CPI-613 and Fluorouracil in Treating Patients With Metastatic Colorectal Cancer That Cannot Be Removed by Surgery

A Phase I Clinical Trial of Fluorouracil (5-FU) + CPI-613 Combination in Previously Treated Metastatic Colorectal Cancer Patients

This pilot phase I trial studies the side effects and best dose of CPI-613 when given together with fluorouracil in treating patients with colorectal cancer that has spread to other parts of the body and cannot be removed by surgery. CPI-613 may kill tumor cells by turning off their mitochondria. Mitochondria are used by tumor cells to produce energy and are the building blocks needed to make more tumor cells. By shutting off these mitochondria, CPI-613 deprives the tumor cells of energy and other supplies that they need to survive and grow in the body. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving CPI-613 with fluorouracil may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Rectum; Stage IIIA Rectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Rectal Cancer; Mucinous Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Colon; Stage IIIA Colon Cancer; Stage IIIB Colon Cancer; Stage IIIC Colon Cancer; Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: fluorouracil; Other: pharmacological study; Drug: 6,8-bis(benzylthio)octanoic acid

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of CPI-613 (6,8-bis[benzylthio]octanoic acid), when used in combination with 5-FU (fluorouracil), in patients with non-resectable metastatic colorectal cancer who have failed FOLFOX (leucovorin calcium, fluorouracil and oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride) and, if Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type, then a epidermal growth factor receptor (EGFR) inhibitor-based regimen.

SECONDARY OBJECTIVES:

I. To assess the pharmacokinetic (PK), safety and efficacy of various doses of CPI-613, when used in combination with 5-FU, in patients with non-resectable metastatic colorectal cancer.

OUTLINE: This is a dose-escalation study of 6,8-bis(benzylthio)octanoic acid.

Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-4 and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Comprehensive Cancer Center of Wake Forest University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically and cytologically confirmed metastatic colorectal adenocarcinoma (colon, rectal or colorectal cancer) that is not resectable
• Have failed or have not tolerated FOLFOX, FOLFIRI and, if KRAS wild type, then a EGFR inhibitor-based regimen
• Eastern Cooperative Oncology Group (ECOG) performance status being 0-2
• Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation
• Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists
• At least 2 weeks must have elapsed from any prior surgery
• Granulocyte count >= 1500/mm^3
• White blood cell (WBC) >= 3500 cells/mm^3 or >= 3.5 bil/L
• Platelet count >= 100,000 cells/mm^3 or >= 100 bil/L
• Absolute neutrophil count (ANC) >= 1500 cells/mm^3 or >= 1.5 bil/L
• Hemoglobin >= 9 g/dL or >= 90 g/L
• Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x upper normal limit (UNL), alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 3 x UNL (=< 5 x UNL if liver metastases present)
• Bilirubin =< 1.5 x UNL
• Serum creatinine =< 1.5 mg/dL or 13 umol/L
• International normalized ratio or INR must be =< 1.5 unless on therapeutic blood thinners
• No evidence of active infection and no serious infection within the past month
• Mentally competent, ability to understand and willingness to sign the informed consent form
• At least one measurable lesion as assessed by computed tomography (CT) scan using Response Evaluation Criteria in Solid Tumors (RECIST) criteria

Exclusion Criteria:

• Therapy with CPI-613 prior to participating in this trial
• Known hypersensitivity to 5-FU injection, poor nutritional state, known dipyrimidine dehydrogenase deficiency, or taking sorivudine (such as Usevir, brovavir, etc.)
• History of hypersensitivity to active or inactive excipients of any component of treatment
• Previous radiotherapy for central nervous system metastases
• Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication, within the past 2 weeks prior to initiation of treatment with study drugs
• Serious medical illness that would potentially increase patients' risk for toxicity
• Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease)
• History of abdominal fistula or gastrointestinal perforation =< 6 months prior to treatment with study drugs
• Pregnant women, or women of child-bearing potential not using reliable means of contraception
• Lactating females
• Fertile men unwilling to practice contraceptive methods during the study period
• Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
• Unwilling or unable to follow protocol requirements
• Symptomatic heart disease including but not limited to symptomatic congestive heart failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic myocardial infarction or symptomatic congestive heart failure
• Patients with a history of myocardial infarction that is < 3 months prior to registration
• Evidence of active infection, or serious infection within the past month
• Patients with known human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
• Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of CPI-613 treatment; steroid use for management of refractory pain or for contrast induced allergy is allowed
• Requirement for immediate palliative treatment of any kind including surgery
• Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of the patient

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (6,8-bis(benzylthio)octanoic acid, fluorouracil); Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1-4 and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity.	Other: laboratory biomarker analysis; Correlative studies; Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: 6,8-bis(benzylthio)octanoic acid; Given IV; Other Names: CPI-613; alpha-lipoic acid analogue CPI-613

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MTD of 6,8-bis(benzylthio)octanoic acid in combination with fluorouracil based on the incidence of dose-limiting toxicities graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0	Up to 2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of toxicity of 6,8-bis(benzylthio)octanoic acid and fluorouracil combination graded according to NCI CTCAE version 4.0	Examine toxicities by assessing each toxicity by grade.	Up to 3 years
PK parameters (maximum observed concentration, area under the curve, half-life, elimination rate constant, drug clearance, and volume of distribution) of 6,8-bis(benzylthio)octanoic acid in plasma samples		Week 1: days 1 and 4 before infusion of 6,8-bis(benzylthio)octanoic acid and at 30 minutes, 1, 1.5, 2, 4, 6 and 8 (optional) hours after the completion of infusion

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	Plot a PFS curve using Kaplan-Meier methods, examine median PFS.	Time from the first dose of 6,8-bis(benzylthio)octanoic acid to disease progression, assessed up to 3 years
Overall response rate (ORR) (i.e., sum of complete response [CR] and partial response [PR])	Assess ORR and its 95% confidence interval.	Up to 3 years
Disease control rate (DCR) (i.e., sum of CR, PR, and stable disease)	Assess DCR and its 95% confidence interval.	Up to 3 years

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Caio Rocha Lima, MD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): January 6, 2015
• Primary Completion (Actual): February 19, 2019
• Study Completion (Actual): January 11, 2023

Study Registration Dates

• First Submitted: September 2, 2014
• First Submitted That Met QC Criteria: September 2, 2014
• First Posted (Estimated): September 5, 2014

Study Record Updates

• Last Update Posted (Actual): August 7, 2023
• Last Update Submitted That Met QC Criteria: August 2, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms, Cystic, Mucinous, and Serous; Recurrence; Adenocarcinoma; Rectal Neoplasms; Cystadenocarcinoma; Colonic Neoplasms; Adenocarcinoma, Mucinous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Antioxidants; Vitamin B Complex; Fluorouracil; Thioctic Acid
• Other Study ID Numbers: IRB00028139; P30CA012197 (U.S. NIH Grant/Contract); NCI-2014-01779 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CCCWFU #59314 (Other Identifier: Comprehensive Cancer Center of Wake Forest University)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No