Study Evaluating Efficacy and Safety of FFX Versus Combination of CPI-613 With mFFX in Patients With Metastatic Adenocarcinoma of the Pancreas
NCT ID: NCT03504423
Last Updated: 2023-01-03
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
528 participants
INTERVENTIONAL
2018-11-09
2022-01-02
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
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
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.
Folfirinox
Folfirinox
Interventions
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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
Folfirinox
Folfirinox
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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.
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
Exclusion Criteria
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)
18 Years
75 Years
ALL
No
Sponsors
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Cornerstone Pharmaceuticals
INDUSTRY
Responsible Party
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Principal Investigators
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Philip A Philip, MD, PhD, FRCP
Role: PRINCIPAL_INVESTIGATOR
Karmanos Cancer Institute at Wayne State University
Locations
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Banner MD Anderson Cancer Center
Gilbert, Arizona, United States
The University of Arizona Cancer Center
Tucson, Arizona, United States
City of Hope
Duarte, California, United States
USC Norris Comprehensive Cancer Center
Los Angeles, California, United States
UCLA Medical Center
Los Angeles, California, United States
Pacific Hematology Oncology Associates
San Francisco, California, United States
Smilow Cancer Hospital at Yale-New Haven
New Haven, Connecticut, United States
Georgetown University Medical Center
Washington D.C., District of Columbia, United States
Mayo Clinic Hospital
Jacksonville, Florida, United States
Mount Sinai Medical Center
Miami Beach, Florida, United States
Northwestern Memorial Hospital - Arkes Family Pavilion
Chicago, Illinois, United States
University of Chicago
Harvey, Illinois, United States
The University of Kansas Cancer Center - Clinical Research Center - Fairway Office Park
Fairway, Kansas, United States
University of Massachusetts Memorial Medical Center
Worcester, Massachusetts, United States
University of Micihgan
Ann Arbor, Michigan, United States
Karmanos cancer Center
Detroit, Michigan, United States
Mayo Clinic Cancer Center (MCCC)
Rochester, Minnesota, United States
Washington University
St Louis, Missouri, United States
Comprehensive Cancer centers of Nevada
Las Vegas, Nevada, United States
Englewood Hospital and Medical Center
Englewood, New Jersey, United States
Atlantic Health System
Morristown, New Jersey, United States
University of New Mexico Cancer Center
Albuquerque, New Mexico, United States
Roswell Park Cancer Institute
Buffalo, New York, United States
New York University Langone Medical Center
New York, New York, United States
Stony Brook University Hospital
Stony Brook, New York, United States
UNC Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States
Levine cancer Institute
Charlotte, North Carolina, United States
Wake Forest Baptist Health
Winston-Salem, North Carolina, United States
University of Cincinnati Cancer Institute
Cincinnati, Ohio, United States
Cleveland Clinic - Taussig Cancer Center
Cleveland, Ohio, United States
University Hospitals - Seidman Cancer Center
Cleveland, Ohio, United States
Oregon Health and Science University
Portland, Oregon, United States
University of Pittsburgh-Hillman cancer ceter
Pittsburgh, Pennsylvania, United States
Vanderbilt University Medical Center-Vanderbilt-Ingram Cancer Center-Henry-Joyce Cancer Clinic
Nashville, Tennessee, United States
The University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Huntsman cancer Institute
Salt Lake City, Utah, United States
University of Virginia Cancer Center - Emily Couric Clinical Cancer Center
Charlottesville, Virginia, United States
VCU Massey Cancer Center
Richmond, Virginia, United States
Blue Ridge Cancer Care
Roanoke, Virginia, United States
Seattle Cancer Care Alliance
Seattle, Washington, United States
Hôpital Erasme
Brussels, Brussels Capital, Belgium
UZ Leuven
Leuven, VBR, Belgium
CHRU Brest - Hôpital Morvan
Brest, , France
Hôpital Beaujon
Clichy, , France
Centre Hospitalier Départemental Vendée - Hôpital de la Roche-sur-Yon
La Roche-sur-Yon, , France
L'ICM, Institut régional du Cancer de Montpellier
Montpellier, , France
CHU de Nantes - Hôpital Nord Laennec
Nantes, , France
CHU Hopitaux de Bordeaux - Hôpital Saint-André
Pessac, , France
CHU de Poitiers
Poitiers, , France
Centre Eugène Marquis
Rennes, , France
Institut de Cancérologie de Lorraine
Vandœuvre-lès-Nancy, , France
Gustave Roussy Cancer Campus Grand Paris (Institut de Cancerologie Gustave-Roussy)
Villejuif, , France
SLK-Kliniken Heilbronn GmbH
Heilbronn, Baden-Wurttemberg, Germany
Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH
Bochum, , Germany
Universitaetsklinikum Tuebingen
Tübingen, , Germany
Hillel Yaffe Medical Center
Hadera, Haifa District, Israel
Rambam Medical Center
Haifa, , Israel
Shaare Zedek Medical Center
Jerusalem, , Israel
Sanz Medical Center - Laniado Hospital
Netanya, , Israel
The Chaim Sheba Medical Center - Sheba Cancer Research Center (SCRC)
Ramat Gan, , Israel
Tel Aviv Sourasky Medical Center
Tel Aviv, , Israel
Assaf-Harofeh Medical Center
Ẕerifin, , Israel
The Catholic University of Korea - Seoul St. Mary's Hospital (Kangnam St. Mary's Hospital)
Seocho, Seoul, South Korea
Seoul National University Hospital
Busan, , South Korea
Kyungpook National University Chilgok Hospital
Daegu, , South Korea
Gachon University Gil Hospital
Incheon, , South Korea
Inha University Hospital
Incheon, , South Korea
Seoul National University Bundang Hospital
Seongnam-si, , South Korea
Seoul National University Hospital
Seoul, , South Korea
Korea University Anam Hospital
Seoul, , South Korea
Severance Hospital - Yonsei Cancer Center
Seoul, , South Korea
Samsung Medical Center
Seoul, , South Korea
National Cancer Center
Seoul, , South Korea
Ajou University Hospital
Suwon, , South Korea
Countries
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References
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Philip PA, Sahai V, Bahary N, Mahipal A, Kasi A, Rocha Lima CMS, Alistar AT, Oberstein PE, Golan T, Metges JP, Lacy J, Fountzilas C, Lopez CD, Ducreux M, Hammel P, Salem M, Bajor D, Benson AB, Luther S, Pardee T, Van Cutsem E. Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study. J Clin Oncol. 2024 Nov;42(31):3692-3701. doi: 10.1200/JCO.23.02659. Epub 2024 Aug 1.
Liu N, Yan M, Tao Q, Wu J, Chen J, Chen X, Peng C. Inhibition of TCA cycle improves the anti-PD-1 immunotherapy efficacy in melanoma cells via ATF3-mediated PD-L1 expression and glycolysis. J Immunother Cancer. 2023 Sep;11(9):e007146. doi: 10.1136/jitc-2023-007146.
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.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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PANC003
Identifier Type: -
Identifier Source: org_study_id
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