Pancreatic Ductal Adenocarcinoma (PDAC)
Conditions
Keywords
Pancreatic cancer, Resectable pancreatic cancer, Localized pancreatic cancer, MTAP deleted pancreatic cancer
Brief summary
The purpose of this study is to assess the safety, feasibility, and recommended dose of navlimetostat (BMS-986504) combined with mFOLFIRINOX before and after surgery in patients with localized pancreatic cancer with MTAP deletion.
Interventions
DRUGNavlimetostat
Investigational, small molecule anticancer agent being developed for the treatment of malignancies with homozygous deletion of the MTAP gene.
Chemotherapy regimen composed of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin
Sponsors
Daniel Nussbaum, M.D.
Bristol-Myers Squibb
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years. 2. Histologically and/or cytologically confirmed pancreatic ductal adenocarcinoma. 3. MTAP deletion or loss in tumor tissue as diagnosed by next generation sequencing. 4. Treatment naïve and clinically staged as resectable or borderline resectable, without evidence of distant metastatic disease. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Eligible to receive mFOLFIRINOX and undergo curative-intent pancreatic resection. 7. Females are eligible to participate if they are not pregnant or breastfeeding. If childbearing potential must have a negative serum or urine pregnancy test at screening. IOCBP are not permitted to use hormonal contraceptive methods alone as a highly effective method of contraception and must use an additional non-hormonal highly effective method of contraception (as described in Appendix B). 8. WOCBP are not permitted to use hormonal contraceptive methods alone as a highly effective method of contraception and must use an additional non-hormonal highly effective method of contraception (as described in Appendix B). 9. A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies: 1. Is not an IOCBP, OR 2. Is an IOCBP and using a combination of a hormonal and a non-hormonal contraceptive method or a non-hormonal method alone that is highly effective (with a failure rate of \< 1% per year), as described in Appendix B, during the intervention period and for at least 9 months after the last dose of study intervention, or according to approved local product label requirements for individual agents, whichever is longer. IOCBP participants must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period. 10. Females of child-bearing potential and males with partners of child-bearing potential must agree not to donate eggs (ova, oocytes) for the purpose of reproduction or sperm and to practice sexual abstinence or use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and for 9 months after the last dose of the study medication. 11. If needed, male (as assigned at birth) participants should be advised to seek advice about sperm donation and cryopreservation of germ cells before treatment. 12. Breastfeeding partners of male (as assigned at birth) participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms. 13. Capable of understanding and complying with the protocol requirements and has signed the informed consent document. 14. Adequate organ and marrow function as defined below: 1. Absolute neutrophil count ≥ 1,500/μl 2. Platelets ≥ 100,000/μl 3. Hemoglobin \> 9 g/dL 4. AST/ALT ≤ 3 X upper limit of normal (ULN) 5. Total bilirubin ≤ 1.5 X upper limit of normal (ULN) 6. Calculated CrCL ≥50 mL/min using the Cockcroft-Gault formula. 7. INR or PT ≤ 1.5× ULN; if receiving anticoagulant therapy, PT or aPTT should be within therapeutic range. 15. Provide written, informed consent to participate in the study and follow the study procedures. 16. Willing to provide mandatory tissue and blood samples for research purposes.
Exclusion criteria
1. Prior treatment for pancreatic adenocarcinoma other than up to two doses of mFOLFIRINOX administered prior to initiation of navlimetostat. 2. Concurrent severe and/or uncontrolled medical conditions which may compromise participation in the study. 3. Female patients who are pregnant or breast feeding. 4. Patients of either sex, not willing to use an effective method of birth control. 5. Live vaccines within 30 days of planned start of study medication, during treatment and for 90 days after treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. 6. Patients taking medications specified by the protocol as prohibited for administration in combination with study drugs. 7. Radiotherapy to the primary tumor prior to or planned post-surgery. 8. Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications. 9. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the start of study or anticipation of need for major surgical procedure during the course of the study other than surgical resection of the pancreatic tumor. 10. Serious, non-healing wound, ulcer, or bone fracture. 11. History of myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or surgery within 6 months prior to study enrollment. 12. Cardiac abnormalities including: 1. LVEF \< 50% 2. QTcF prolongation \> 480 msec, except for right bundle branch block, per the investigator's assessment. 13. Uncontrolled/symptomatic or significant cardiovascular conditions within 6 months prior to randomization, including, but not limited to, any of the following: cardiac angioplasty or stenting, unstable angina pectoris, myocardial infarction, stroke/transient ischemic attack, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, New York Heart Association class III-IV congestive heart failure, pericarditis, myocarditis, atrial fibrillation, or other arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). 14. Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be switched to alternative treatment prior to study entry. 15. HIV seropositivity, active hepatitis B or C infection, or other serious chronic infection requiring ongoing treatment. 16. Known dihydropyrimidine dehydrogenase (DPD) deficiency 17. Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee. 18. Known chronic liver disease, autoimmune hepatitis, or sclerosing cholangitis. 19. Receiving any other agent which would be considered as a treatment for the primary neoplasm. 20. Treatment with another investigational device or study drug or participation in another drug study within 30 days of screening. Other investigational procedures while participating in this study are excluded. 21. Known hypersensitivity to the active substances or to any of the excipients. 22. Patients with another malignancy for which treatment is required, per investigator's clinical judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | Up to 15 months | Adverse events are assessed at every study visit and logged according to NCI-CTCAE v6.0. |
| Recommended phase 2 dose of navlimetostat, as measured by the number of participants who experience a dose limiting toxicity during the first cycle of the phase 1b portion of the study | Dose limiting toxicities are assessed throughout the first 28 days on combination treatment. | Dose limiting toxicities are assessed throughout the first 28 days on combination treatment and are logged according to NCI-CTCAE v6.0 |
| Feasibility of perioperative navlimetostat combined with mFOLFIRINOX | Measured from the start of study treatment with navlimetostat through 14 days after surgery. | Feasibility is measured by the proportion of evaluable participants who receive at least four doses of mFOLFIRINOX and at least one dose of navlimetostat prior to surgery, undergo surgical resection within 60 days of completing mFOLFIRINOX, and do not experience significant unexpected postoperative complications considered at least possibly related to navlimetostat within 14 days of surgery. |
| Severity of Adverse Events | Up to 15 months | Adverse events are assessed at every study visit and logged according to NCI-CTCAE v6.0. |
| Incidence of dose limiting toxicities | The first 28 days of combination treatment | Incidence of protocol-defined dose limiting toxicites, as assessed and graded per NCI-CTCAE v 6.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic response rate | Measured within one week post-operatively | Pathologic response rate is measured by College of American Pathologists (CAP) score of patients who undergo surgery. CAP scores range from 0-3, where 0=Complete response and 3=Poor or no response. |
| Recurrence free survival (RFS) | Up to three years | RFS is defined as the time from surgery to documented recurrence or death due to any cause. |
| Overall survival (OS) | Up to three years | OS is defined as the time from the first dose of navlimetostat to death due to any cause. |
| Event free survival (EFS) | Up to three years | EFS is defined as the time from the first dose of navlimetostat to clinical or radiographic progression, death due to any cause, or navlimetostat discontinuation due to toxicity |
Countries
United States
Contacts
CONTACTEmily Bolch
CONTACTDuke University GI Oncology Research
PRINCIPAL_INVESTIGATORDaniel Nussbaum, MD
Duke University
STUDY_CHAIRJohn Strickler, MD
Mayo Clinic Comprehensive Cancer Center
Outcome results
None listed