Clinical trial NCT03504423: Study Evaluating Efficacy and Safety of FFX Versus Combination of CPI-613 With mFFX in Patients With Metastatic Adenocarcinoma of the Pancreas
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pancreatic Cancer Metastatic
Lead sponsor: Cornerstone Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2018-04-20
Enrollment: 528
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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


Eligibility criteria: 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

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: 38 months
Secondary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: 38 months
measure: Overall Response Rate (ORR)
timeFrame: 38 months
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Tucson
country: United States
facility: The University of Arizona Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: USC Norris Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Medical Center
state: California
city: San Francisco
country: United States
facility: Pacific Hematology Oncology Associates
state: California
city: New Haven
country: United States
facility: Smilow Cancer Hospital at Yale-New Haven
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Hospital
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital - Arkes Family Pavilion
state: Illinois
city: Harvey
country: United States
facility: University of Chicago
state: Illinois
city: Fairway
country: United States
facility: The University of Kansas Cancer Center - Clinical Research Center - Fairway Office Park
state: Kansas
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Micihgan
state: Michigan
city: Detroit
country: United States
facility: Karmanos cancer Center
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center (MCCC)
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Las Vegas
country: United States
facility: Comprehensive Cancer centers of Nevada
state: Nevada
city: Englewood
country: United States
facility: Englewood Hospital and Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: New York University Langone Medical Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Hospital
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Levine cancer Institute
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Cancer Institute
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic - Taussig Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals - Seidman Cancer Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh-Hillman cancer ceter
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center-Vanderbilt-Ingram Cancer Center-Henry-Joyce Cancer Clinic
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman cancer Institute
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center - Emily Couric Clinical Cancer Center
state: Virginia
city: Richmond
country: United States
facility: VCU Massey Cancer Center
state: Virginia
city: Roanoke
country: United States
facility: Blue Ridge Cancer Care
state: Virginia
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Bruxelles
country: Belgium
facility: Hôpital Erasme
state: Brussel
city: Leuven
country: Belgium
facility: UZ Leuven
state: VBR
city: Brest
country: France
facility: CHRU Brest - Hôpital Morvan
city: Clichy
country: France
facility: Hôpital Beaujon
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier Départemental Vendée - Hôpital de la Roche-sur-Yon
city: Montpellier
country: France
facility: L'ICM, Institut régional du Cancer de Montpellier
city: Nantes Cedex 1
country: France
facility: CHU de Nantes - Hôpital Nord Laennec
city: Pessac
country: France
facility: CHU Hopitaux de Bordeaux - Hôpital Saint-André
city: Poitiers
country: France
facility: CHU de Poitiers
city: Rennes
country: France
facility: Centre Eugène Marquis
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Villejuif
country: France
facility: Gustave Roussy Cancer Campus Grand Paris (Institut de Cancerologie Gustave-Roussy)
city: Heilbronn
country: Germany
facility: SLK-Kliniken Heilbronn GmbH
state: BW
city: Bochum
country: Germany
facility: Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen
city: Hadera
country: Israel
facility: Hillel Yaffe Medical Center
state: Haifa
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Netanya
country: Israel
facility: Sanz Medical Center - Laniado Hospital
city: Ramat Gan
country: Israel
facility: The Chaim Sheba Medical Center - Sheba Cancer Research Center (SCRC)
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Zerifin
country: Israel
facility: Assaf-Harofeh Medical Center
city: Seocho
country: Korea, Republic of
facility: The Catholic University of Korea - Seoul St. Mary's Hospital (Kangnam St. Mary's Hospital)
state: Seoul
city: Busan
country: Korea, Republic of
facility: Seoul National University Hospital
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Hospital
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital - Yonsei Cancer Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: National Cancer Center
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital
Study officials:
affiliation: Karmanos Cancer Institute at Wayne State University
name: Philip A Philip, MD, PhD, FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.