Hydroxychloroquine + Carboplatin, Paclitaxel and Bevacizumb in Non-Small Cell Lung Cancer (NSCLC)

The purpose of this study is to examine the combination of one standard treatment for lung cancer plus an additional drug, hydroxychloroquine. The standard treatment for lung cancer being used includes 2 chemotherapy drugs, called paclitaxel and carboplatin, plus a drug that targets blood vessels, called bevacizumab (also known as avastin).

Recent medical science suggests that the investigators may be able to make anticancer therapy work better if they can block autophagy. Autophagy is a cellular process that helps normal cells live through times of stress, for example during times of starvation. Studies suggest that cancer cells may take advantage of autophagy to survive longer and to survive despite treatment with chemotherapy. The investigators want to know if blocking autophagy while giving standard treatment for lung cancer will improve the treatment of lung cancer. The investigators will use hydroxychloroquine, which blocks autophagy, in addition to standard treatment in the treatment of lung cancer.

The primary endpoint is to determine the recommended Phase II dose of paclitaxel, carboplatin, bevacizumab in combination with hydroxychloroquine in patients with advanced or recurrent NSCLC.

The primary objective of this study is to assess the antitumor activity, as measured by tumor response rate, of paclitaxel, carboplatin, bevacizumab and hydroxychloroquine in patients with advanced or recurrent NSCLC cancer.

Secondary Endpoint(s):

• To measure time to progression, percent one-year survival and overall survival.
• To assess toxicity of this regimen.
• To develop pharmacodynamic markers for autophagy detection in patient specimens.
• To characterize the effects of hydroxychloroquine on autophagy in patients in vivo.

• Drug: Paclitaxel
  200 mg/m2 intravenously over 3 hours on Day 1
  Other Name: Taxol®
• Drug: Carboplatin
  intravenously over 15-30 minutes on Day 1 (dose to be determined [TBD] during the Phase I portion
  Other Name: Paraplatin®
• Drug: Hydroxychloroquine
  (dose TBD during the Phase I portion) Days 1-21
• Drug: Bevacizumab
  15 mg/kg intravenously (initial infusion over 90 minutes)
  Other Name: Avastin®

Inclusion Criteria:

• Signed a protocol-specific informed consent.
• 18 years of age or older.
• ECOG Performance Status 0 or 1.
• Histologically or cytologically confirmed non-small cell lung cancer EXCEPT squamous cell carcinoma. Mixed tumors will be categorized by the predominant cell type unless small cell elements are present, in which case the patient is ineligible. Cytologic or histologic elements can be established on metastatic tumor aspirate or biopsy. Sputum cytology alone is not sufficient.
• Advanced stage NSCLC (stage IIIB with malignant pleural effusion, or stage IV, or recurrent disease).
• Measurable disease according to RECIST criteria.
• No known CNS metastases. A head CT or brain MRI is required within 28 days of enrollment.
• No prior cytotoxic chemotherapy or targeted therapy in the advanced or metastatic setting. Post-operative adjuvant therapy for previously resected NSCLC is allowed as long as the last dose was given greater than 1 year before study entry, and there is current evidence of disease progression.
• Prior radiation to sites other than the brain is allowed, if completed at least 2 weeks prior to treatment and provided that all radiation-related toxicities have resolved to ≤ Grade 1.
• No active malignancy other than NSCLC. Patients with a history of basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, or ductal or lobular carcinoma in situ of the breast within the past 3 years must have been treated with curative intent. Patients with a history of prior malignancy are eligible provided they were treated with curative intent and have been free of disease for > 3 years.
• Adequate organ function
• No history of gross hemoptysis (defined as bright red blood of a half-teaspoon or more) within 3 months prior to enrollment.
• None of the following conditions within 6 months prior to enrollment: myocardial infarction, stroke or symptomatic peripheral vascular disease.
• No major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment, or anticipate the need for such while on active treatment. Placement of vascular access device is not considered major surgery, but the incision must have healed before initiation of treatment.
• No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to enrollment.
• No serious non-healing wound, ulcer or bone fracture.
• Patients must have a systolic blood pressure ≤ 150 mm Hg and diastolic blood pressure ≤ 100 mm Hg (the use of antihypertensive medications to achieve these goals is allowed).
• Patients must not have unstable angina or NYHA classification of congestive heart failure of Grade ≥ 2 (see Appendix C).
• No history of significant vascular disease (eg aortic aneurysm).
• Patients must not have psoriasis or porphyria.
• No known hypersensitivity to 4-aminoquinoline compound.
• Patients must not have retinal or visual field changes from prior 4-aminoquinoline compound use.
• Patients must not have known G-6P deficiency.
• No current or recent (within 28 days of enrollment) full dose anticoagulants or thrombolytic agents.
• No know bleeding diathesis or coagulopathy.
• No known GI pathology that would interfere with drug bioavailability.
• No peripheral or sensory neuropathy > Grade 1 at study entry.
• No known prior hypersensitivity to carboplatin, paclitaxel, bevacizumab or hydroxychloroquine or any of their components.
• No ongoing or active infection at study entry.
• Patients must not be receiving treatment for rheumatoid arthritis or systemic lupus erythematosus.
• Patients must not have HIV or be taking HAART therapy.
• Patients must not have a history of any condition (social or medical) that, in the opinion of the Investigator, might interfere with the patient's ability to comply with the protocol or pose additional or unacceptable risk to the patient.
• Women must NOT be pregnant or breastfeeding.

• Women must :

  • Have a negative serum or urine pregnancy test within 7 days prior to study entry if she is a woman of child-bearing potential
  • Be at least one year post-menopausal
  • Be surgically sterile
• Patients of childbearing or child fathering potential must be willing to use an acceptable method of birth control prior to study entry and for the duration of the study. Acceptable methods of contraception include hormonal, barrier methods, intrauterine device, tubal ligation/vasectomy or abstinence.
• Must not be taking hydroxychloroquine for treatment or prophylaxis of malaria.