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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: hydroxychloroquine

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Hospital/University Medical Center
    • Hamilton, New Jersey, United States, 08690
      • Cancer Institute of New Jersey at Hamilton
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School/The University Hospital Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 116 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FOLFOX6 + Bevacizumab + Hydroxychloroquine; 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; hydroxychloroquine 200 mg po BID daily
Experimental: XELOX + Bevacizumab + Hydroxychloroquine; 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; hydroxychloroquine 200 mg po BID daily

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

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rebecca A. Moss, MD, Rutgers Cancer Institute of New Jersey

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2009
• Primary Completion (Actual): August 6, 2015
• Study Completion (Actual): April 27, 2016

Study Registration Dates

• First Submitted: October 30, 2009
• First Submitted That Met QC Criteria: October 30, 2009
• First Posted (Estimate): November 1, 2009

Study Record Updates

• Last Update Posted (Actual): September 21, 2021
• Last Update Submitted That Met QC Criteria: September 20, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: stage IV rectal cancer; stage IV colon cancer; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: 0220090022; P30CA072720 (U.S. NIH Grant/Contract); CINJ-070806; 070806 (Other Identifier: Rutgers Cancer Institute of New Jersey)