A Phase 1b/2 Trial of AMG 479 or AMG 102 in Combination with Platinum-based Chemotherapy as First-Line Treatment for Extensive Stage Small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the developed
world, accounting for over 1,000,000 deaths each year globally (Parkin, Bray et
al. 2005). Small cell lung cancer represents approximately 10 to 30% of all new
lung cancer cases (DeVita, Hellman et al. 2005), with incidence rates declining
among men but continuing to increase among women in most regions (Devesa, Bray
et al. 2005). About 77,000 of the 550,000 new cases (14 %) of lung cancer
diagnosed in 2004 in the United States and Europe were classified as having
small cell histology. These tumors are characterized by rapid growth kinetics,
early dissemination to regional lymph nodes and distant sites, and sensitivity
to radiotherapy and chemotherapy (Pass 2005).
The treatment of subjects with SCLC is dependent on disease extent: limited or
extensive stage disease. Limited disease includes tumors confined to one
hemithorax, with or without regional lymph node metastases, including hilar,
ipsilateral and contralateral mediastinal, and ipsilateral and contralateral
supraclavicular lymph nodes (Stahel, Ginsberg et al. 1989), which can be safely
encompassed within a tolerable radiation field (Kalemkerian, Akerley et al.
2008). Extensive disease extends beyond these boundaries and may include
malignant pleural or pericardial effusion or hematogenous metastases (Shepherd,
Crowley et al. 2007). Approximately 60% to 70% of subjects with SCLC present
with extensive disease (Hanna, Bunn et al. 2006). Although ORRs of up to 69%
have been reported in recent phase 3 trials with first-line chemotherapy for
extensive disease, relapse occurs early in the majority of subjects, and
virtually all (~ 95%) eventually succumb to their disease (Noda, Nishiwaki et
al. 2002; Eckardt, von Pawel et al. 2006; Hanna, Bunn et al. 2006). The mOS for
patients with extensive disease (7 to 9 months, with a 5-year mOS of 2%) has
remained unchanged over the last several decades (Jackman and Johnson 2005).

Primary Objective:
Part 1: To identify a dose of AMG 479 in combination with etoposide plus
carboplatin and/or etoposide plus cisplatin, and of AMG 102 in combination with
etoposide plus carboplatin and/or etoposide plus cisplatin that can be
administered safely and is tolerated as determined by the incidence of
dose-limiting toxicity (DLT)
Part 2: To estimate the relative treatment effect of AMG 479 (at the dose
selected in Part 1) in combination with chemotherapy (etoposide plus
carboplatin and/or etoposide plus cisplatin, as determined in part 1), and of
AMG 102 (at the dose selected in Part 1) in combination with chemotherapy,
compared with placebo plus chemotherapy, as measured by the respective hazard
ratios (HR) for overall survival (OS).

This study has 2 parts.
Part 1 is a multi-center, open-label dose de-escalation phase 1b segment of AMG
479 in combination with etoposide plus cisplatin (Cohort 1) or carboplatin
(Cohort 2), and of AMG 102 in combination with etoposide plus cisplatin (Cohort
3) or carboplatin (Cohort 4). Once respective doses of AMG 479 and of AMG 102
have been identified that are safe and tolerated based on the incidence of DLT,
Part 2 will open for enrollment.
Part 2 is a randomized, double-blind, placebo-controlled phase 2 segment of AMG
479 (at the dose selected in Part 1), and of AMG 102 (at the dose selected in
Part 1), and of placebo plus platinum-based chemotherapy (etoposide plus
carboplatin and/or etoposide plus cisplatin, as determined in part 1) as
first-line treatment for subjects with extensive stage SCLC. Subjects (n = 180)
will be randomized in a 1:1:1 ratio to each treatment arm (n = 60 per arm).
Randomization will be stratified according to gender (female; male) and
chemotherapy (etoposide and cisplatin; etoposide and carboplatin).
In both parts of the study, chemotherapy (etoposide plus carboplatin or
cisplatin) will be administered on day 1 of each 21-day (Q3W) cycle. Etoposide
will also be administered on day 2 and 3 of each Q3W cycle. Premedication (see
Section 6.2.2.3), vigorous hydration and diuresis (see Section 6.2.2.4) will be
required for chemotherapy treatment. Investigational product (IP; AMG 479 [Part
1, Cohorts 1 and 2; Part 2, Arm A] or AMG 102 [Part 1, Cohorts 3 and 4; Part 2,
Arm B] or placebo [Part 2, Arm C]) will be administered after the chemotherapy
infusion on day 2 of the initial cycle, and day 1 of each Q3W cycle thereafter.
Four cycles of chemotherapy will be given. Patients with best tumor response
(maximum tumor regression, per RECIST) after thesecond on-study treatment tumor
assessment will receive an additional 2 cycles (a total of 6 cycles) of
chemotherapy. Subjects who complete 4 to 6 cycles of chemotherapy or who
discontinue chemotherapy early will continue to receive IP (AMG 479, or AMG
102, or placebo) single agent maintenance therapy on day 1 of each Q3W cycle
for up to 24 months from the date of first study treatment administration
(study day 1). Subjects who have completed 24 months of IP may be eligible for
continued treatment with IP by extension protocol or as provided for by the
local country*s regulatory mechanism (see Section 13). Study treatment will
cease if a subject experiences progressive disease (PD), death, unacceptable
toxicity, withdraws consent, or due to an administrative decision (by the
investigator or Amgen).
Radiological imaging to assess PD (per modified RECIST) will be performed every
6 weeks (± 7 days) during the first 6 months of the study, and every 9 weeks (±
7 days) thereafter, until subjects develop PD (per modified RECIST) or begin a
new cancer treatment.
A follow-up visit will occur 30 days (+ 7 days) and 60 days (+ 14 days) after
the last dose of protocol-specified treatment. Subjects will be contacted every
3 months (± 2 weeks) in the long-term follow-up, for up to 36 months from the
date of the last subject randomized, to assess survival. Please refer to the
Study Schema for an overview of the 2-part study design.

Investigational Product:
Part 1: Cohorts 1a and 2a: AMG 479 18 mg/kg intravenous (IV) on day 2 of the
initial cycle, and day 1 of each Q3W cycle thereafter AMG 479 18 mg/kg IV on
day 1 of each Q3W cycle during IP maintenance treatment
Cohort 3a and 4a:
AMG 102 15 mg/kg IV on day 2 of the initial cycle, and day 1 of each Q3W cycle
thereafter
AMG 102 15 mg/kg IV on day 1 of each Q3W cycle during IP maintenance treatment
Lower doses of AMG 479 and/or AMG 102 may be explored based on safety and PK
data, to determine the maximum tolerated dose. Refer to Section 6.1.1.1 for
details.
Part 2: AMG 479 (Arm A), AMG 102 (Arm B), at the respective doses selected in
Part 1,
or matching placebo (Arm C), IV Q3W:
day 2 of the initial cycle, and day 1 of each Q3W cycle thereafter

An individual subject may receive IP treatment for up to 24 months from study
day 1. Study treatment will cease if a subject experiences PD, death,
unacceptable toxicity, withdraws consent, or due to an administrative decision
(by the investigator or Amgen). After stopping study treatment, subjects will
be followed every 3 months for up to 36 months to assess disease status and
survival. Subjects who have completed 24 months of IP may be eligible for
continued treatment with IP by extension protocol or as provided for by the
local country*s regulatory mechanism.
The subject accrual period is estimated to be approximately 6 to 12 months for
Part 1, and approximately 18 months for Part 2. The end of the clinical study
is when all subjects have completed the study treatment and long-term follow-up
(up to a maximum of 36 months from the date the last subject is randomized).
The maximum duration of the study is approximately 66 months (from the first
subject enrolled in Part 1 until approximately 36 months from the last subject
enrolled in Part 2).