.0%) of the 60 DOXIL-treated patients and 12 (63.2%) of
the 19 DaunoXome-treated patients experienced clinical benefit, i.e. a
sustained (at least 4 weeks) improvement from baseline in at least one
of the five AIDS-KS symptom categories in the absence of disease
progression or severe drug-induced toxicity. At least one patient
reported clinical benefit in each of the symptom categories.

With a more conservative definition of clinical benefit, requiring
improvement in at least one symptom category that lasted at least 4
weeks, with no worsening of other symptom categories and no increase in
medical interventions either before or during that period, 22 (36.7%)
DOXIL-treated patients and 3 (15.8%) DaunoXome-treated patients
experienced clinical benefit.

Tumor response was a secondary endpoint. Partial response was defined as
no new lesions, sites of disease, or worsening edema; flattening of 50%
of previously raised lesions or area of indicator lesions decreasing by
50%, and response lasting at least 28 days. All tumor responses were
partial responses, reported in 55% of DOXIL-treated patients and in
31.6% of those treated with DaunoXome. In all cases there was a positive
correlation between tumor response and clinical benefit, regardless of
which of the two definitions of benefit were applied.

Both study drugs were well tolerated. Nausea, neutropenia, and asthenia
were the most common treatment-related adverse events reported for both
drugs.

While clinical benefit was observed with both treatment arms, it was not
possible to clearly delineate the degree of improvement that resulted
from systemic chemotherapy and the degree of improvement due to
antiretroviral therapy. Changes in antiretroviral therapy immediately
prior to or during study, prior to scoring of clinical benefit, may have
confounded the assessment of the effect of DOXIL on the AIDS-KS. The
number of DOXIL patients (n=21) not confounded by changes in
antiretroviral therapy prior to initiation of treatment with DOXIL was
insufficient for the FDA to make a definitive conclusion regarding the
clinical benefit of the patients treated with DOXIL. However in
analyzing these 21 patients, there was a correlation with clinical
benefit and response. Using the protocol definition of clinical benefit,
all 8 of the 8 responders (100%) experienced clinical benefit, 8 of the
12 patients with stable disease (67%) experienced clinical benefit and
the one patient with progressive disease did not experience clinical
benefit. The correlation is also present when applying the conservative
definition of clinical benefit, as 5 of the 8 responders (62%)
experienced clinical benefit, 5 of the 12 with stable disease (42%)
experienced clinical benefit and the 1 patient with progressive disease
did not experience clinical benefit.

1.  []{#__RefHeading___Toc32293586 .anchor}Regulatory History of DOXIL
    in Kaposi's Sarcoma Indication

On 17 November 1995, DOXIL was granted accelerated approval under the
accelerated approval regulations 21 CFR 314.500, Subpart H for the
treatment of AIDS-KS in patients with disease that has progressed on
prior combination chemotherapy or in patients who are intolerant to such
therapy based on the results of an interim analysis from an open-label,
single-arm, multicenter study.

On 28 June 1995, in accordance with the accelerated approval
regulations, a commitment letter was submitted to the FDA to conduct a
double-blind, randomized, confirmatory study to evaluate the clinical
benefit of DOXIL in .patients with AIDS-KS. The confirmatory study
(Study 30-38, *A Double-Blind, Randomized Evaluation of Clinical
Benefits of DOXIL in Patients with AIDS-Related Kaposi's Sarcoma Treated
with DOXIL or DaunoXome^®^*) was designed in close collaboration with
the FDA (13 June 1995 meeting with FDA) and was intended to satisfy the
requirements for full approval of DOXIL under Subpart H.

On 02 October 2001, the final clinical study report for Study 30-38 was
submitted to FDA as part of an efficacy supplement to NDA 50-718. On
31 July 2002, the FDA communicated to the Sponsor that the results of
the clinical study were inadequate and did not provide substantial
evidence of a clinical benefit for DOXIL in the treatment of AIDS-KS.
FDA also communicated that antiretroviral therapy may be more effective
treatment for AIDS-KS than any of the available anti-KS agents. Study
enrollment occurred from September 1996 to September 2000, coinciding
with the introduction of highly active antiretroviral therapy (HAART).
Changes in anti-HIV medications during or immediately preceding the
clinical trial could have had an effect on the AIDS-KS, making
assessment of the effect of DOXIL or DaunoXome on AIDS-KS difficult. The
FDA requested that the Sponsor submit a new clinical study protocol and
development plan to further assess the clinical benefit of DOXIL in
AIDS-KS, and to satisfy full approval of the AIDS-KS indication for
DOXIL under the accelerated approval regulations in 21 CFR 314, Subpart
H. On 27 November 2002, the Sponsor provided a proposed development
plan, protocol outline, and timelines to meet the phase IV commitment.
On 22 January 2003 the Sponsor received comments from FDA on the
protocol design and discussions with FDA are ongoing to finalize the
design of the phase IV commitment trial.

## Description of Commitment Studies

### Original Commitment Study: Sequus/Alza Study 30-38

Study 30-38 was designed as a prospective, double blind, randomized,
multicenter trial. Study 30-38 enrolled 80 patients with AIDS-KS.
Enrollment was limited to patients with KS-associated symptoms that
could be assessed for potential clinical benefit from DOXIL treatment.
Following two baseline visits to measure disease, patients were
randomized in a 3:1 manner to treatment with either DOXIL (20 mg/m^2^)
or DaunoXome (40 mg/m^2^) every 2 weeks for up to 6 cycles of treatment.
At each study visit, patients were evaluated for clinical benefit
defined as an improvement in functional activity, pulmonary or
gastrointestinal symptoms, KS-associated pain, self-image and objective
tumor response. Objective tumor response was reported as a Complete
Response, Clinical Complete Response, Partial Response, Stable Disease,
Progressive Disease, or Relapsed Disease.

Study results from this study were presented at the 2002 ASCO Annual
Meeting.^16^

#### Summary of Study Sites 

Eighty (80) patients were enrolled in 7 study sites throughout the
United States.

#### Patient Population 

Patients had to meet all of the following key criteria to be enrolled in
the study:

1.  AIDS-KS of a severity requiring systemic chemotherapy

2.  One or more of the following symptoms:

-   KS-associated edema

-   Symptomatic evaluable pulmonary KS

-   Symptomatic evaluable gastrointestinal KS

-   KS-associated pain

-   KS lesions that are disfiguring or impair self-image

3.  Five or more measurable mucocutaneous lesions

#### Endpoints

The primary efficacy endpoint was the proportion of patients who
experienced clinical benefit as defined in the protocol.

Other planned efficacy endpoints were as follows:

-   For each individual AIDS-KS symptom category, the proportion of
    patients who experienced clinical benefit based on an improvement
    from baseline

-   Duration of clinical benefits

-   The proportion of patients who experienced clinical benefit based on
    changes in medical interventions

-   Response rate (proportion of patients who achieved a Complete or
    Partial response that lasted for ≥ 28 days)

-   Duration of response

-   Time to progression

-   Survival

#### Efficacy and Safety Monitoring

##### Efficacy

The primary measures of efficacy were the proportion of patients
experiencing clinical benefits and the duration of those benefits.
Clinical benefit was defined as improvement in at least 1 of the
following 5 symptom categories lasting for at least 4 weeks in the
absence of disease progression or severe drug-induced toxicity:

-   Functional activity impaired by KS lymphedema

-   Pulmonary symptoms (in patients with documented pulmonary KS)

-   Gastrointestinal symptoms (in patients with documented
    gastrointestinal KS)

-   Moderate-to-severe KS-associated pain despite analgesics

-   Self-image altered by disfiguring KS lesions

Patients assessed the 5 symptom categories at each visit using an
eleven-item questionnaire and rated the interference of symptoms with
daily activities using a four-point scale.

Additional efficacy parameters examined included:

-   Tumor response (ACTG criteria)

-   Changes in medical interventions used to treat the 5 symptom
    categories (i.e., diuretic or analgesic use for lymphedema,
    antiemetic use or RBC transfusions for gastrointestinal KS, etc.)

-   Evaluation of photographs of patients by an independent reviewer
    blinded to patient treatment information

##### Safety

Safety of the study drugs was assessed by examination of adverse events
and clinical laboratory assessments at each visit.

#### Statistical Design

This was a prospective, double blind, randomized, multicenter trial. The
proportion of patients who experienced clinical benefit was estimated
and the corresponding two-sided 95% confidence intervals of proportion
were provided.

Duration of clinical benefit, duration of response, time to progression,
and survival were estimated for each treatment group using the
Kaplan-Meier method. Response rates of the two treatment groups were
estimated. The corresponding two-sided 95% confidence intervals of
response rate were provided.

The primary goal of this study was to describe the clinical benefits of
DOXIL therapy in patients with Kaposi\'s sarcoma. The study was not
designed or statistically powered to test for significant differences in
clinical benefit or response rate between DOXIL and DaunoXome.

### Proposed New Commitment Study

On 31 July 2002 the FDA sent a letter to the Sponsor that stated that
the results of Study 30-38 did not provide substantial evidence of a
clinical benefit for DOXIL in the treatment of AIDS- KS and requested a
new phase IV commitment trail designed to demonstrate such clinical
benefit in this patient population. On 27 November 2002, the Sponsor
responded with a submission that included a proposed development plan,
protocol outline and timeline to meet the phase IV commitment. The
Sponsor has received comments from the FDA on this protocol design and
discussions are ongoing with the FDA to finalize the design of the phase
IV commitment trial.

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

### Study 30-38

Changes in antiretroviral therapy immediately prior to or during the
study confounded the FDA's ability to adequately assess the effect of
DOXIL on AIDS-related Kaposi's sarcoma. As the widespread use of HAART
did not begin until after Study 30-38 was initiated, the impact of HAART
on subjects enrolled in 30-38 was not taken into account when designing
the original study. As a result, the FDA felt that the data were
insufficient to convert DOXIL from accelerated approval to full
approval.

### Proposed New Phase IV Commitment Trial

Difficulties that may be encountered with conducting any study in
patients with AIDS-KS include the following:

#### Changes in Medical Practice 

-   **HAART utilization:** Patients who present with AIDS and KS are
    often treated with HAART and DOXIL concomitantly to achieve rapid
    cytoreduction, especially if the presenting AIDS-KS lesions are
    life-threatening, symptomatic or cosmetically disfiguring.
    Regression of AIDS-KS may occur 6-18 months after initiation of
    HAART as a consequence of viral suppression and immune
    reconstitution. In addition, the institution of HAART has resulted
    in reduction in the overall incidence of AIDS-KS.

-   Protocols that require patients to have documented sustained
    suppression of viral replication for a long pre-specified period
    (6-18 months) prior to enrollment into a study evaluating the safety
    and efficacy of new AIDS-KS agents will result in a significant
    reduction in the numbers of eligible AIDS-KS patients. Many patients
    with AIDS-KS who require systemic chemotherapy also may require
    modification of HAART for reasons of efficacy or safety, further
    complicating their eligibility for a pivotal trial or their
    continued participation in that trial.

-   **DOXIL is the standard of care:** DOXIL is commercially available
    and is regarded as the standard of care for first- or second-line
    treatment of AIDS-KS when systemic chemotherapy is appropriate.
    Currently 70% of patients with AIDS-KS are treated with DOXIL (IMS
    Health database).

#### Other Considerations

-   **Incidence of AIDS-KS:** The widespread use of HAART has resulted
    in a markedly decreased incidence of AIDS-KS. It will be challenging
    to achieve enrollment targets with the low incidence of AIDS-KS in
    the United States.

-   **Ethical considerations:** Ethical considerations and patient
    concerns/acceptance make it very difficult to conduct a
    placebo-controlled trial in this patient population. Delay of an
    active therapy of AIDS-KS is not an acceptable option to either
    patients or treating physicians. Furthermore, as DOXIL is regarded
    as the standard of care for patients with AIDS-KS for whom systemic
    chemotherapy is medically indicated, it may be equally as difficult
    to conduct a trial utilizing a "second choice" agent as a
    comparator.

## References

-   
-   
-   

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2.  Dezube, BJ. Acquired Immunodeficiency Syndrome-Related Kaposi's
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3.  The Surveillance, Epidemiology, and End Results (SEER) Program of
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4.  International Collaboration on HIV and Cancer. Highly Active
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5.  Tam, HK et al. Effect of Highly Active Antiretroviral Therapy on
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8.  Kaposi\'s Sarcoma (PDQ®): Treatment. National Cancer Institute,
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9.  Kaposi's Sarcoma. American Foundation for AIDS Research (amfAR),
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13. Tandem Cancer Audit, Current Chemotherapy Protocol, 09/01-08/02
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15. IMS Health Retail and Provide Perspective Audit and IMS Health
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16. Final Results of a Phase III Randomized Trial of DOXIL^®^/CAELYX™ vs
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