A Multicenter, Open Label, Randomized Study of AMG 951 in Subjects with Previously Untreated Stage IIIb/IV Non-Small Cell Lung Cancer (NSCLC) Treated with Chemotherapy with or without Bevacizumab

In this study, the study medication AMG 951 is evaluated for the treatment of
patients with non-small cell lung carcinoma. AMG 951 is considered
experimental. Carboplatin and paclitaxel are chemotherapy medications that have
been approved as a treatment regimen for non-small cell lung cancer by
Regulatory Agencies. Bevacizumab (Avastin) is not approved for non-small cell
lung cancer treatment. Bevacizumab has been approved for use in colorectal
cancer.
AMG 951 will be administered in this study along with the carboplatin and
paclitaxel chemotherapy regimen and bevacizumab.
AMG 951 is produced using recombinant DNA technology. AMG 951 binds to specific
places on cancer cells and causes the cells to die in laboratory studies. This
experimental drug has prevented or slowed the growth of several different types
of human cancer cells grown in animals. Up to now, in the first study of AMG
951 in humans, doses of 15 mg/kg, 8 mg/kg and 4 mg/kg (similar to the doses to
be given in this study) have been given safely with no significant side effects
in 50 people.
Approximately 200 subjects will participate in the research study.
Approximately twenty centers in Europe will be involved. The study may also be
expanded to other regions of the world as necessary.

Objectives:
Phase 1b: To determine the maximum tolerated dose (MTD) (up to 8mg/kg/day)
through safety and tolerability of multiple doses of AMG 951 administered by
intravenous (IV) infusion to subjects with NSCLC in combination with
chemotherapy and bevacizumab

Phase 2: To evaluate the objective response rate by modified RECIST for AMG 951
at varying dose schedules in combination with carboplatin / paclitaxel ±
bevacizumab for subjects with NSCLC.

Study design:
This is a phase 1b/2 multicenter, open label, randomised study of AMG 951 in
subjects with previously untreated stage IIIb/IV NSCLC treated with
chemotherapy with or without bevacizumab.

For the phase 1b portion of the study, six subjects per group will receive
Paclitaxel (200 mg / m2 over 3 hours (± 10 minutes)), carboplatin (AUC=6.0
mg/mL.min IV over 15-30 minutes) and bevacizumab (15 mg/kg IV over 90 minutes
(+ 10 minutes)) on day 1. This will be followed by AMG 951 at the assigned
dose (continuous IV infusion over 60 minutes ± 10 minutes). AMG 951 will be
given once daily on days 1-5. Up to 6 cycles of treatment will be
administered.
Six subjects will be enrolled into cohort A1 to receive chemotherapy,
bevacizumab and AMG 951 at 4 mg/kg/day. Following review of the DLT data, a
further six subjects will be enrolled into either cohort A2 (chemotherapy,
bevacizumab and AMG 951 at 8 mg/kg/day) or cohort A3 (chemotherapy, bevacizumab
and AMG 951 at 1.5 mg/kg/day). Only subjects eligible to receive bevacizumab
will be enrolled into the phase 1b study. Subjects with squamous NSCLC and/or
CNS metastases will not be enrolled into the phase 1b study.

For the phase 2 portion of the study, subjects will be assigned to a set of
treatment groups depending on their eligibility to receive bevacizumab.
Subjects with squamous NSCLC and/or CNS metastases will not be eligible to
receive bevacizumab and will be assigned to either cohort A or B. Subjects who
are eligible to receive bevacizumab will be assigned to cohort C, D or E.
Cohorts are defined as follows:

Subjects with squamous NSCLC or CNS mets:
Cohort A: Chemotherapy alone
Cohort B: Chemotherapy plus 8 mg/kg AMG 951 for 5 days

Subjects without squamous NSCLC and without CNS mets:
Cohort C: Chemotherapy and bevacizumab
Cohort D: Chemotherapy, bevacizumab plus 8 mg/kg AMG 951 for 5 days
Cohort E: Chemotherapy, bevacizumab plus 8 mg/kg AMG 951 for 2 days

Phase 1b:
Six subjects will be enrolled into cohort A1 to receive chemotherapy,
bevacizumab and AMG 951 at 4 mg/kg/day. Following review of the DLT data, a
further six subjects will be enrolled into either cohort A2 (chemotherapy,
bevacizumab and AMG 951 at 8 mg/kg/day) or cohort A3 (chemotherapy, bevacizumab
and AMG 951 at 1.5 mg/kg/day). Only subjects eligible to receive bevacizumab
will be enrolled into the phase 1b study. Subjects with squamous NSCLC and/or
CNS metastases will not be enrolled into the phase 1b study.

Phase II:
Subjects with squamous NSCLC or CNS mets:
Cohort A: Chemotherapy alone
Cohort B: Chemotherapy plus 8 mg/kg AMG 951 for 5 days

Subjects without squamous NSCLC and without CNS mets:
Cohort C: Chemotherapy and bevacizumab
Cohort D: Chemotherapy, bevacizumab plus 8 mg/kg AMG 951 for 5 days
Cohort E: Chemotherapy, bevacizumab plus 8 mg/kg AMG 951 for 2 days

Burden for the patients:

Regular visits to the hospital to undergo the procedures as defined in Appendix
A: medical and medication history, physical exam, vital signs, brain CT/MRI
scan, ECG, hematology, chemistry, AMG 951 and antibody levels. Adverse events
and concomitant medications will be recorded throughout study participation.

Risk:
In five randomised clinical trials, the incidence of arterial thromboembolic
events including cerebrovascular accidents (CVAs), transient ischaemic attacks
(TIAs) and myocardial infarctions (MIs) was higher in patients receiving
bevacizumab in combination with chemotherapy compared to those who received
chemotherapy alone.
A history of arterial thromboembolic events or age over 65 years was associated
with an increased risk of developing arterial thromboembolic events during
therapy. Caution should be taken when treating these patients with bevacizumab.
Therapy should be permanently discontinued in patients who develop arterial
thromboembolic events.
Prior anthracycline exposure and/or prior radiation to the chest wall may be
possible risk factors for the development of Congestive Heart Failure. Caution
should be exercised before initiating Bevacizumab therapy in patients with
these risk factors.
The highest dose of bevacizumab tested in humans (20 mg/kg of body weight,
intravenous) was associated with severe migraine in several patients. Overdose
with this product have not been reported.