Riluzole in Combination With mFOLFOX6 and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This phase I trial is to find out the best dose, possible benefits, and/or side effects of riluzole and how well it works in combination with standard of care mFOLFOX6 and bevacizumab in treating patients with colorectal cancer that has spread to other places in the body (metastatic). Riluzole is a well-tolerated oral medication that has demonstrated it may make chemotherapy work better. Chemotherapy drugs, such as oxaliplatin, leucovorin calcium and fluorouracil, work in different ways to stop the growth of [cancer/tumor] cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab is an antibody that targets the blood vessel by blocking the activity of a protein called vascular endothelial growth factor alpha (VEGF-A). It helps to make the mFOLFOX6 more effective. Giving riluzole, mFOLFOX6, and bevacizumab may kill more tumor cells compared to mFOLFOX6 and bevacizumab alone in treating patients with colorectal cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. Characterize the safety and toxicity of riluzole in combination with modified (m) leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) 6/bevacizumab and determine the recommended phase II dose (RP2D) of riluzole in combination with mFOLFOX6/bevacizumab in patients with metastatic colorectal cancer. SECONDARY OBJECTIVE: I. Determine the pharmacokinetics of riluzole in patients with metastatic CRC. EXPLORATORY OBJECTIVES: I. Assess the efficacy of the combination treatment. II. Determine the effect of riluzole in downstream GRM3 signaling by immunofluorescent staining of phosphorylated (p)AKT and pCREB in pre- and post-treatment tumor tissues. III. Assess FCGRT/FcRn expression, bevacizumab pharmacokinetics, inflammatory cytokines, and cachexia associated factors as early biomarkers for resistance to therapy. IV. Assess cytotoxic T cells in peripheral blood to evaluate the immunomodulatory effect of this therapy. OUTLINE: This is a dose-escalation study of riluzole. Patients receive riluzole orally (PO) twice daily (BID) on days 1-14. Patients also receive oxaliplatin via intravenous piggyback (IVPB) over 2 hours, leucovorin calcium IVPB over 2 hours, and bevacizumab IVPB over 30 minutes on day 1 and fluorouracil via intravenous (IV) push over 5 minutes and then IV continuously over 46 hours on days 1-2. Treatment repeats every 2 weeks for up to 8 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days.

Official Title
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A Phase I Study of Riluzole in Combination With mFOLFOX6/Bevacizumab in Patients With Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Carcinoma, Stage IV Colorectal Cancer AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVC Colorectal Cancer AJCC v8

Intervention / Treatment
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* Biological: Bevacizumab
* Drug: Fluorouracil
* Drug: Leucovorin Calcium
* Drug: Oxaliplatin
* Drug: Riluzole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with metastatic colorectal cancer, who are appropriate candidates to receive mFOLFOX6/bevacizumab. Patients who progressed on FOLFOX-based regimen are allowed Willingness to undergo both pre-treatment and post-treatment tumor tissue biopsies (pre-treatment tumor tissue will be sent to pathology lab to confirm metastatic colorectal cancer as the standard of care) Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Age >= 18 years Absolute neutrophil count >= (ANC) 1,500/ul Platelets >= 100,000/ul Hemoglobin >= 9 g/dl Serum total bilirubin < 1.5 x ULN Serum albumin >= 2.5 g/dl If no liver involvement, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 1.5 x ULN. If liver involvement, AST and ALT =< 3.0 x ULN Ability to understand and the willingness to sign a written informed consent document A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study (and for up to 12 weeks after the last dose of study drug) to minimize the risk of pregnancy. If the partner is pregnant or breastfeeding, the subject must use a condom Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of study drug to minimize the risk of pregnancy. WOCBP must have a negative serum or urine pregnancy test within 72 hours before the start of the investigational product Exclusion Criteria: Patients who are receiving any other investigational agents Patients with history of hepatitis B or C Patients with severe renal impairment (CrCl < 30 mL/min) Prior full field radiotherapy < 4 weeks or limited field radiotherapy < 2 weeks prior to first study drug administration. Patients with central nervous system (CNS) metastases may participate in this trial provided they are clinically stable. Patients who are < 1 month from radiation therapy must not be included Patients with existing grade 2 peripheral neuropathy Patients with a history of thrombotic or embolic events within the last six months such as a cerebrovascular accident (including transient ischemic attacks), pulmonary embolism or deep vein thrombosis Cardiac conditions as follows: Active coronary artery disease, unstable or newly diagnosed angina or myocardial infarction less than 6 months prior to first study drug administration Class III-IV New York Heart Association (NYHA) congestive heart failure Uncontrolled hypertension (Systolic blood pressure [BP] > 150 mmHg and diastolic BP > 90 mmHg for 24 hours) despite optimal medical management Corrected QT (QTc) (Friderica) prolongation > 480 msec Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, cardiac arrhythmia, active bleeding diatheses, and psychiatric illness/social situations that would limit compliance with study requirements Major surgical procedure or significant traumatic injury less than 3 weeks or those who receive minor surgical procedures within 1 week from first dose of study drug administration Known inability to swallow capsules Inability to comply with study and/or follow-up procedures Pregnant women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (riluzole, mFOLFOX6, bevacizumab)<br>Patients receive riluzole PO BID on days 1-14. Patients also receive oxaliplatin via IVPB over 2 hours, leucovorin calcium IVPB over 2 hours, and bevacizumab IVPB over 30 minutes on day 1 and fluorouracil via IV push over 5 minutes and then IV continuously over 46 hours on days 1-2. Treatment repeats every 2 weeks for up to 8 cycles in the absence of disease progression or unacceptable toxicity. | Biological: Bevacizumab<br>* Given IVPB<br>* Other names: Zirabev;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Leucovorin Calcium<br>* Given IVPB<br>* Other names: Wellcovorin;Drug: Oxaliplatin<br>* Given IVPB<br>* Other names: SR-96669;Drug: Riluzole<br>* Given PO<br>* Other names: Rilutek;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities (DLTs) | Will be defined by treatment related grade >= 4 adverse events or >= grade 3 alanine aminotransferase or aspartate aminotransferase elevation during the DLT period using the Common Terminology Criteria for Adverse Events version 5.0. | Up to 4 weeks (2 cycles of treatment) (1 cycle = 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile of riluzole (Cmax) | K data analysis will utilize a nonlinear mixed effects approach whereby PK parameter estimates will be generated from the data, and 'dose day' will be evaluated as a covariate on clearance and volume of distribution. The PK parameters including Cmax. Peak Plasma Concentration (Cmax) | Day 1 on cycle 1 (each cycle is 14 days) | 
| Pharmacokinetic (PK) profile of riluzole (AUC) | PK data analysis will utilize a nonlinear mixed effects approach whereby PK parameter estimates will be generated from the data, and 'dose day' will be evaluated as a covariate on clearance and volume of distribution. The PK parameters including AUC. Area under the plasma concentration versus time curve (AUC) | Day 1 on cycle 1 (each cycle is 14 days) |