Study Evaluating Efficacy and Safety of FFX Versus Combination of CPI-613 With mFFX in Patients With Metastatic Adenocarcinoma of the Pancreas

A Phase III Multicenter Open-label Randomized Trial to Evaluate Efficacy and Safety of Folfirinox (FFX) Versus Combination of CPI-613 With Modified Folfirinox (mFFX) in Patients With Metastatic Adenocarcinoma of the Pancreas

A prospective, multicenter, open label, randomized phase III study to evaluate efficacy and safety of FFX versus CPI-613 + mFFX in patients with metastatic adenocarcinoma of the pancreas with age range of 18 to 75 years

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer Metastatic
• Intervention / Treatment: Drug: CPI 613, mFolfirinox; Drug: Folfirinox

• Study Type: Interventional
• Enrollment (Actual): 528
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussel
    • Bruxelles, Brussel, Belgium, 1070
      • Hopital Erasme
  • VBR
    • Leuven, VBR, Belgium, 3000
      • UZ Leuven
• France
  • Brest, France, 29609
    • CHRU Brest - Hôpital Morvan
  • Clichy, France, 92110
    • Hopital Beaujon
  • La Roche-sur-Yon, France, 85925
    • Centre Hospitalier Départemental Vendée - Hôpital de la Roche-sur-Yon
  • Montpellier, France, 34000
    • L'ICM, Institut régional du Cancer de Montpellier
  • Nantes Cedex 1, France, 44093
    • CHU de Nantes - Hôpital Nord Laennec
  • Pessac, France, 33600
    • CHU Hopitaux de Bordeaux - Hôpital Saint-André
  • Poitiers, France, 86000
    • CHU de Poitiers
  • Rennes, France, 35042
    • Centre Eugène Marquis
  • Vandœuvre-lès-Nancy, France, 54500
    • Institut de Cancérologie de Lorraine
  • Villejuif, France, 94805
    • Gustave Roussy Cancer Campus Grand Paris (Institut de Cancerologie Gustave-Roussy)
• Germany
  • Bochum, Germany, 44791
    • Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH
  • Tuebingen, Germany, 72076
    • Universitaetsklinikum Tuebingen
  • BW
    • Heilbronn, BW, Germany, 74078
      • SLK-Kliniken Heilbronn GmbH
• Israel
  • Haifa, Israel, 31096
    • Rambam Medical Center
  • Jerusalem, Israel, 91031
    • Shaare Zedek Medical Center
  • Netanya, Israel, 42150
    • Sanz Medical Center - Laniado Hospital
  • Ramat Gan, Israel, 52621
    • The Chaim Sheba Medical Center - Sheba Cancer Research Center (SCRC)
  • Tel Aviv, Israel, 62431
    • Tel Aviv Sourasky Medical Center
  • Zerifin, Israel, 70300
    • Assaf-Harofeh Medical Center
  • Haifa
    • Hadera, Haifa, Israel, 38101
      • Hillel Yaffe Medical Center
• Korea, Republic of
  • Busan, Korea, Republic of, 49201
    • Seoul National University Hospital
  • Daegu, Korea, Republic of, 41944
    • Kyungpook National University Chilgok Hospital
  • Incheon, Korea, Republic of, 22332
    • Inha University Hospital
  • Incheon, Korea, Republic of, 21556
    • Gachon University Gil Hospital
  • Seongnam-si, Korea, Republic of, 13620
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 6351
    • Samsung Medical Center
  • Seoul, Korea, Republic of, 2841
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 3722
    • Severance Hospital - Yonsei Cancer Center
  • Seoul, Korea, Republic of, 6591
    • National Cancer Center
  • Suwon, Korea, Republic of, 16499
    • Ajou University Hospital
  • Seoul
    • Seocho, Seoul, Korea, Republic of
      • The Catholic University of Korea - Seoul St. Mary's Hospital (Kangnam St. Mary's Hospital)
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
    • Tucson, Arizona, United States, 85724
      • The University of Arizona Cancer Center
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Los Angeles, California, United States, 90033
      • USC Norris Comprehensive Cancer Center
    • Los Angeles, California, United States, 90404
      • UCLA Medical Center
    • San Francisco, California, United States, 94115
      • Pacific Hematology Oncology Associates
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Smilow Cancer Hospital at Yale-New Haven
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Hospital
    • Miami Beach, Florida, United States, 33140
      • Mount Sinai Medical Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital - Arkes Family Pavilion
    • Harvey, Illinois, United States, 60426
      • University of Chicago
  • Kansas
    • Fairway, Kansas, United States, 66205
      • The University of Kansas Cancer Center - Clinical Research Center - Fairway Office Park
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Micihgan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center (MCCC)
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • Nevada
    • Las Vegas, Nevada, United States, 89148
      • Comprehensive Cancer Centers of Nevada
  • New Jersey
    • Englewood, New Jersey, United States, 07631
      • Englewood Hospital and Medical Center
    • Morristown, New Jersey, United States, 07962
      • Atlantic Health System
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • University of New Mexico Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • New York, New York, United States, 10016
      • New York University Langone Medical Center
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
    • Charlotte, North Carolina, United States, 28204
      • Levine Cancer Institute
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Cancer Institute
    • Cleveland, Ohio, United States, 44106
      • Cleveland Clinic - Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals - Seidman Cancer Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh-Hillman cancer ceter
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center-Vanderbilt-Ingram Cancer Center-Henry-Joyce Cancer Clinic
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center - Emily Couric Clinical Cancer Center
    • Richmond, Virginia, United States, 23298
      • VCU Massey Cancer Center
    • Roanoke, Virginia, United States, 24014
      • Blue Ridge Cancer Care
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Histologically or cytologically confirmed metastatic Stage IV adenocarcinoma of the pancreas
2. No prior treatments for stage IV pancreatic adenocarcinoma (prior adjuvant or neoadjuvant treatment is allowed provided completed > 6 months prior to disease recurrence)
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1
4. Male and female patients 18 - 75 years of age
5. Measurable disease determined using guidelines of Response Evaluation Criteria In Solid Tumors (RECIST version 1.1)
6. Expected survival >3 months
7. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted highly effective contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive(s), intrauterine hormone releasing system (IUS), bilateral tubal occlusion or vasectomized partner) during and for 6 months after last study dose and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation, at monthly interval (day 1 of every even numbered cycle), at the end of systemic exposure, and at 30 days after the systemic exposure
8. Males with female partners (of childbearing potential) and female partners (of child bearing potential) with male partners must agree to use double barrier contraceptive measure (a combination of male condom with either cap, diaphragm or sponge with spermicide) in addition to oral contraception or avoidance of intercourse during the study and for 6 months after last study dose is received
9. At least 2 weeks must have elapsed from any prior surgery with resolution of any sequela for randomization

10. Laboratory values ≤2 weeks prior to randomization must be:

    • Adequate hematologic values

      • Platelet count ≥100,000 cells/mm3 or ≥100 bil/L;
      • Absolute neutrophil count [ANC] ≥1,500 cells/mm3 or ≥1.5 bil/L;
      • Hemoglobin ≥9 g/dL or ≥90 g/L)

    • Adequate hepatic function

      • Aspartate aminotransferase [AST/SGOT] ≤3x upper normal limit [UNL] (≤5x UNL if liver metastases present)
      • Alanine aminotransferase [ALT/SGPT] ≤3x UNL (≤5x UNL if liver metastases present)
      • Bilirubin (≤1.5x UNL); bilirubin ≤ 2.5 x ULN for subjects with Gilbert's syndrome
      • Serum albumin > 3.0 g/dL
    • Adequate renal function serum creatinine clearance CLcr > 30 mL/min). (Cocroft-Gault Formula should be used for CrCl calculation)
    • Adequate coagulation function • International Normalized Ratio or INR must be <1.5 unless on therapeutic blood thinners)
11. No evidence of active infection and no serious infection within the past 30 days.
12. Mentally competent, ability to understand and willingness to sign the informed consent form.

Exclusion Criteria:

1. Endocrine or acinar pancreatic carcinoma
2. Known cerebral metastases, central nervous system (CNS), or epidural tumor
3. Prior treatment with any chemotherapy for metastatic adenocarcinoma of the pancreas
4. Completion of a gemcitabine-based adjuvant chemotherapy regimen within less than 6 months at the time of screening.
5. Receipt of neoadjuvant or adjuvant FOLFIRINOX therapy if <6 months prior to disease recurrence
6. Patients with hypersensitivity to devimistat, FFX treatment or any of their excipients
7. Presence of clinically significant abdominal ascites
8. 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 devimistat treatment
9. Serious medical illness that would potentially increase patients' risk for toxicity
10. Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g., active peptic ulcer disease)
11. Female patients who are pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of study treatment
12. Female patients of childbearing potential with a positive pregnancy test assessed by a serum pregnancy test at screening
13. Female patients of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for 6 months after the last dose of study treatment
14. Male patients with a pregnant partner who are unwilling to practice abstinence or use a condom during treatment and for 6 months after completion of study treatment
15. Male patients unwilling to abstain from donating sperm during treatment and for 6 months after completion of study treatment
16. Life expectancy less than 3 months
17. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients
18. Unwilling or unable to follow protocol requirements
19. Active heart disease including but not limited to symptomatic congestive heart failure (NYHA class 3 or 4), symptomatic coronary artery disease, symptomatic angina pectoris, or symptomatic myocardial infarction
20. Patients with a history of myocardial infarction that is <3 months prior to registration
21. Evidence of active infection, or serious infection within the past 30 days.
22. Patients with known HIV infection
23. Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of devimistat treatment (steroids given for supportive care or in response to allergic reactions are allowed at any time)
24. Requirement for immediate palliative surgery, radiation or chemotherapy of any kind. Stenting for bile duct obstruction and need for pain medications are allowed provided all other inclusion criteria are met
25. Prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated cancer from which the patient has been disease-free for at least 3 years prior to screening
26. Unwilling or unable to avoid the concomitant use of strong CYP3A4 inducers or inhibitors during treatment with irinotecan
27. A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (CTCAE grade 1) using Fredericia's QT correction formula (i.e. QTcF)
28. A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of long QT syndrome)
29. The use of concomitant medications that prolong the QT/QTc intervals
30. Contraindications to any of the FFX treatment as follows:

Folinic Acid

• Calcium Folinate is contraindicated in patients who have previously shown hypersensitivity to folinate or any of the excipients.
• Calcium Folinate Injection is contraindicated in the treatment of pernicious anemia or other megaloblastic anemias where vitamin B12 is deficient. Its use can lead to an apparent response of the hematopoietic system, but neurological damage may occur or progress if already present.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take calcium folinate tablets.

Fluorouracil/5FU

• Fluorouracil is contraindicated in patients who have any known hypersensitivity to fluorouracil, are seriously debilitated or are suffering from bone marrow depression after radiotherapy or treatment with other antineoplastic agents, or who are suffering from a potentially serious infection.
• Fluorouracil is strictly contraindicated in pregnant or breast-feeding women.
• Flourouracil should not be used in the management of non-malignant disease.
• Fluorouracil must not be taken or used concomitantly with brivudin, sorivudine and analogues. Brivudin, sorivudine and analogues are potent inhibitors of the enzyme dihydropyrimidine dehydrogenase (DPD) which degrades fluorouracil
• In patients with known complete absence of dihydropyrimidine dehydrogenase (DPD) activity

Oxaliplatin

• Oxaliplatin is contraindicated in patients who have a known history of hypersensitivity to oxaliplatin or to any of the excipients
• are breast-feeding.
• have myelosuppression prior to starting first course, as evidenced by baseline neutrophils <2x109/l and/or platelet count of <100x109l.
• have a peripheral sensitive neuropathy with functional impairment prior to first course.
• have a severely impaired renal function (creatinine clearance less than 30 ml /min)

Irinotecan

• Chronic inflammatory bowel disease and/or bowel obstruction
• History of severe hypersensitivity reactions to Irinotecan hydrochloride trihydrate or to any of the excipients
• Bilirubin > 3 times the ULN
• Severe bone marrow failure.
• WHO performance status > 2.
• Concomitant use with St John's wort

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CPI-613, mFolfirinox; CPI-613, mFolfirinox CPI-613 at 500 mg/m2 IV infusion at a rate of 4mL/min via a central venous port on day 1 and 3 of a 14-day cycle. mFolfirinox (given immediately after CPI-613 administration): Oxaliplatin (Eloxatin) at 65 mg/m2 given as a 2 hr IV infusion, Folinic acid at 400 mg/m2 given as a 90 min (1.5hr) infusion immediately after Oxaliplatin, and concurrently with Irinotecan (irinotecan at 140mg/m2 given as a 90 min IV infusion) via a Y-connector, Flurouracil at 400 mg/m2 as bolus followed by a 46 hr infusion at 2400mg/m2 starting immediately after completion of folinic acid and Irinotecan.	Drug: CPI 613, mFolfirinox; CPI-613: 500mg/m2, IV infusion at a rate of 4mL/min via a central venous port. mFolfirinox: given immediately after CPI-613 administration; Other Names: CPI-613,Oxaliplatin, folinic acid, irinotecan, flurouracil
Active Comparator: Folfirinox; Folfirinox Folfirinox: Oxaliplatin (Eloxatin) at 85 mg/m2 given as a 2 hr IV infusion, Folinic acid at 400 mg/m2 given as a 90 min (1.5hr) infusion immediately after Oxaliplatin, and concurrently with Irinotecan (irinotecan at 180mg/m2 given as a 90 min IV infusion) via a Y-connector, Flurouracil at 400 mg/m2 as bolus followed by a 46 hr infusion at 2400mg/m2 starting immediately after completion of folinic acid and Irinotecan.	Drug: Folfirinox; Folfirinox; Other Names: Oxaliplatin, folinic acid, irinotecan, flurouracil

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the duration from the date of randomization to the date of death from any cause	38 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Defined as the duration from the date of randomization to the date of progressive disease or death from any cause. Progressive Disease is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must have also demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered progression.	38 months
Overall Response Rate (ORR)	Defined as the rate of Complete Response (CR) plus Partial Response (PR): Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of diameters of target lesions;	38 months

Collaborators and Investigators

• Sponsor: Cornerstone Pharmaceuticals
• Investigators: Principal Investigator: Philip A Philip, MD, PhD, FRCP, Karmanos Cancer Institute at Wayne State University

Publications and helpful links

General Publications

• Philip PA, Buyse ME, Alistar AT, Rocha Lima CM, Luther S, Pardee TS, Van Cutsem E. A Phase III open-label trial to evaluate efficacy and safety of CPI-613 plus modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas. Future Oncol. 2019 Oct;15(28):3189-3196. doi: 10.2217/fon-2019-0209. Epub 2019 Sep 12.

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2018
• Primary Completion (Actual): August 16, 2021
• Study Completion (Actual): January 2, 2022

Study Registration Dates

• First Submitted: April 12, 2018
• First Submitted That Met QC Criteria: April 19, 2018
• First Posted (Actual): April 20, 2018

Study Record Updates

• Last Update Posted (Estimate): January 2, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2022
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protective Agents; Topoisomerase Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Oxaliplatin; Leucovorin; Irinotecan; Levoleucovorin; Folic Acid; Folfirinox
• Other Study ID Numbers: PANC003

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

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