Phase I/II Study to Evaluate the Efficacy and Safety of a Combination Chemotherapy

A pilot trial of combination of bortezomib, bevacizumab and carboplatin as first line therapy in patients with metastatic Non-Small Cell Lung Cancer (NSCLC). Phase I and II study of this combination in first line setting will be conducted in order to properly estimate the efficacy and safety of this regimen. This will form the basis for future studies comparing this combination to what is now considered standard regimen for first line therapy in patients with NSCLC, carboplatin, paclitaxel and bevacizumab.

Study design and methodology The study will have two phases. The phase I will use traditional dose escalation model (3-6 patient per dose level) to determine the maximum tolerated dose (MTD). \*\[In phase II, either level III or (MTD) will be used in the same every 21 day cycle to evaluate the efficacy and safety of the regimen in first line treatment of advanced NSCLC\]\* not conducted. Treatments administered In phase I, three dose levels of weekly bortezomib will be studied in conjunction with fixed dose carboplatin and bevacizumab on a 21 day cycle to define the maximum tolerated dose (MTD). A maximum of six cycles will be administered. Patients with complete response, partial response or stable disease after six cycles will be allowed to continue on single agent bevacizumab every 3 weeks as maintenance therapy until disease progression. If no dose limiting toxicity (DLT) is observed in 3 patients during the first cycle, the next dose level will be accrued. If 1 DLT is observed, 3 additional patients will be accrued to the dose level. If no additional DLTs are observed, the next dose level will be accrued. However, if 2 or more DLTs are observed in a given dose level, MTD will be defined. MTD will be defined as the dose below which ≥2 DLTs were observed. The following three levels will be studied: Level I (every 21 day cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.3 mg/m2 D8 : bortezomib 1.3 mg/m2 Level II (every 21 day cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.6 mg/m2 D8 : bortezomib 1.6 mg/m2 Level III(every 21 day cycle):D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.8 mg/m2 D8 : bortezomib 1.8 mg/m2 If 2 or more DLT are observed in Level 1, level -1 will be accrued. Level -1: (every 21 day cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1 mg/m2 D8: bortezomib 1 mg/m2 \*\[In phase II, either level III or the MTD dose level will be used in the same every 21 day cycle to evaluate the efficacy and safety of the regimen in first line treatment of advanced NSCLC. Efficacy data collected The following evaluations will be conducted to assess the efficacy of the combination: * response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria * disease free and overall survival, time to progress (TTP) and duration of response Safety data collected The following evaluations will be conducted to assess the safety of the combination chemotherapy: • toxicity based on National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0\]\* Not conducted Statistical procedures In phase I portion, 9-18 patients will be enrolled. The patients treated at recommended dose level for phase II will also be eligible for response evaluation as part of phase II. \*\[The primary objective of the phase II study is to estimate the efficacy and safety of the combination therapy with carboplatin, bortezomib and bevacizumab as the first line therapy in patients with advanced NSCLC. The primary endpoints are response rate and progression-free survival (PFS). (NOT CONDUCTED) In phase II portion, the optimal two-stage design for phase II clinical trials described by Simon et al. will be utilized. Overall survival, progression free survival and time to progression will be estimated using Kaplan-Meier methods. Time to progression, progression free survival and survival will be calculated from the date of study entry.\]\* (Phase II not conducted.)