Phase I/II Study to Evaluate the Efficacy and Safety of Combination Chemotherapy With Carboplatin, Bortezomib and Bevacizumab as First Line Therapy in Patients With Advanced Non-small Cell Lung Cancer
Patient population Stage IIIB with pleural effusion or stage IV Non-Small Cell Lung Cancer.
No prior chemotherapy. Specific inclusion and exclusion criteria are detailed in section
3.2. Number of patients Phase I: 9-18 patients Phase II: 19-55 patients A maximum of 55
patients (range 31-55). 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 the phase II portion, the optimal two-stage design for phase II clinical trials described
by Simon et al. will be utilized (33).
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
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.
NUMBER OF EVALUABLE PATIENTS WITH UNACCEPTABLE TOXICITIES NEXT DOSE LEVEL 0/3 Accrue 3 new
patients for next highest dose level. 1/3 Accrue additional 3 patients at current dose
level. 1/3 + 0/3 Accrue 3 new patients for next dose level. 1/3 + 1/3 Accrue 3 new patients
to previous dose level (if only 3 patients were enrolled to that cohort. If 6
patients had been enrolled already, then declare that Previous dose as MTD).
1/3 + 2/3 Stop: Previous dose = MTD 2/3 Stop: Previous dose = MTD
The following three levels will be studied:
Level I (q21d cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.3 mg/m2 D8 :
bortezomib 1.3 mg/m2
Level II(q21d cycle): D1: carboplatin AUC 6, bevacizumab 15 mg/kg, bortezomib 1.6 mg/m2 D8 :
bortezomib 1.6 mg/m2
Level III(q21d 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: (q21d 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 q21day 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 RECIST criteria
- disease free and overall survival, TTP and duration of response Safety data collected
The following evaluations will be conducted to assess the safety of the combination
• toxicity based on NCI-CTCAE version 3.0 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).
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The primary objective is to estimate the efficacy and safety of combination therapy with Carboplatin, bortezomib and Bevacizumab as first line therapy in advanced NSCLC. The primary endpoints are response rate and progression-free survival (PFS).
William Walsh, MD
University of MassachusettsMedical School
United States: Institutional Review Board
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