Hydroxychloroquine, Capecitabine, Oxaliplatin, and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as capecitabine and oxaliplatin, 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. Hydroxychloroquine may help chemotherapy and bevacizumab work better and kill more tumor cells. PURPOSE: This phase II trial is studying how well giving hydroxychloroquine together with capecitabine, oxaliplatin, and bevacizumab works in treating patients with metastatic colorectal cancer.

Detailed Description
-----------------
OBJECTIVES: Primary To assess the progression-free survival (PFS) of patients with metastatic colorectal carcinoma treated with hydroxychloroquine in combination with capecitabine, oxaliplatin, and bevacizumab and to compare this to a previously reported median PFS of 7.9 months. Secondary To measure the overall response rate. To measure the duration of response for responding patients. To measure the disease-control rate (complete response, partial response, or stable disease for at least 2 courses). To document the safety and feasibility of this regimen in these patients. To develop surrogate biomarkers for autophagy detection in patient tissue specimens and to characterize the effects of hydroxychloroquine on autophagy in patients in vivo. OUTLINE: This is a multicenter study. Patients receive bevacizumab IV over 30-90 minutes and oxaliplatin IV over 2 hours on day 1. Patients also receive oral capecitabine twice daily on days 1-15 and oral hydroxychloroquine twice daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Peripheral blood and tumor tissue samples may be collected for biomarker and other laboratory studies. After completion of study treatment, patients are followed up for 1 year.

Official Title
-----------------
Autophagy and Anti-Angiogenesis in Metastatic Colorectal Carcinoma: A Phase II Trial of Hydroxychloroquine to Augment Effectiveness of XELOX-Bevacizumab. A Study of the Cancer Institute of New Jersey Oncology Group (CINJOG)

Conditions
-----------------
Colorectal Cancer

Intervention / Treatment
-----------------
* Drug: hydroxychloroquine


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically or cytologically confirmed colorectal carcinoma Metastatic disease Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as > 20 mm by conventional techniques or > 10 mm by spiral CT scan Brain metastases allowed provided they have been treated and stable for > 4 weeks PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy ≥ 12 weeks ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 AST/ALT ≤ 3 times upper limit of normal (ULN) Total bilirubin ≤ 1.5 times ULN PT (INR) ≤ 1.5 Creatinine < 1.5 times ULN Creatinine clearance ≥ 30 mL/min Urine protein:creatinine ratio < 1.0 OR < 1 g protein by 24-hour urine collection Not on dialysis Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception before, during, and for 4 weeks after completion of study treatment Prior non-colonic malignancies allowed provided there is no current clinical evidence of persistent or recurrent disease AND the patient is not on active therapy, including hormonal therapy No uncontrolled hypertension, defined as systolic BP > 150 mm Hg or diastolic BP > 90 mm Hg, despite antihypertensive medications No cardiac disease, including any of the following: NYHA class III-IV congestive heart failure Unstable angina (anginal symptoms at rest) New onset angina (began within the past 3 months) Myocardial infarction within the past 6 months Uncontrolled arrhythmia No thrombolic or embolic events (e.g., cerebrovascular accident including transient ischemic attacks) within the past 6 months No serious non-healing wound, ulcer, or bone fracture No significant traumatic injury within the past 28 days No neuropathy ≥ grade 2 No evidence of bleeding diathesis or coagulopathy No condition that would impair the patient's ability to swallow whole pills No malabsorption problem No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months No known G-6PD deficiency No retinal or visual field changes from prior 4-aminoquinoline compound use No history of allergic reactions attributed to compounds of similar chemical or biologic composition to capecitabine or hydroxychloroquine No other concurrent serious systemic disorders (including active infections) that, in the investigator's opinion, would compromise the safety of the patient or compromise the patient's ability to complete the study PRIOR CONCURRENT THERAPY: See Disease Characteristics No prior chemotherapy for metastatic disease, except for adjuvant therapy that was completed ≥ 6 months before the first evidence of metastasis More than 28 days since prior major surgical procedure or open biopsy No concurrent anticoagulation with warfarin Concurrent low molecular weight heparin (or an equivalent drug) allowed No concurrent hydroxychloroquine for treatment or prophylaxis of malaria No concurrent combination antiretroviral therapy for HIV-positive patients No concurrent St. John wort No other concurrent investigational or anticancer agents or therapies

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: FOLFOX6 + Bevacizumab + Hydroxychloroquine<br>Arm A: FOLFOX6 + Bevacizumab + Hydroxychloroquine: Bevacizumab will be administered intravenously 5 mg/kg in 100 cc Normal Saline every 14 days on day one. Drug: hydroxychloroquine hydroxychloroquine 200 mg po BID daily | Drug: hydroxychloroquine<br>* hydroxychloroquine 200 mg po BID daily<br>|
| Experimental: XELOX + Bevacizumab + Hydroxychloroquine<br>Arm B: XELOX + Bevacizumab + Hydroxychloroquine: Bevacizumab will be administered intravenously 7.5 mg/kg in 100 cc Normal Saline every 21 days. Drug: hydroxychloroquine hydroxychloroquine 200 mg po BID daily | Drug: hydroxychloroquine<br>* hydroxychloroquine 200 mg po BID daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Computed Kaplan-Meier survival curve estimates for progression free survival (PFS) and compared to historical controls of median PFS of 240 days. Evaluated response using RECIST criteria every 12 weeks. | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Response rate was evaluated every 12 weeks using RECIST criteria. CR+PR+Stable= overall response | 6 years | 
| Overall Survival | Computed using Kaplan-Meier survival curve estimates which were compared to historical controls (median overall survival) was 21.3 months (596). | 6 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IV colon cancer, stage IV rectal cancer, recurrent colon cancer, recurrent rectal cancer