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
Overview
- Phase
- Phase 3
- Intervention
- Paclitaxel
- Conditions
- Lung Cancer
- Sponsor
- ECOG-ACRIN Cancer Research Group
- Enrollment
- 1516
- Locations
- 433
- Primary Endpoint
- Overall Survival
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Pemetrexed disodium may stop the growth of tumor cells by blocking some enzymes needed for cell growth. It is not yet known whether giving bevacizumab or pemetrexed disodium alone or in combination is more effective in treating non-squamous non-small cell lung cancer.
PURPOSE: This randomized phase III trial is studying bevacizumab and pemetrexed disodium alone or in combination after induction therapy to see how well they work in treating patients with advanced non-squamous non-small cell lung cancer.
Detailed Description
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. 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 (Arm I): 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 A: Patients receive bevacizumab IV over 30-90 minutes on day 1. * Arm B: Patients receive pemetrexed disodium IV over 10 minutes on day 1. * Arm C: Patients receive bevacizumab as in arm A and pemetrexed as in arm B. 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 correlative studies. After completion of study therapy, patients are followed up every 3 months for 2 years and then every 6 months for 2-5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A (Induction then Maintenance with Bevacizumab)
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. Patients in arm A receive bevacizumab IV over 30-90 minutes on day 1 of every cycle until progression or unacceptable toxicity.
Intervention: Paclitaxel
Arm A (Induction then Maintenance with Bevacizumab)
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. Patients in arm A receive bevacizumab IV over 30-90 minutes on day 1 of every cycle until progression or unacceptable toxicity.
Intervention: Carboplatin
Arm A (Induction then Maintenance with Bevacizumab)
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. Patients in arm A receive bevacizumab IV over 30-90 minutes on day 1 of every cycle until progression or unacceptable toxicity.
Intervention: Bevacizumab
Arm B (Induction then Maintenance with Pemetrexed)
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. Patients in arm B receive pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.
Intervention: Paclitaxel
Arm B (Induction then Maintenance with Pemetrexed)
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. Patients in arm B receive pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.
Intervention: Carboplatin
Arm B (Induction then Maintenance with Pemetrexed)
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. Patients in arm B receive pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.
Intervention: Bevacizumab
Arm B (Induction then Maintenance with Pemetrexed)
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. Patients in arm B receive pemetrexed IV over 10 minutes on day 1 of every cycle until progression or unacceptable toxicity.
Intervention: Pemetrexed Disodium Heptahydrate
Arm C (Induction then Maintenance with Bevacizumab & Pemetrexed)
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. Patients in arm C receive bevacizumab as in arm A and pemetrexed as in arm B.
Intervention: Paclitaxel
Arm C (Induction then Maintenance with Bevacizumab & Pemetrexed)
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. Patients in arm C receive bevacizumab as in arm A and pemetrexed as in arm B.
Intervention: Carboplatin
Arm C (Induction then Maintenance with Bevacizumab & Pemetrexed)
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. Patients in arm C receive bevacizumab as in arm A and pemetrexed as in arm B.
Intervention: Bevacizumab
Arm C (Induction then Maintenance with Bevacizumab & Pemetrexed)
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. Patients in arm C receive bevacizumab as in arm A and pemetrexed as in arm B.
Intervention: Pemetrexed Disodium Heptahydrate
Outcomes
Primary Outcomes
Overall Survival
Time Frame: Assessed every 6 weeks during induction therapy and every 3 cycles during maintenance therapy; after discontinuation of study therapy, assessed every 3 months for 2 years and every 6 months for years 3-5
Overall survival is defined as the time from randomization to death or date last known alive. The primary analysis is among patients who were randomized to the maintenance therapy. Patients who received induction therapy only and did not participate in the randomization part of the study were not included in this analysis.
Secondary Outcomes
- Progression-free Survival(Assessed every 6 weeks during induction therapy and every 3 cycles during maintenance therapy; after discontinuation of study therapy, assessed every 3 months for 2 years and every 6 months for years 3-5)
- Response Rate(Assessed every 6 weeks during induction therapy and every 3 cycles during maintenance therapy; after discontinuation of study therapy, assessed every 3 months for 2 years and every 6 months for years 3-5)