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

• Sponsor: Rutgers, The State University of New Jersey (Other)
• Overall Status: Completed
• CT.gov ID: NCT01006369
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 38
• Locations: 4
• Arms: 2
• Actual Duration (Months): 83.9
• Patients Per Site: 9.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: hydroxychloroquine	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: May 1, 2009
• Actual Primary Completion Date: Aug 6, 2015
• Actual Study Completion Date: Apr 27, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [6 years]

   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.

Secondary Outcome Measures

1. Overall Response Rate [6 years]

   Response rate was evaluated every 12 weeks using RECIST criteria. CR+PR+Stable= overall response

2. Overall Survival [6 years]

   Computed using Kaplan-Meier survival curve estimates which were compared to historical controls (median overall survival) was 21.3 months (596).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cooper Hospital/University Medical Center	Camden	New Jersey	United States	08103
2	Cancer Institute of New Jersey at Hamilton	Hamilton	New Jersey	United States	08690
3	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
4	New Jersey Medical School/The University Hospital Cancer Center	Newark	New Jersey	United States	07103

Sponsors and Collaborators

• Rutgers, The State University of New Jersey
• National Cancer Institute (NCI)

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Elizabeth Poplin, MD, Professor of Medicine, Rutgers, The State University of New Jersey
• ClinicalTrials.gov Identifier: NCT01006369
• Other Study ID Numbers: 0220090022; CINJ-070806; P30CA072720; 070806
• First Posted: Nov 1, 2009
• Last Update Posted: Sep 21, 2021
• Last Verified: Sep 1, 2021

• Keywords provided by Elizabeth Poplin, MD, Professor of Medicine, Rutgers, The State University of New Jersey: stage IV colon cancer; stage IV rectal cancer; recurrent colon cancer; recurrent rectal cancer
• Additional relevant MeSH terms: Colorectal Neoplasms; Hydroxychloroquine

Study Results

Participant Flow

Recruitment Details	Subjects were recruited through the Rutgers Cancer Institute of New Jersey of New Jersey Oncology Group. The study was open to accrual on 05/8/2009 and terminated on 04/27/2016.
Pre-assignment Detail	We are reporting results on 38 eligible patients. Nine patients were not eligible for participation.

Arm/Group Title	FOLFOX6 + Bevacizumab + Hydroxychloroquine	XELOX + Bevacizumab + Hydroxychloroquine
Arm/Group Description	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 hydroxychloroquine: hydroxychloroquine 200 mg po BID daily	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 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. hydroxychloroquine: hydroxychloroquine 200 mg po BID daily
Period Title: Overall Study
STARTED	13	25
COMPLETED	1	0
NOT COMPLETED	12	25

Baseline Characteristics

Arm/Group Title	FOLFOX6 + Bevacizumab + Hydroxychloroquine	XELOX + Bevacizumab + Hydroxychloroquine	Total
Arm/Group Description	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 hydroxychloroquine: hydroxychloroquine 200 mg po BID daily	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 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. hydroxychloroquine: hydroxychloroquine 200 mg po BID daily	Total of all reporting groups
Overall Participants	13	25	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 84.6%	14 56%	25 65.8%
>=65 years	2 15.4%	11 44%	13 34.2%
Sex: Female, Male (Count of Participants)
Female	4 30.8%	12 48%	16 42.1%
Male	9 69.2%	13 52%	22 57.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 15.4%	1 4%	3 7.9%
Not Hispanic or Latino	11 84.6%	24 96%	35 92.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 15.4%	4 16%	6 15.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	3 12%	3 7.9%
White	11 84.6%	18 72%	29 76.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%	25 100%	38 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	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.
Time Frame	6 years

Outcome Measure Data

Analysis Population Description

Subjects received FOLFOX6 or XELOX at physicians discretion with bevacizumab abd HCQ 200 mg po daily BID until progressive disease or intolerable side effects. Subjects were not analyzed by treatment assigned.

Arm/Group Title	FOLFOX6 + Bevacizumab + Hydroxychloroquine
Arm/Group Description	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 hydroxychloroquine: hydroxychloroquine 200 mg po BID daily
Measure Participants	38
Median (95% Confidence Interval) [days]	424

2. Secondary Outcome

Title	Overall Response Rate
Description	Response rate was evaluated every 12 weeks using RECIST criteria. CR+PR+Stable= overall response
Time Frame	6 years

Outcome Measure Data

Analysis Population Description

Subjects were assigned to FOLFOX6 or XELOX at physicians discretion and were analyzed as one group. Overall response rate was 75%

Arm/Group Title	FOLFOX6 + Bevacizumab + Hydroxychloroquine
Arm/Group Description	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 hydroxychloroquine: hydroxychloroquine 200 mg po BID daily
Measure Participants	38
Number [percentage of participants responding]	75 576.9%

3. Secondary Outcome

Title	Overall Survival
Description	Computed using Kaplan-Meier survival curve estimates which were compared to historical controls (median overall survival) was 21.3 months (596).
Time Frame	6 years

Outcome Measure Data

Analysis Population Description

Subjects were assigned to FOLFOX6 or XELOX at physician discretion and were analyzed together.

Arm/Group Title	FOLFOX6 + Bevacizumab + Hydroxychloroquine
Arm/Group Description	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 hydroxychloroquine: hydroxychloroquine 200 mg po BID daily
Measure Participants	38
Median (95% Confidence Interval) [days]	788

Adverse Events

Time Frame	Adverse events were collected over a period of 128 days per patient.
Arm/Group Title	FOLFOX6 + Bevacizumab + Hydroxychloroquine		XELOX + Bevacizumab + Hydroxychloroquine
Arm/Group Description	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 hydroxychloroquine: hydroxychloroquine 200 mg po BID daily		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 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. hydroxychloroquine: hydroxychloroquine 200 mg po BID daily
All Cause Mortality
	FOLFOX6 + Bevacizumab + Hydroxychloroquine		XELOX + Bevacizumab + Hydroxychloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/13 (84.6%)		14/25 (56%)
Serious Adverse Events
	FOLFOX6 + Bevacizumab + Hydroxychloroquine		XELOX + Bevacizumab + Hydroxychloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/13 (30.8%)		12/25 (48%)
Gastrointestinal disorders
Dysphagia	0/13 (0%)	0	1/25 (4%)	1
Diarrhea	0/13 (0%)	0	3/25 (12%)	3
Obstruction, GI - colon	1/13 (7.7%)	1	1/25 (4%)	1
Gastrointestinal - other (specific)	0/13 (0%)	0	2/25 (8%)	2
Dehydration	1/13 (7.7%)	1	1/25 (4%)	1
General disorders
Death	0/13 (0%)	0	2/25 (8%)	2
Allergic reaction/hypersensitivity	0/13 (0%)	0	1/25 (4%)	1
Pain - chest wall	0/13 (0%)	0	1/25 (4%)	1
Metabolism and nutrition disorders
Potassium, serum low	1/13 (7.7%)	1	0/25 (0%)	0
Nervous system disorders
Neuropathy: motor	1/13 (7.7%)	1	2/25 (8%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/13 (0%)	0	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	FOLFOX6 + Bevacizumab + Hydroxychloroquine		XELOX + Bevacizumab + Hydroxychloroquine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/13 (100%)		25/25 (100%)
Blood and lymphatic system disorders
Decreased hemoglobin	4/13 (30.8%)	4	9/25 (36%)	9
Hemolysis	2/13 (15.4%)	2	0/25 (0%)	0
Leukocytes (total WBC)	2/13 (15.4%)	2	2/25 (8%)	2
Lymphopenia	4/13 (30.8%)	4	4/25 (16%)	4
Neutrophils/granulocytes (ANC/AGC)	13/13 (100%)	32	10/25 (40%)	10
Platelets	4/13 (30.8%)	4	4/25 (16%)	4
Hemorrhage, pulmonary upper respiratory - nose	2/13 (15.4%)	2	1/25 (4%)	1
Cardiac disorders
Hypertension	3/13 (23.1%)	3	4/25 (16%)	4
Gastrointestinal disorders
Anorexia	3/13 (23.1%)	3	4/25 (16%)	4
Constipation	1/13 (7.7%)	1	5/25 (20%)	5
Diarrhea	2/13 (15.4%)	2	17/25 (68%)	17
Dysphagia	1/13 (7.7%)	1	1/25 (4%)	1
Nausea	3/13 (23.1%)	3	9/25 (36%)	9
Dehydration	0/13 (0%)	0	4/25 (16%)	4
Mucositis/stomatitis - oral cavity	0/13 (0%)	0	3/25 (12%)	3
Vomiting	1/13 (7.7%)	1	7/25 (28%)	7
General disorders
Insomnia	2/13 (15.4%)	2	1/25 (4%)	1
Fatigue	0/13 (0%)	0	16/25 (64%)	16
Fever	0/13 (0%)	0	4/25 (16%)	4
Weight loss	2/13 (15.4%)	2	3/25 (12%)	3
Pain	6/13 (46.2%)	6	3/25 (12%)	3
Metabolism and nutrition disorders
Potassium, serum low (hypokalemia)	1/13 (7.7%)	1	3/25 (12%)	3
ALT, SGPT	0/13 (0%)	0	3/25 (12%)	3
AST, SGOT	0/13 (0%)	0	2/25 (8%)	2
Albumin, serum low	0/13 (0%)	0	2/25 (8%)	2
Glucose, serum high	0/13 (0%)	0	4/25 (16%)	4
Lipase	0/13 (0%)	0	2/25 (8%)	2
Nervous system disorders
Mood alteration - depression	1/13 (7.7%)	1	0/25 (0%)	0
Neurology - motor	1/13 (7.7%)	1	1/25 (4%)	1
Neuropathy - sensory	4/13 (30.8%)	4	24/25 (96%)	24
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/13 (0%)	0	2/25 (8%)	2
Hiccups	0/13 (0%)	0	2/25 (8%)	2
Skin and subcutaneous tissue disorders
Rash	1/13 (7.7%)	1	0/25 (0%)	0
Dry skin	0/13 (0%)	0	2/25 (8%)	2
Rash: hand-foot skin reaction	0/13 (0%)	0	8/25 (32%)	8
Vascular disorders
Thrombosis	1/13 (7.7%)	1	0/25 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.