Clinical Trials /

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

NCT04761614

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Riluzole in Combination With mFOLFOX6 and Bevacizumab in Treating Patients With Metastatic Colorectal Cancer
  • Official Title: A Phase I Study of Riluzole in Combination With mFOLFOX6/Bevacizumab in Patients With Metastatic Colorectal Cancer

Clinical Trial IDs

  • ORG STUDY ID: OSU-20096
  • SECONDARY ID: NCI-2021-00018
  • NCT ID: NCT04761614

Conditions

  • 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

Interventions

DrugSynonymsArms
BevacizumabAnti-VEGF, Anti-VEGF Humanized Monoclonal Antibody, Anti-VEGF rhuMAb, Avastin, Bevacizumab awwb, Bevacizumab Biosimilar BEVZ92, Bevacizumab Biosimilar BI 695502, Bevacizumab Biosimilar CBT 124, Bevacizumab Biosimilar CT-P16, Bevacizumab Biosimilar FKB238, Bevacizumab Biosimilar GB-222, Bevacizumab Biosimilar HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar Mvasi, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar RPH-001, Bevacizumab Biosimilar SCT501, Bevacizumab Biosimilar Zirabev, Bevacizumab-awwb, Bevacizumab-bvzr, BP102, BP102 Biosimilar, HD204, Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer, Mvasi, Recombinant Humanized Anti-VEGF Monoclonal Antibody, rhuMab-VEGF, SCT501, ZirabevTreatment (riluzole, mFOLFOX6, bevacizumab)
Fluorouracil5 Fluorouracil, 5 Fluorouracilum, 5 FU, 5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-Fu, 5FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757Treatment (riluzole, mFOLFOX6, bevacizumab)
Leucovorin CalciumAdinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, Citrovorum Factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, WellcovorinTreatment (riluzole, mFOLFOX6, bevacizumab)
Oxaliplatin1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669Treatment (riluzole, mFOLFOX6, bevacizumab)
RiluzoleRilutekTreatment (riluzole, mFOLFOX6, bevacizumab)

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (riluzole, mFOLFOX6, bevacizumab)ExperimentalPatients 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.
  • Bevacizumab
  • Fluorouracil
  • Leucovorin Calcium
  • Oxaliplatin
  • Riluzole

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLTs)
Time Frame:Up to 4 weeks (2 cycles of treatment) (1 cycle = 14 days)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Pharmacokinetic (PK) profile of riluzole (Cmax)
Time Frame:Day 1 on cycle 1 (each cycle is 14 days)
Safety Issue:
Description: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)
Measure:Pharmacokinetic (PK) profile of riluzole (AUC)
Time Frame:Day 1 on cycle 1 (each cycle is 14 days)
Safety Issue:
Description: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)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Ning Jin

Last Updated

February 21, 2021