Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title 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
IRB E5508
CC 12-108
Hospital Beachwood, Fairview, Hillcrest, Independence, Mansfield, North Coast Cancer, South Pointe, Strongsville, Wooster
Stage N/A
Phase Phase 3
Disease Lung
Drug Bevacizumab , Carboplatin, Paclitaxel , Pemetrexed
Description
- Primary Objective
- To compare the overall survival associated with maintenance therapy with bevacizumab, pemetrexed or the combination in patients with advanced stage NSCLC
- Secondary Objectives
- To determine the response rate in the three treatment arms
- To evaluate the progression-free survival
- To define the toxicity associated with each regimen
- To conduct correlative science studies that will help to select predictive bio-markers with a primary focus on the following:
- To determine the frequency of polymorphisms in VEGF 3578 AA, 1154 AA, ABCB1 G2677TT/AA and ERCC-118 TT in patients with NSCLC receiving paclitaxel, carboplatin and bevacizumab therapy and determine the association between genotypes and response rate.
- To determine the association between bevacizumab and pemetrexed population pharmacokinetics and patient specific covariates with bevacizumab or pemetrexed toxicity.
- To determine the frequency of TSER*3 polymorphisms in NSCLC and the association between TSER polymorphisms and benefit from pemetrexed.
- To evaluate TS and ERCC1 expression by RT-PCR and MTAP mutations as a predictor of pemetrexed 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.
Inclusion Criteria
Step 1
- Cytological or histological confirmation of non-small cell lung cancer.
- Predominant non-squamous histology (patients with NSCLC NOS are eligible). Mixed tumors will be categorized by the predominant cell type. If small cell elements are present the patient is ineligible.
- Stage IV disease (includes M1a, M1b stages or recurrent disease) (according to the 7th edition of the TNM classification system). Patients with T4NX disease (stage III B) with nodule in ipsilateral lung lobe are eligible if they are not candidates for combined chemotherapy and radiation.
- No prior malignancy within the last 3 years with the exception of superficial melanoma, basal cell carcinoma or carcinoma in situ.
- No prior systemic chemotherapy for advanced stage lung cancer.
- Prior adjuvant chemotherapy is allowed if at least 12 months have elapsed since the prior chemotherapy administration and registration.
- At least 2 weeks must have elapsed between completion of prior radiotherapy and registration.
- Prior use of paclitaxel, pemetrexed or bevacizumab is not allowed. Prior use of carboplatin is allowed if it was given as part of adjuvant chemotherapy.
- Age ≥ 18 years.
- Patients with brain metastasis must have received local therapy to the brain and have no evidence of progression in the brain for at least 2 weeks from the time of completion of local therapy, prior to registration.
- No major hemoptysis within 4 weeks prior to registration (defined as bright red blood of half tea-spoon or more).
- Patients must have acceptable bone marrow, renal and hepatic function within 2 weeks of registration as defined below:
- Leukocytes ≥ 3,000/mm³
- Absolute neutrophil count ≥ 1,500/ mm³
- Platelets ≥ 100,000/mm³
- Total bilirubin ≤ institutional upper limits of normal
- AST(SGOT) and ALT(SGPT) ≤ 3 X institutional upper limit of normal
- Creatinine within normal institutional limits OR Creatinine clearance ≥ 60 mL/min/1.73m² (normalized to BSA) for patients with creatinine levels above institutional normal (See Appendix VI).
- Urine dipstick must be ≤ 0-1+. If urine dipstick results are > 1+, calculation of Urine Protein Creatinine (UPC) is required. Patients must have a UPC ratio < 1 to participate in the study (see section 8.3.13 for calculation details).
- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements are excluded.
- Patients must have measurable or nonmeasurable disease as defined by the RECIST criteria in Section 6.1.2. Baseline measurements and evaluation of all sites of disease must be obtained ≤ 4 weeks prior to registration.
- Patients with history of hypertension should be adequately controlled (BP < 150/100) with appropriate anti-hypertensive therapy or diet
- Patients must have an ECOG Performance Status of 0 or 1 (See Appendix II).
- No history of arterial thrombotic events or major bleed within 12 months prior to registration
- Concomitant use of therapeutic anti-coagulation is allowed.
- Patients must not have had any major surgery, or significant traumatic injury within 6 weeks prior to registration. Biopsy procedures and chest tube insertion are not considered major surgery for the purpose of this protocol.
- Patients must not have had a core biopsy within 7 days prior to registration.
- Patients must not have significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to registration.
- Patients with clinically significant cardiovascular disease are excluded.
- Patients must not have a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to registration.
- No history of serious non-healing wounds.
- Patients with cavitary lesions in the lungs are not eligible.
- Women must not be pregnant or breast-feeding due to the lack of adequate safety data with the use of bevacizumab and pemetrexed in this group. All females of childbearing potential must have a blood test within 2 weeks prior to registration to rule out pregnancy.
- Both fertile men and women must agree either to abstain from sexual intercourse or to use adequate contraceptive measures during study treatment and for at least 6 months after completion of the study drugs.
- Patients with HIV disease who are taking anti-retroviral therapy are excluded since there are no safety data with the concomitant use of chemotherapy and antiretroviral agents.
Step 2
- Patient must have an overall response per RECIST criteria (see section 6.1.4) of stable or better after 4 cycles of induction therapy on step 1. NOTE: If patient discontinues Induction treatment early due to toxicities, but has received a minimum of 3 complete cycles of induction therapy and has an overall response per RECIST criteria of stable or better, they may be evaluated for step 2.
- Patient must have an ECOG performance status of 0 or 1 (See Appendix II).
- Patients must be registered to Step 2 within 6 weeks of the last day of chemotherapy administration on Step 1.
- Patients must have acceptable bone marrow, renal and hepatic function within 2 weeks of registration as defined below:
- Leukocytes ≥ 3,000/mm³
- Absolute neutrophil count ≥ 1,500/mm³
- Platelets ≥ 100,000/mm³
- Total bilirubin ≤ institutional upper limit of normal
- AST(SGOT) and ALT(SGPT) ≤ 3 X institutional upper limit of normal
- Creatinine ≤ institutional upper limit of normal OR Creatinine clearance ≥ 60 mL/min/1.73m² (normalized to BSA) for patients with creatinine levels above institutional normal.
- Urine dipstick must be ≤ 0-1+. If urine dipstick results are > 1+, calculation of Urine Protein Creatinine (UPC) is required. Patients must have a UPC ratio < 3.5 to participate in the study (see section 8.3.13 for calculation details).
