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

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)”

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.

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.

Intervention(s) in this Clinical Trial

• Biological: bevacizumab
  • Arm A: FOLFOX6 + Bevacizumab + Hydroxychloroquine: Bevacizumab will be administered intravenously 5 mg/kg in 100 cc Normal Saline every 14 days on day one Arm B: XELOX + Bevacizumab + Hydroxychloroquine: Bevacizumab will be administered intravenously 7.5 mg/kg in 100 cc Normal Saline every 21 days
• Drug: XELOX regimen
  • Capecitabine will be started at a dose of 1,000 mg/m2/day bid po (total daily dose = 2,000 mg/m2) for 14 days (28 doses) of the 21 day cycle. This cycle will be repeated every 21 days. Oxaliplatin will be started at a dose of 130 mg/m2, in 250 ml of D5W over 2 hours given day 1 of each cycle. This cycle will be repeated every 21 days.
• Drug: hydroxychloroquine
  • hydroxychloroquine 200 mg po BID daily

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: FOLFOX6 + Bevacizumab + Hydroxychloroquine
• Experimental: XELOX + Bevacizumab + Hydroxychloroquine

Primary Measures

• Progression-free survival
  • Time Frame: 4 years
    Safety Issue?: No

Secondary Measures

• Overall response rate
  • Time Frame: 4 years
    Safety Issue?: No
• Duration of response
  • Time Frame: 4 years
    Safety Issue?: No
• Disease-control rate
  • Time Frame: 4 years
    Safety Issue?: No
• Safety and feasibility
  • Time Frame: 4 years
    Safety Issue?: Yes
• Biological activity of hydroxychloroquine as evidenced by Beclin-1, p62, and LC3 biomarker response in peripheral blood mononuclear cells
  • Time Frame: 4 years
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: University of Medicine and Dentistry New Jersey Other

Overall Clinical Trial Officials and Contacts

Rebecca A. Moss, MD Principal Investigator Cancer Institute of New Jersey  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01006369

Study ID Number: CDR0000643549

ClinicalTrials.gov Identifier: NCT01006369

Health Authority: United States: Institutional Review Board

Clinical trial summary from the National Cancer Institute's PDQ® database