Modulation of Autophagy in Patients With Advanced/Recurrent Non-small Cell Lung Cancer - Phase II

Study Overview
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Brief Summary
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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. Some patients who have a specific type of lung cancer can also receive another drug, a drug that targets blood vessels, called bevacizumab (also known as avastin). Hydroxychloroquine is an FDA approved drug for the treatment of malaria, rheumatoid arthritis and lupus erythematosis.

Official Title
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Modulation of Autophagy With Hydroxychloroquine in Patients With Advanced/Recurrent Non-small Cell Lung Cancer - a Phase II Study. A Study of The Cancer Institute of New Jersey Oncology Group (CINJOG)

Conditions
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Non-small Cell Lung Cancer, Advanced Non-small Cell Lung Cancer, Recurrent Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Hydroxychloroquine
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed a protocol-specific informed consent. 18 years of age or older. ECOG Performance Status 0 or 1. Cancer criteria: Histologically or cytologically confirmed non-small cell lung cancer. 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 IVa ((malignant pleural effusion (is now staged as stage IVa by the most recent staging system), or stage IV, or recurrent disease)). Measurable disease according to RECIST criteria. Patient with CNS metastasis are required to have stable disease documented by being off treatment (surgery, or Whole Brain radiation therapy) for at least 2 weeks, and four (4) weeks is preferred. No delay in onset of therapy is required for those patients who undergo stereotactic RT to the brain lesion(s). A contrast enhanced brain CT or brain MRI is required within 35 days of enrollment. Patients with brain metastases who qualify for protocol therapy will be included in Cohort 2 (ineligible for treatment with Bevacizumab). Prior radiation to sites other than the brain is allowed, if completed at least 2 weeks before treatment and provided that all radiation-related toxicities have resolved to ≤ Grade 1. Stereotactic irradiation to any site excludes the need for a waiting period. Laboratory requirements - Adequate organ function, as evidenced by ALL the following: absolute neutrophil count (ANC) ≥ 1500/mm³ platelet count ≥ 100,000/mm³ hemoglobin ≥ 9 gm/dL total bilirubin ≤ 1.5 x ULN; if patient has Gilbert's disease, then patient must have isolated hyperbilirubinemia (e.g. no other liver function test abnormality), with maximum bilirubin ≤ 2 X institutional ULN. AST and ALT ≤ 2.5 x ULN in the absence of liver metastases; AST and ALT ≤ 5 x ULN in the presence of liver metastases alkaline phosphatase ≤ 2.5 x ULN creatinine ≤ 1.5 X institutional ULN or calculated creatinine clearance ≥ 60 ml/min as estimated using the Cockcroft-Gault formula. Comorbidities For Cohort 1: (Bevacizumab eligible) For patients who have had a 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, may participate and receive Bevacizumab at the start of the second or third cycle as they would under standard care. Placement of vascular access device is not considered major surgery, but the incision must have healed before initiation of treatment. 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). Adequate organ function INR ≤ 1.5 and aPTT WNL. Urine Protein Creatinine (UPC) ratio < 1.0 or 24 hour urine protein ratio < 1000 mg UPC ratio of spot urine is an estimation of the 24 urine protein excretion. A UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm. To obtain a UPC ratio: Obtain at least 4 mL of a random urine sample Determine protein and creatinine concentration Calculate the UPC using one of the following formulae [urine protein]/[urine creatinine] - if both values are reported in mg/dL [(urine protein) x 0.088]/[urine creatinine] - if urine creatinine is reported in mmol/L For ALL (Cohort 1 and Cohort 2): 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, OR Be at least one year post-menopausal, OR 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. Exclusion Criteria: Cancer criteria: 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. 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. Comorbidities For Cohort 1: (Bevacizumab eligible) 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 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 not have unstable angina or NYHA classification of congestive heart failure of Grade ≥ 2. No history of significant vascular disease (eg aortic aneurysm). No current or recent (within 28 days of enrollment) full dose anticoagulants or thrombolytic agents. For Cohort 2 (Bevacizumab ineligible): None of the following conditions within 6 months prior to enrollment: myocardial infarction, stroke or symptomatic peripheral vascular disease. Patients must not have unstable angina or NYHA classification of congestive heart failure of Grade ≥ 2. No history of significant vascular disease (eg aortic aneurysm). For ALL (Cohort 1 and Cohort 2): Patients must not have psoriasis or porphyria. No known hypersensitivity to 4-aminoquinoline compound. Patients must not have known or suspected G-6P deficiency. 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 compliance with the protocol or pose additional or unacceptable risk to the patient. Women must NOT be pregnant or breastfeeding. Must not be taking hydroxychloroquine for treatment or prophylaxis of malaria.

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: Cohort 2: Bevacizumab ineligible patients<br>Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min Hydroxychloroquine 200 mg PO BID | Drug: Paclitaxel<br>* Paclitaxel will be given at a dose of 200 mg/m2(by IV over 3 hours on Day 1). Cycles every 3 weeks for 4-6 Cycles. Prior to receiving paclitaxel, all patients will receive the following premedication: Dexamethasone 20 mg po 12 and 6 hours prior to paclitaxel infusion (patients may be treated with dexamethasone 20 mg iv < 1 hour prior to infusion with paclitaxel if the patient did not take the oral dexamethasone) Diphenydramine 50 mg iv (or equivalent) < 1 hour prior to paclitaxel infusion Ranitidine 50 mg iv < 1 hour prior to paclitaxel infusion (alternatively other H2-blockers may be used)<br>* Other names: Taxol;Drug: Carboplatin<br>* Carboplatin will be given at AUC = 6 by IV over 15-30 minutes on Day 1 immediately following paclitaxel. Cycles every 3 weeks for 4-6 Cycles.<br>* Other names: Paraplatin;Drug: Hydroxychloroquine<br>* Hydroxychloroquine will be given as a flat dose of 200 mg orally BID (total daily dose of 400 mg). Cycles every 3 weeks for 4-6 Cycles.<br>* Other names: Plaquenil;|
| Experimental: Cohort 1: Bevacizumab eligible patients<br>Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min Bevacizumab 15 mg/kg IV over 90 min for Hydroxychloroquine 200 mg PO BID | Drug: Paclitaxel<br>* Paclitaxel will be given at a dose of 200 mg/m2(by IV over 3 hours on Day 1). Cycles every 3 weeks for 4-6 Cycles. Prior to receiving paclitaxel, all patients will receive the following premedication: Dexamethasone 20 mg po 12 and 6 hours prior to paclitaxel infusion (patients may be treated with dexamethasone 20 mg iv < 1 hour prior to infusion with paclitaxel if the patient did not take the oral dexamethasone) Diphenydramine 50 mg iv (or equivalent) < 1 hour prior to paclitaxel infusion Ranitidine 50 mg iv < 1 hour prior to paclitaxel infusion (alternatively other H2-blockers may be used)<br>* Other names: Taxol;Drug: Carboplatin<br>* Carboplatin will be given at AUC = 6 by IV over 15-30 minutes on Day 1 immediately following paclitaxel. Cycles every 3 weeks for 4-6 Cycles.<br>* Other names: Paraplatin;Drug: Hydroxychloroquine<br>* Hydroxychloroquine will be given as a flat dose of 200 mg orally BID (total daily dose of 400 mg). Cycles every 3 weeks for 4-6 Cycles.<br>* Other names: Plaquenil;Drug: Bevacizumab<br>* Cohort 1 only: Bevacizumab will be given by IV on Day 1 of each 21-day cycle at a dose of 15 mg/kg. Cycles every 3 weeks for 4-6 Cycles.<br>* Other names: Avastin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor Activity, as Measured by Tumor Response Rate of Hydroxychloroquine, Paclitaxel, Carboplatin, and Bevacizumab (for Eligible Patients) in Patients With Advanced or Recurrent NSCLC Cancer | Assessed using RECIST criteria. Determined using a Simon's two-stage minimax design with a 5% significance level and 80% power. | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Kaplan-Meier estimates of survival were calculated. The median survival times and 95% confidence intervals are presented. | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung cancer, Non-small cell lung cancer, Advanced non-small cell lung cancer, Recurrent non-small cell lung cancer