Trial Information

Phase I/II Trial of Induction Carboplatin/Paclitaxel With Bevacizumab Followed by Concurrent Thoracic Conformal Radiation Therapy With Carboplatin/Paclitaxel, Bevacizumab and Erlotinib in Stage IIIA/B Non-Small Cell Lung Cancer

OBJECTIVES:

Primary

- Determine the maximum tolerated dose of bevacizumab and erlotinib hydrochloride when
given together with carboplatin, paclitaxel, and thoracic conformal radiotherapy in
patients with stage IIIA or IIIB non-small cell lung cancer. (Phase I [closed to
accrual as of 1/3/2008])

- Determine the safety and toxicity profile of this regimen in these patients. (Phase I
[closed to accrual as of 1/3/2008])

- Determine the progression-free survival of patients treated with induction therapy
comprising carboplatin, paclitaxel, and bevacizumab followed by chemoradiotherapy
comprising thoracic conformal radiotherapy, carboplatin, paclitaxel, bevacizumab, and
erlotinib hydrochloride and consolidation therapy comprising bevacizumab and erlotinib
hydrochloride. (Phase II)

- Determine the overall toxicity profile of this regimen in these patients. (Phase II)

Secondary

- Determine the response rate in patients treated with induction therapy comprising
carboplatin, paclitaxel, and bevacizumab. (Phase I[closed to accrual as of 1/3/2008]
and II)

- Determine the toxicity profile of induction therapy in these patients. (Phase I [closed
to accrual as of 1/3/2008] and II)

- Determine the overall response rate and survival profile in patients treated with this
regimen. (Phase I [closed to accrual as of 1/3/2008] and II)

- Determine the feasibility and tolerability of administering consolidation therapy
comprising erlotinib hydrochloride and bevacizumab after treatment with combined
modality therapy (induction therapy and chemoradiotherapy) in these patients. (Phase I
[closed to accrual as of 1/3/2008] and II)

- Collect tumor and blood samples from these patients for future analysis of correlation
between molecular markers and clinical benefit. (Phase I [closed to accrual as of
1/3/2008] and II)

OUTLINE: This is a nonrandomized, open-label, controlled, phase I (closed to accrual as of
1/3/2008), dose-escalation study of bevacizumab and erlotinib hydrochloride, followed by a
phase II study.

- Phase I (closed to accrual as of 1/3/2008):

- 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. Treatment
repeats every 21 days for 2 courses. Patients with stable or responding disease
proceed to chemoradiotherapy.

- Chemoradiotherapy: Patients receive chemoradiotherapy according to their assigned
dose cohort:

- Cohort 1: Patients undergo thoracic conformal radiotherapy (TCRT) on days
1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. Patients also receive
carboplatin IV and paclitaxel IV on days 1, 8, 15, 22, 29, 36, and 43 and
bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43.

- Cohort 2: Patients undergo TCRT and receive carboplatin, paclitaxel, and
bevacizumab as in cohort 1. Patients also receive oral erlotinib
hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and 44-47.

- Cohort 3: Patients undergo TCRT and receive carboplatin, paclitaxel, and
bevacizumab as in cohort 1. Patients also receive higher doses of oral
erlotinib hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and
44-47.

Cohorts of 5 patients receive chemoradiotherapy as described above until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
(with grade 4 toxicity) or 3 (with grade 3 toxicity) of 5 patients experience dose-limiting
toxicity.

Three to 6 weeks after completion of chemoradiotherapy, patients proceed to consolidation
therapy.

- Consolidation therapy: Patients receive bevacizumab IV on day 1 and oral erlotinib
hydrochloride on days 1-21. Treatment repeats every 21 days for up to 6 courses in the
absence of disease progression or unacceptable toxicity.

- Phase II:

- Induction therapy: Patients receive induction therapy as in phase I (closed to accrual
as of 1/3/2008).

- Chemoradiotherapy: Patients undergo TCRT and receive carboplatin and paclitaxel as in
phase I (closed to accrual as of 1/3/2008). Patients also receive bevacizumab and
erlotinib hydrochloride as in phase I (closed to accrual as of 1/3/2008) at the
MTD/drug combination determined in phase I (closed to accrual as of 1/3/2008).

- Consolidation therapy: Patients receive consolidation therapy as in phase I (closed to
accrual as of 1/3/2008).

Tumor tissue and peripheral blood is collected at baseline for future correlative and
biomarker studies.

After completion of study therapy, patients are followed every 2 months for 2 years, every 4
months for 2 years, every 6 months for 2 years, and then annually thereafter.