Lung Cancer
Conditions
Keywords
lung cancer, Carboplatin, bortezomib, Bevacizumab
Brief summary
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.
Detailed description
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.)
Interventions
Level I (every 21 day cycle, D8), 1.3 mg/m2: Day 1: bevacizumab 15 mg/kg ,carboplatin Area Under the Curve (AUC 6) 900mg, bortezomib 1.3 mg/m2 Day 8 : bortezomib 1.3 mg/m2 Level II (every 21 day cycle): Day 1: bevacizumab 15 mg/kg, carboplatin Area Under the Curve (AUC 6) 900mg, bortezomib 1.6 mg/m2 Day 8 : bortezomib 1.6 mg/m2 Level III(every 21 day cycle): Day 1: bevacizumab 15 mg/kg, carboplatin Area Under the Curve (AUC 6) 900mg, bortezomib 1.8 mg/m2 Day 8 : bortezomib 1.8 mg/m2
Level II (every 21 day cycle, D8), 1.6 mg/m2
DRUGBortezomib 1.8 mg/m2
Level III (every 21 day cycle, D8) 1.8 mg/m2
Carboplatin AUC6
DRUGBevacizumab
Bevacizumab 15 mg/kg
DRUGTaxotere
Taxotere 70 + G-CSF
Sponsors
Millennium Pharmaceuticals, Inc.
Genentech, Inc.
University of Massachusetts, Worcester
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed SCLC (adeno- and large cell, anaplastic carcinoma and broncho-alveolar-carcinoma). Patients with squamous-cell histology are eligible with extra thoracic or peripheral lung lesions only. * Sputum cytology alone not acceptable evidence of cell type. Cytologic specimens obtained by brushing, washings, or needle aspiration of defined lesions will be acceptable. Mixed tumors will be categorized by the predominant cell type unless a small cell anaplastic elements are present, in which case the patient is ineligible. * Stage III B because of pleural effusion or Stage IV disease * Measurable disease. * Age: 18 years or older * No history of thrombotic, hemorrhagic, or coagulopathy disorders * international normalized ratio (INR\<1.5) and a prothrombin time (PTT) no greater than normal limits of normal within 1 week prior to registration. NB: subjects with lung cancer placed on anticoagulant therapy for a thrombotic event are not eligible for this study. * No gross hemoptysis (defined as bright red blood of ½ teaspoon or more) * No central nervous system (CNS) or brain metastasis * Laboratory Criteria (completed \<2 weeks before enrollment): * Hematologic: white blood cell (WBC) \> 3500/mm3 or absolute neutrophil count (ANC) \> 1500/mm3 and platelet count \> 100 000/ mm3; * Hepatic: Total bilirubin \< 1.5 mg/dl * Renal: Creatinine \< 1.5 mg/dl. or calculated * Creatinine clearance \> 45 ml/min (NB: Urine protein:creatinine ratio in
Exclusion criteria
) * Eastern Cooperative Oncology Group (ECOG) performance status \< 2 * Be free of active infection. * Be available for active follow up. * No prior chemotherapy for metastatic disease. * Be disease free for \> 5 years if they had a prior second malignancy other than treated basal cell carcinoma or squamous cell skin cancer, or carcinoma in situ of the cervix. * Female subject post-menopausal; surgically sterilized or willing to use an acceptable method of birth control for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Who Require Dose Delay/Reduction in Dose of Bortezomibin the First Cycle | up to 21 days for each dosing cycle | Dose limiting toxicity at Level 1,2 and 3: Number of subjects who required dose delay/reduction in dose of bortezomib in the first cycle of treatment. DLT defined by any of the following during first cycle: (1) GR4 neutropenia or thrombocytopenia, (2) Greater than GR3 non-hematological toxicity except alopecia or inadequately treated nausea or vomiting or (3) neurosensory toxicity of GR2 with pain or any neurotoxicity greater than GR2. |
Countries
United States
Participant flow
Pre-assignment details
Treatment q21 day cycle, maximum of 6 cycles. Patients with CR, PR, SD continued on single agent bevacizumab 15 mb/kg q 3 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Dose Level 1, 2 and 3 1.3 mg/m\^2 Bortezomib, 1.6 mg/m\^2 Bortezomib, and 1.8 mg/m\^2 Bortezomib
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). | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Phase I: Dose Level 1, 2 and 3 |
|---|---|
| Age, Continuous | 63 years |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 7 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Number of Subjects Who Require Dose Delay/Reduction in Dose of Bortezomibin the First Cycle
Dose limiting toxicity at Level 1,2 and 3: Number of subjects who required dose delay/reduction in dose of bortezomib in the first cycle of treatment. DLT defined by any of the following during first cycle: (1) GR4 neutropenia or thrombocytopenia, (2) Greater than GR3 non-hematological toxicity except alopecia or inadequately treated nausea or vomiting or (3) neurosensory toxicity of GR2 with pain or any neurotoxicity greater than GR2.
Time frame: up to 21 days for each dosing cycle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Dose Level 1 | Number of Subjects Who Require Dose Delay/Reduction in Dose of Bortezomibin the First Cycle | 0 participants |
| Phase 1 Dose Level II: | Number of Subjects Who Require Dose Delay/Reduction in Dose of Bortezomibin the First Cycle | 0 participants |
| Phase I Dose Level III | Number of Subjects Who Require Dose Delay/Reduction in Dose of Bortezomibin the First Cycle | 0 participants |