Hydroxychloroquine, Carboplatin, Paclitaxel, and Bevacizumab in Recurrent Advanced Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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OBJECTIVES: Primary To determine the recommended phase II dose of hydroxychloroquine and carboplatin in combination with paclitaxel and bevacizumab in patients with advanced recurrent non-small cell lung cancer. (Phase I) To assess the antitumor activity, as measured by tumor response rate, of this regimen in these patients. (Phase II) Secondary To measure time to progression, progression-free survival, and overall survival of these patients. To assess the incidence of toxicity of this regimen in these patients. 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.

Official Title
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(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

Conditions
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Lung Cancer

Intervention / Treatment
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* Biological: bevacizumab
* Drug: carboplatin
* Drug: hydroxychloroquine
* Drug: paclitaxel


Participation Criteria
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Eligibility Criteria
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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 No mixed histology with small cell component Diagnosis established on metastatic tumor aspirate or biopsy (not sputum cytology alone) and meets 1 of the following staging criteria: Stage IIIB disease with malignant pleural effusion Stage IV disease 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: Unstable angina New York Heart Association class II-IV congestive heart failure History of significant vascular disease (e.g., aortic aneurysm) Symptomatic peripheral vascular disease within the past 6 months Myocardial infarction within the past 6 months Stroke within the past 6 months 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 Vascular access device placement with wound recovery allowed before study 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab<br>Cohort 1: Bevacizumab Eligible Patients All on Day 1 Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min Bevacizumab 15 mg/kg IV over 90 min for PLUS Hydroxychloroquine 200 mg PO BID Cycles every 3 weeks for 4-6 Cycles | Biological: bevacizumab<br>* Only patients eligible for bevacizumab will receive bevacizumab. Dose is at 15 mg/kg on day 1 of each cycle.<br>Drug: carboplatin<br>* Carboplatin will be given at AUC = 6 by IV over 15-30 minutes on Day 1 immediately following paclitaxel<br>Drug: hydroxychloroquine<br>* 200 mg orally BID (total daily dose of 400 mg)<br>Drug: paclitaxel<br>* Dose of 200 mg/m2 IV on day 1 of each cycle<br>|
| Experimental: Hydroxychloroquine, Carboplatin, Paclitaxel<br>Cohort 2: Bevacizumab Ineligible Patients All on Day 1 Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min PLUS Hydroxychloroquine 200 mg PO BID Cycles every 3 weeks for 4-6 Cycles | Drug: carboplatin<br>* Carboplatin will be given at AUC = 6 by IV over 15-30 minutes on Day 1 immediately following paclitaxel<br>Drug: hydroxychloroquine<br>* 200 mg orally BID (total daily dose of 400 mg)<br>Drug: paclitaxel<br>* Dose of 200 mg/m2 IV on day 1 of each cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase II Dose of Hydroxychloroquine and Carboplatin When Administered With Paclitaxel and Bevacizumab (Phase I) |  | Followed for the duration of the phase 1 treatment, an average of 18 weeks | 
| Overall Response (Phase II) |  | Treatment start date to date of best response | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (Phase II) |  | Treatment start date and date of progression | 
| Progression-free Survival at 1 Year (Phase II) |  | Treatment start date to 1 year | 
| Overall Survival (Phase II) |  | Treatment start date to date of death | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the lung, large cell lung cancer, recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer