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

Pancreatic Cancer Metastatic Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03504423
• Other study ID #: PANC003
• Status: Completed
• Phase: Phase 3
• Start date: November 9, 2018
• Est. completion date: January 2, 2022

Study information

• Verified date: September 2021
• Source: Cornerstone Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 528
• Est. completion date: January 2, 2022
• Est. primary completion date: August 16, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Adenocarcinoma
• Pancreatic Cancer Metastatic

Intervention

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
• Folfirinox
Folfirinox

Locations

Country	Name	City	State
Belgium	Hôpital Erasme	Bruxelles	Brussel
Belgium	UZ Leuven	Leuven	VBR
France	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 Cedex 1
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
Germany	Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH	Bochum
Germany	SLK-Kliniken Heilbronn GmbH	Heilbronn	BW
Germany	Universitaetsklinikum Tuebingen	Tuebingen
Israel	Hillel Yaffe Medical Center	Hadera	Haifa
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	Zerifin
Korea, Republic of	Seoul National University Hospital	Busan
Korea, Republic of	Kyungpook National University Chilgok Hospital	Daegu
Korea, Republic of	Gachon University Gil Hospital	Incheon
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	The Catholic University of Korea - Seoul St. Mary's Hospital (Kangnam St. Mary's Hospital)	Seocho	Seoul
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam-si
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	National Cancer Center	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital - Yonsei Cancer Center	Seoul
Korea, Republic of	Ajou University Hospital	Suwon
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	University of Micihgan	Ann Arbor	Michigan
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Levine cancer Institute	Charlotte	North Carolina
United States	University of Virginia Cancer Center - Emily Couric Clinical Cancer Center	Charlottesville	Virginia
United States	Northwestern Memorial Hospital - Arkes Family Pavilion	Chicago	Illinois
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	Karmanos cancer Center	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	Englewood Hospital and Medical Center	Englewood	New Jersey
United States	The University of Kansas Cancer Center - Clinical Research Center - Fairway Office Park	Fairway	Kansas
United States	Banner MD Anderson Cancer Center	Gilbert	Arizona
United States	University of Chicago	Harvey	Illinois
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Mayo Clinic Hospital	Jacksonville	Florida
United States	Comprehensive Cancer centers of Nevada	Las Vegas	Nevada
United States	UCLA Medical Center	Los Angeles	California
United States	USC Norris Comprehensive Cancer Center	Los Angeles	California
United States	Mount Sinai Medical Center	Miami Beach	Florida
United States	Atlantic Health System	Morristown	New Jersey
United States	Vanderbilt University Medical Center-Vanderbilt-Ingram Cancer Center-Henry-Joyce Cancer Clinic	Nashville	Tennessee
United States	Smilow Cancer Hospital at Yale-New Haven	New Haven	Connecticut
United States	New York University Langone Medical Center	New York	New York
United States	University of Pittsburgh-Hillman cancer ceter	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	VCU Massey Cancer Center	Richmond	Virginia
United States	Blue Ridge Cancer Care	Roanoke	Virginia
United States	Mayo Clinic Cancer Center (MCCC)	Rochester	Minnesota
United States	Washington University	Saint Louis	Missouri
United States	Huntsman cancer Institute	Salt Lake City	Utah
United States	Pacific Hematology Oncology Associates	San Francisco	California
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Stony Brook University Hospital	Stony Brook	New York
United States	The University of Arizona Cancer Center	Tucson	Arizona
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Cornerstone Pharmaceuticals

Countries where clinical trial is conducted

United States,  Belgium,  France,  Germany,  Israel,  Korea, Republic of, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (OS)	Defined as the duration from the date of randomization to the date of death from any cause	38 months
Secondary	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
Secondary	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