Study of Hydroxychloroquine With FOLFIRI and Bevacizumab in DTP-high Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a two arm, 2-center, Phase II, study of 5-FU, irinotecan, bevacizumab (FOLFIRI-beva) and hydroxychloroquine (HCQ) in patients with previously untreated metastatic colorectal cancer (mCRC). Up to 155 patients will be screened for DTP-signature and up to 31 evaluable patients who are determined to be DTP-signature high will be treated with FOLFIRI-beva and HCQ. Patients will continue to receive treatments until evidence of disease progression, intolerable side effects, withdrawal of consent or death.

Official Title
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A Phase II Study of 5-FU, Irinotecan, Bevacizumab and Hydroxychloroquine in Drug-Tolerant Persister (DTP)-Selected Patients With Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Hydroxychloroquine
* Drug: Irinotecan
* Drug: Leucovorin
* Drug: Fluorouracil
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed colorectal cancer, not amenable to curative resection. Microsatellite stable/mismatch repair proficient (MSS/pMMR) colorectal cancer. No prior systemic therapy for metastatic disease. Evaluable disease based on RECIST 1.1 criteria. Adequate hematological, hepatic and renal functions Eastern Cooperative Oncology Group (ECOG) Performance status 0-1. Estimated life expectancy of > 6 months. Negative pregnancy test for female patients with child-bearing potential. No history of retinal disorder. No history of glucose-6-phosphate dehydrogenase deficiency (G6PD) . Considered to be DTP-signature high to receive HCQ treatment Exclusion Criteria: Women who are pregnant or nursing. Have received radiotherapy, chemotherapy, biological therapy, or investigational treatment less than four weeks (six weeks for nitrosoureas or mitomycin C) prior to first dose of FOLFIRI-beva or have not recovered from all acute toxicities from prior treatments to grade 1 or less, with the exception of alopecia and those deemed not to affect safety assessment. Have concurrent malignancy with exception of malignancy that was treated curatively and without evidence of recurrence within 3 years of study enrollment, or fully resected basal or squamous cell skin cancer and any carcinoma in situ which are considered to be of low risk of recurrence. Have had major surgery within 28 days of study enrollment. Placement of a venous access device within 28 days of starting therapy is allowed. Have any medical condition that would impair the administration of oral agents including significant bowel resection, inflammatory bowel disease or uncontrolled nausea or vomiting. Known central nervous system metastasis. Patients with history of central nervous system metastases are eligible if they are clinically and radiographically stable for at least 3 months and not taking steroids or anticonvulsants.

Ages Eligible for Study
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Minimum Age: 18 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: High DTP-signature<br>Take HCQ, 400 mg by mouth, twice daily. Receive FOLFIRI+bevacizumab (irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46 - 48 hours, bevacizumab 5 mg/kg), intravenously, every 2 weeks | Drug: Hydroxychloroquine<br>* Anti-Inflammatory - antimalarial - aminoquinolines<br>Drug: Irinotecan<br>* Antineoplastic agent<br>Drug: Leucovorin<br>* Folic acid derivative<br>* Other names: Folinic acid;Drug: Fluorouracil<br>* Antineoplastic agent<br>* Other names: 5-FU;Drug: Bevacizumab<br>* Antineoplastic agent<br>|
| Active Comparator: Low DTP-signature<br>Receive FOLFIRI+bevacizumab (irinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 over 46 - 48 hours, bevacizumab 5 mg/kg), intravenously, every 2 weeks | Drug: Irinotecan<br>* Antineoplastic agent<br>Drug: Leucovorin<br>* Folic acid derivative<br>* Other names: Folinic acid;Drug: Fluorouracil<br>* Antineoplastic agent<br>* Other names: 5-FU;Drug: Bevacizumab<br>* Antineoplastic agent<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Percentage of participants who have a partial response or complete response to study treatment. | Start of study treatment to end of study, up to 48 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Average length of time that participants' diseases do not worsen. | Start of study treatment to time of disease progression, up to 48 months. | 
| Overall survival | Average length of time that participants are alive. | Start of study treatment to time of death, up to 48 months. | 
| Incidences and severity of adverse events | Number of adverse events per grade | Start of study treatment to end of study, up to 48 months. |