(NJ 1508) Modulation of Autophagy With Hydroxychloroquine in Combination With Carboplatin, Paclitaxel and Bevacizumab in Patients With Advanced/Recurrent Non-Small Cell Lung Cancer - A Phase I/II Study
(NJ 1508) Modulation of Autophagy With Hydroxychloroquine in Combination With Carboplatin, Paclitaxel and Bevacizumab in Patients With Advanced/Recurrent Non-Small Cell Lung Cancer - A Phase I/II Study
RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine, carboplatin, and paclitaxel and 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 tumor cells by blocking blood flow to the tumor. Giving hydroxychloroquine together with carboplatin, paclitaxel and bevacizumab may kill more tumor cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of hydroxychloroquine when given together with carboplatin, paclitaxel, and bevacizumab and to see how well they work in treating patients with recurrent advanced non-small cell lung cancer.
OBJECTIVES:
Primary
Secondary
OUTLINE: This is a multicenter study. This is a phase I, dose-escalation study of carboplatin and hydroxychloroquine followed by a phase II study.
Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 90 minutes on day 1 and oral hydroxychloroquine on days 1-21. Treatment repeats every 21 days for a total of 4 courses. Patients then receive bevacizumab IV over 30-90 minutes every 21 days and oral hydroxychloroquine daily for up to 1 year in the absence of disease progression or unacceptable toxicity.
After completion of study therapy, patients are followed every 6 months.
DISEASE CHARACTERISTICS:
Histologically or cytologically confirmed advanced non-small cell lung cancer, meeting the following criteria:
Recurrent disease
No component of squamous cell carcinoma
Mixed tumors will be categorized by predominant cell type
Diagnosis established on metastatic tumor aspirate or biopsy (not sputum cytology alone) and meets 1 of the following staging criteria:
Measurable disease
More than 1 year since post-operative adjuvant therapy for previously resected non-small cell lung cancer with evidence of disease progression
No known CNS metastases by CT scan or brain MRI within the past 28 days
PATIENT CHARACTERISTICS:
ECOG performance status 0-1
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 9 g/dL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 2 times ULN and no other liver function test abnormality in patients with Gilbert disease)
AST/ALT ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases)
Alkaline phosphatase ≤ 2.5 times ULN
Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
INR ≤ 1.5 and aPTT normal
Urine protein:creatinine ratio < 1.0 OR urine protein ratio < 1,000 mg by 24-hour urine collection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No ongoing or active infection
No psoriasis or porphyria
No HIV positivity
No significant traumatic injury within the past 28 days
No serious non-healing wound, ulcer, or bone fracture
No peripheral or sensory neuropathy > grade 1
No hypertension that cannot be controlled by antihypertensive medication (i.e., blood pressure > 150/100 mm Hg despite optimal medical therapy)
No cardiovascular disease, including any of the following:
No other active malignancy within the past 3 years, except curatively treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or ductal or lobular carcinoma in situ of the breast, or other curatively treated malignancy with no evidence of disease > 3 years
No retinal or visual field changes from prior 4-aminoquinoline compound therapy
No known hypersensitivity to 4-aminoquinoline compound
No known glucose-6-phosphate (G-6P) deficiency
No known bleeding diathesis or coagulopathy
No known gastrointestinal pathology that would interfere with drug bioavailability
No known prior hypersensitivity to carboplatin, paclitaxel, bevacizumab, hydroxychloroquine, or any of their components
No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
No history of gross hemoptysis (i.e., bright red blood of a ½ teaspoon or more) within the past 3 months
No history of any social or medical condition that, in the investigator's opinion, might interfere with the patient's ability to comply with the protocol or pose additional or unacceptable risk to the patient
PRIOR CONCURRENT THERAPY:
See Disease Characteristics
At least 2 weeks since prior radiation to sites other than the brain, and recovered to ≤ grade 1
At least 28 days since prior and no concurrent full-dose anticoagulants or thrombolytic agents
At least 28 days since prior major surgical procedure or open biopsy and no anticipated need for such during study therapy
No prior cytotoxic chemotherapy or targeted therapy in the advanced or metastatic setting
No concurrent treatment for rheumatoid arthritis or systemic lupus erythematosus
No concurrent combination antiretroviral therapy
No concurrent hydroxychloroquine for treatment or prophylaxis of malaria
No concurrent aurothioglucose
No other concurrent investigational or commercial agent or therapy for this malignancy