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CTSU E5508

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

Eligibility 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 within normal institutional limits
  • 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
  • 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.

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 RECIST criteria. 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.

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, such as thoracotomy, lapartomy, craniotomy, or significant traumatic injury within 6 months 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, ulcers, or bone fractures.

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 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.

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.

Treatment Plan

All eligible patients will receive 4 cycles of Taxol/Carbo/Bevacizumab given in 21 day cycles

  • Taxol 200 mg/m2 IV over 3 hours every 21 days
  • Carboplatin AUC=6 IV over 15-30 min every 21 days
  • Bevacizumab 15 mg/kg IV over 30-90 min every 21 days

Patients who do not progress after 4 cycles will be randomized to one of three maintenance arms.

  • Arm A Bevacizumab 15 mg/kg IV over 30-90 min every 21 days
  • Arm B Pemetrexed 500 mg/m2 IV over 10 min every 21 days
  • Arm C Pemetrexed 500 mg/m2 IV over 10 min every 21 days, followed by Bevacizumab 15 mg/kg IV over 30-90 min every 21 days

Treatment will continue until progression or unacceptable toxicity. No drugs are provided free for this protocol. All are commercially available and approved for this indication.