Trial Information

Randomized Phase III Study of Maintenance Therapy With Bevacizumab, Pemetrexed, or a Combination of Bevacizumab and Pemetrexed Following Carboplatin, Paclitaxel and Bevacizumab for Advanced Non-Squamous NSCLC

OBJECTIVES:

Primary

- To compare the overall survival (OS) of patients with advanced non-squamous non-small
cell lung cancer (NSCLC) treated with maintenance therapy with bevacizumab vs
pemetrexed disodium vs bevacizumab and pemetrexed disodium following induction therapy.

Secondary

- To determine the response rate in patients treated with these regimens.

- To evaluate the progression-free survival (PFS) of patients treated with these
regimens.

- To define the toxicity of these regimens in these patients.

- To determine the frequency of polymorphisms in VEGF 3578 AA, 1154 AA, ABCB1 G2677TT/AA,
and ERCC-118 TT in patients treated with induction therapy comprising paclitaxel,
carboplatin and bevacizumab and determine the association between genotypes and
response rate.

- To determine the association between bevacizumab and pemetrexed disodium population
pharmacokinetics and patient-specific covariate with bevacizumab or pemetrexed disodium
toxicity.

- To determine the frequency of TSER*3 polymorphisms in NSCLC and the association between
TSER polymorphisms and benefit from pemetrexed disodium.

- To evaluate TS and ERCC1 expression by RT-PCR and MTAP mutations in existing tumor
specimens as a predictor of pemetrexed disodium response.

- To evaluate polymorphisms within CYPs 2C8, 3A4, 3A5 and/or the UGT1A1 collectively or
monogenically as markers for variation in efficacious and/or toxic response of
individuals to treatment with taxanes.

- To explore the association between proteomic profiles and ICAM, VEGF, and FGF-beta with
the clinical outcomes of the study (OS, PFS, and response) (Closed as of 04/01/2010).

- To evaluate the ability of FOX03a to predict first-line treatment outcome in
non-squamous NSCLC.(Closed as of 04/01/2010)

- To evaluate the ability of ADSS1 to predict outcome of pemetrexed maintenance treatment
in non-squamous NSCLC.(Closed as of 04/01/2010)

- To develop proteomic classifiers to identify patient populations that would benefit
from bevacizumab or pemetrexed therapy.(Closed as of 04/01/2010)

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to
gender (male vs female), stage of disease (IIIB-T4Nx [with nodule in ipsilateral lung lobe
and not candidate for combined chemotherapy and radiation] and IV M1a vs IV M1b vs
recurrent), best response to first-time therapy (complete response/partial response vs
stable disease), and smoking status (never vs smoker).

- Induction therapy: Patients receive paclitaxel IV over 3 hours, carboplatin IV over
15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21
days for 4 courses in the absence of disease progression or unacceptable toxicity.

- Maintenance Therapy: Patients achieving complete response, partial response or stable
disease following induction therapy are randomized to 1 of 3 treatment arms. Treatment
begins within 6 weeks of the last day of induction chemotherapy administration.

- Arm I: Patients receive bevacizumab IV over 30-90 minutes on day 1.

- Arm II: Patients receive pemetrexed disodium IV over 10 minutes on day 1.

- Arm III: Patients receive bevacizumab as in arm I and pemetrexed as in arm II. In
all arms, courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetics, protein biomarkers, proteomic profiling (closed as of 04/01/10), and other
analyses.

After completion of study therapy, patients are followed up every 3 months for 2 years and
then every 6 months for 2-5 years.