CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer

A Phase I Open-Label Dose-Escalation Clinical Trial of CPI-613 in Combination With Modified FOLFIRINOX in Patients With Metastatic Pancreatic Cancer and Good Performance Status

This phase I trial studies the side effects and best dose of CPI-613 when given together with combination chemotherapy in treating patients with metastatic pancreatic cancer. Drugs used in chemotherapy, CPI-613, leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Study Overview

• Status: Completed
• Conditions: Acinar Cell Adenocarcinoma of the Pancreas; Duct Cell Adenocarcinoma of the Pancreas; Recurrent Pancreatic Cancer; Stage IV Pancreatic Cancer
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil; Drug: irinotecan hydrochloride; 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 modified leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin (mFOLFIRINOX), in patients with metastatic pancreatic cancer.

SECONDARY OBJECTIVES:

I. To assess the safety of CPI-613/mFOLFIRINOX combination in patients with metastatic pancreatic cancer.

II. To collect tissue for future genomic analyses. III. To obtain preliminary data on efficacy of treatment with CPI-613/mFOLFIRINOX.

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 and 3. Patients also receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV continuously over 46 hours on day 1. Treatment repeats every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 21
• 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 pancreatic adenocarcinoma
• Eastern Cooperative Oncology Group (ECOG) performance status being 0-1
• Expected survival > 2 months
• 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 or hormonal therapy
• 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 oxalic 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 =< 2.0 mg/dL or 177 µmol/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

Exclusion Criteria:

• Endocrine or acinar pancreatic carcinoma
• Previous radiotherapy for cerebral metastases, central nervous system (CNS) or epidural tumor
• Prior treatment with any chemotherapy for metastatic disease from pancreatic cancer
• Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication within the past 4 weeks prior to initiation of CPI-613 treatment
• 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)
• Pregnant women, or women of child-bearing potential not using reliable means of contraception (because the teratogenic potential of CPI-613 is unknown)
• Lactating females
• Fertile men unwilling to practice contraceptive methods during the study period
• Life expectancy less than 2 months
• Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
• Unwilling or unable to follow protocol requirements
• Active 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
• Patients who have received immunotherapy of any type within the past 4 weeks prior to initiation of CPI-613 treatment
• Requirement for immediate palliative treatment of any kind including surgery
• Patients that have received a chemotherapy regimen with stem cell support in the previous 6 months
• 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, mFOLFIRINOX); Patients receive 6,8-bis(benzylthio)octanoic acid IV over 2 hours on days 1 and 3. Patients also receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, irinotecan hydrochloride IV over 90 minutes, and fluorouracil IV continuously over 46 hours on day 1. Treatment repeats every 2 weeks for 6 months in the absence of disease progression or unacceptable toxicity.

Other: laboratory biomarker analysis; Correlative studies; Drug: oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; L-OHP; Drug: leucovorin calcium; Given IV; Other Names: CF; CFR; LV; Drug: fluorouracil; Given IV; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil; Drug: irinotecan hydrochloride; Given IV; Other Names: irinotecan; Campto; Camptosar; U-101440E; CPT-11; 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	Measure Description	Time Frame
Maximum Tolerated Dose	of 6,8-bis(benzylthio)octanoic acid when used in combination with mFOLFIRINOX determined by dose-limiting toxicities graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Toxicities	For exploratory purposes - Any toxicities greater than Grade 2 or above will be assessed for safety of use of CPI-613 and mFOLFIRINOX.	Approximately 2 month after start of treatment or completion of Cycle 2
Overall Survival	For exploratory purposes - Overall survival curve will be measured using Kaplan-Meier methods. Medial survival rates will be examined using a 95% confidence interval.	Approximately 6 months after start of treatment
Progression-Free Survival	For exploratory purposes - The duration of clinical response (evaluated by progression free survival) will be measured from the date a first objective response is documented until the first sign of progression assessed by MRI.	Approximately 2 months after start of treatment
Clinical Response	For exploratory purposes - CA-19-9 will be collected every fourth cycle along with MRI of the abdomen and contrast CT of the chest for clinical response.	Approximately 2 months after start of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Toxicities	For exploratory purposes - Any toxicities greater than Grade 2 or above will be assessed for safety of use of CPI-613 and mFOLFIRINOX.	Approximately 2 month after start of treatment or completion of Cycle 2
Overall Survival	For exploratory purposes - Overall survival curve will be measured using Kaplan-Meier methods. Medial survival rates will be examined using a 95% confidence interval.	Approximately 6 months after start of treatment
Progression-Free Survival	For exploratory purposes - The duration of clinical response (evaluated by progression free survival) will be measured from the date a first objective response is documented until the first sign of progression assessed by MRI.	Approximately 2 months after start of treatment
Number of Participants with a Clinical Response	For exploratory purposes - CA-19-9 will be collected every fourth cycle along with MRI of the abdomen and contrast CT of the chest for clinical response.	Approximately 2 months after start of treatment

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

Publications and helpful links

General Publications

• Alistar A, Morris BB, Desnoyer R, Klepin HD, Hosseinzadeh K, Clark C, Cameron A, Leyendecker J, D'Agostino R Jr, Topaloglu U, Boteju LW, Boteju AR, Shorr R, Zachar Z, Bingham PM, Ahmed T, Crane S, Shah R, Migliano JJ, Pardee TS, Miller L, Hawkins G, Jin G, Zhang W, Pasche B. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2017 Jun;18(6):770-778. doi: 10.1016/S1470-2045(17)30314-5. Epub 2017 May 8.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2013
• Primary Completion (Actual): February 28, 2017
• Study Completion (Actual): March 16, 2023

Study Registration Dates

• First Submitted: April 16, 2013
• First Submitted That Met QC Criteria: April 16, 2013
• First Posted (Estimated): April 18, 2013

Study Record Updates

• Last Update Posted (Actual): July 12, 2023
• Last Update Submitted That Met QC Criteria: July 10, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Carcinoma, Acinar Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antioxidants; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Irinotecan; Calcium; Levoleucovorin; Thioctic Acid
• Other Study ID Numbers: IRB00022532; P30CA012197 (U.S. NIH Grant/Contract); NCI-2013-00674 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CCCWFU 57112 (Other Identifier: Wake Forest Baptist Comprehensive Cancer Center)

Drug and device information, study documents

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