A Phase 1b/2 Study of AMG 655 in Combination With Doxorubiicn for the First-Line Treatment of Locally Advanced or Metastatic, Unresectable Soft Tissue Sarcoma

In this study, the study medication AMG 655 is evaluated for the treatment of
patients with Soft Tissue Sarcoma (STS). Doxorubicin chemotherapy, alone or in
combination, is a standard of care in the management of unresectable soft
tissue sarcoma. The tumor necrosis factor (TNF)-related apoptosis-inducing
ligand (TRAIL) pathway is a potential therapeutic target for cancer. Several
lines of evidence support developing AMG 655 in combination with chemotherapy
to treat sarcoma. Sarcoma tumor samples express high levels of TRAIL receptor 1
and TRAIL receptor 2 by immunohistochemistry. With in vitro models, including
human cell lines, primary tissue culture, and human tumor xenograft models,
TRAIL has been shown to induce apoptosis in multiple sarcoma subtypes, and its
activity is enhanced in combination with chemotherapy, in particular
doxorubicin. The TRAIL receptor 2 targeted antibody lextumumab achieved
prolonged disease stabilization in a number of subjects with refractory soft
tissue sarcoma. This protocol is the first study of AMG 655 in combination with
doxorubicin. Based on the safety profile observed in the AMG 655 first in human
study, and the mechanism of action and drug product characteristics of
doxorubicin and AMG 655, overlapping toxicities between AMG 655 and doxorubicin
are not expected.
Approximately 30 sites will participate in this study and will be distributed
across the United States and Europe. The approximately sample size for this
study is 117. Approximately 5 to 27 subjects in part 1 and approximately 90
subjects part 2.

Part 1 (phase 1b): to identify a dose of AMG 655 in combination with
doxorubicin that is safe and tolerated as determined by the incidence of dose
limiting toxicity
Part 2 (phase2): To estimate the efficacy, as measured by progression-free
survival, of AMG 655 at the dose selected in part 1, in combination with
doxorubicin.

This is a multi-center, 2-part phase 1b/2 study of AMG 655 in combination with
doxorubicin as first-line therapy for subjects with locally advanced or
metastatic, unresectabel soft tissue sarcoma (STS).

Part 1: is an open label phase 1b segment to identify a dose of AMG 655 in
combination with doxorubicin that is safe and tolerable as determined by the
incidence of dose limiting toxicity. Approximately 6 subjects will initially be
enrolled to receive the target dose of AMG 655 (15mg/kg Q3W) in combination
with doxorubicin (75 mg/m2 Q3W). The first 3 subjects will be enrolled at a
rate of 1 or less then 1 subject per week. If the target dose regimen is safe
based on the incidence of dose limiting toxicity, part 2 will open for
enrollment. If it is not safe, alternate lower dose levels will be explored
(e.g., 5mg/kg; 1.5 mg/kg), to identify the maximum tolerated dose of AMG 655 in
combination with doxorubicin.

Part 2: is a randomized double-blind placebo-controlled phase 2 investigation
of doxorubicin in combination with AMG 655 at the target dose, the maximum
tolerated dose (if lower than the target dose; as determined in part 1), or an
alternate lower dose. Part 2 will randomize subjects (n=90) in a 2:1 ratio to
receive AMG 655 (arm A; n=60), or placebo (arm B; n=30), in combination with
doxorubicin. Subjects will be stratified according to histological cell type
(liposarcoma versus leiomyosarcoma versus other), and Eastern Cooperative
Oncology Group performance status (ECOG 0 versus ECOG 1)

In both parts of the study, doxorubicin will be administered on day 1 of each
21-day cycle, followed by AMG 655 (part 1; part 2, arm A) or placebo (part 2
arm B). No more than 6 cycles of doxorubicin will be given. AMG 655 or placebo
monotherapy may continue after doxorubicin has been discontinued, until disease
progression, death unacceptable toxicity, consent withdrawal, or administrative
decision, for up to 30 months from the first administration of study treatment.

In part 2 of the study, subjects in the placebo group (arm B) may have the
opportunity to receive open label single agent AMG 655 ('roll over treatment')
upon disease progression.

Subjects will receive doxorubicin and AMG 655 (part 1; part 2, arm A) or
placebo (part 2, arm B), for up to 6 cycles, followed by AMG 655 or placebo
alone, until disease progression, death, AMG 655 or placebo intolerability,
consent withdrawal, or administrative decision, for up to 30 months from the
first administration of study treatment. Eligible subjects on arm B may then
receive single Agent AMG 6565 roll over treatment until subsequent disease
progression, death, unacceptable toxicity, consent withdrawal, or
administrative decision, for up to 30 months from the first administration of
study treatment. The median survival on the control arm, not including a
treatment effect from potential subsequent AMG 655, is anticipated to be
approximately to 12 months (van Glabdeke et al, 1999).

The maximum duration of the study is approximately 52 to 60 months (from the
first subject enrolled in part 1 until approximately 36 months form the last
subject randomized in part 2).

The safety follow-up visit will occur 30 days (+ 3 days) after the last dose of
investigational treatment. The day 60 follow-up visit will occur 60 days (+14
days) after the last dose of investigational treatment. Subject will be
contacted every 3 months (+/- 2 weeks) in the long-term follow-up, until 36
months after the last subject has been randomized, to assess survival and
disease progression, if not documented previously.