Neoadjuvant Folfirinox Combined With Pembrolizumab Followed by Surgery for Patients With Resectable Pancreatic Cancer

Sponsor

Baylor College of Medicine (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05132504

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Locations

Arm

Anticipated Duration (Months)

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Abbreviated Title: Neoadjuvant FOLFIRINOX combined with Pembrolizumab followed by surgery for patients with resectable pancreatic cancer Trial Phase: Phase II Clinical Indication: Pancreatic ductal adenocarcinoma; Adenocarcinoma; AJCC I, II, or III; 1st Line neoadjuvant

Trial Type: Interventional prospective Type of control: Historical Route of administration:

IV Treatment Groups: Neoadjuvant FOLFIRINOX combined with Pembrolizumab followed by surgery for patients with resectable pancreatic cancer Number of trial participants: 30 Estimated enrollment period: 24 months Estimated duration of trial: 3.5 Years Duration of Participation: 9 months Estimated average length of treatment per patient: 9 months

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Ductal Adenocarcinoma	Drug: Pembrolizumab Drug: Folfirinox	Phase 2

Detailed Description

This is a Phase II trial of NEOADJUVANT FOLFIRINOX CHEMOTHERAPY WITH PEMBROLIZUMAB followed by SURGERY and Adjuvant PEMBROLIZUMAB for Patients with LOCALIZED, RESECTABLE Adenocarcinoma of the pancreas. Investigators hypothesize that appropriately timed neoadjuvant FOLFIRINOX with anti-PD-1 mAb (pembrolizumab) can be administered safely and feasibly, and that this combination will lead to improved clinical response associated with enhanced numbers of immune cells in surgically resected pancreatic tumors. Patients will receive 6 cycles of FOLFIRINOX with 2 cycles of PEMBROLIZUMAB before surgical resection. Following surgery patients will receive 5FU based chemotherapy for up to 6 cycles with 5 more cycles of PEMBROLIZUMAB. Patients will receive a total of 9 doses of Q6week cycles of PEMBROLIZUMAB.

Toxicities will be continuously monitored using the method proposed by Ivanova et al. [Ivanova, A., Qaqish, B.F., and Schell, M.J. (2005). Continuous toxicity monitoring in phase II trials in oncology. Biometrics 61: 540-545.]. The method generates a Pocock-type stopping boundary for repeated testing for toxicity. Sequential boundaries will be used to monitor dose-limiting toxicity rate. The accrual will be halted if excessive numbers of dose-limiting toxicities are seen, that is, if the number of dose-limiting toxicities is equal to or exceeds boundary number out of the number of patients with full follow-up. This is a Pocock-type stopping boundary that yields the probability of crossing the boundary at most 5% when the rate of dose-limiting toxicity is equal to the acceptable rate of 25%.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Study of Neoadjuvant Folfirinox Chemotherapy Followed by Pembrolizumab Followed by Surgery for Patients With Localized, Resectable Adenocarcinoma of the Pancreas

Anticipated Study Start Date :

Sep 30, 2022

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jul 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Neoadjuvant Folfirinox and Pembrolizumab followed by sx for patients with pancreatic cancer Patients will receive 6 cycles of Folfirinox (Oxaliplatin 85 mg/m2, Leucovorin 400 mg/m2, Irinotecan 180 mg/m2, 5-Fluorouracil 2,400 mg/m2) with 2 cycles of Pembrolizumab 400 mg before surgical resection. Following surgery patients will receive 5-Fluorouracil based chemotherapy for up to 6 cycles with 5 more cycles of Pembrolizumab. Patients will receive a total of 9 doses of Q6week cycles of Pembrolizumab.	Drug: Pembrolizumab Pembrolizumab will be initiated starting with the Cycle 2 Day 1 and will be administered every 6 weeks with a max amount of 9 cycles throughout the study. Other Names: keytruda Drug: Folfirinox Once eligibility has been confirmed and the patient has been registered to the study, the patient will begin induction modified FOLFIRINOX (Oxaliplatin, Leucovorin, Irinotecan, 5-Fluorouracil) chemotherapy treatment. Each cycle is 14 days; a total of six cycles will be administered. Patients will receive growth factor support at the discretion of treating physician. Other Names: mFolfirinox

Arm

Intervention/Treatment

Experimental: Neoadjuvant Folfirinox and Pembrolizumab followed by sx for patients with pancreatic cancer

Patients will receive 6 cycles of Folfirinox (Oxaliplatin 85 mg/m2, Leucovorin 400 mg/m2, Irinotecan 180 mg/m2, 5-Fluorouracil 2,400 mg/m2) with 2 cycles of Pembrolizumab 400 mg before surgical resection. Following surgery patients will receive 5-Fluorouracil based chemotherapy for up to 6 cycles with 5 more cycles of Pembrolizumab. Patients will receive a total of 9 doses of Q6week cycles of Pembrolizumab.

Drug: Pembrolizumab

Pembrolizumab will be initiated starting with the Cycle 2 Day 1 and will be administered every 6 weeks with a max amount of 9 cycles throughout the study.

Other Names:

keytruda

Drug: Folfirinox

Once eligibility has been confirmed and the patient has been registered to the study, the patient will begin induction modified FOLFIRINOX (Oxaliplatin, Leucovorin, Irinotecan, 5-Fluorouracil) chemotherapy treatment. Each cycle is 14 days; a total of six cycles will be administered. Patients will receive growth factor support at the discretion of treating physician.

Other Names:

mFolfirinox

Outcome Measures

Primary Outcome Measures

Determine if the neoadjuvant FOLFIRINOX chemotherapy followed by pembrolizumab followed by surgery will improve the overall response rate (ORR) for patients with localized, resectable adenocarcinoma of the pancreas. [3 years]
The primary endpoints are overall response rate (ORR) defined as the proportion of patients with pathologic CR or PR. The primary analysis will compare the observed ORR to the null proportion of 5% using an exact binomial test. In addition, the percentage of ORR for the intervention with its 95% confidence interval will be presented.

Secondary Outcome Measures

Estimate the effect of combination neoadjuvant therapy on the R0 resection rate [3 years]
The percentage of R0 resection will be estimated with its 95% confidence interval.
Determine if the addition of pembrolizumab to neoadjuvant mFOLFIRINOX leads to improved CD8+ T cell frequencies in resected tumor samples in comparison to archived matched controls from patients meeting the same I/E criteria as those in the study. [3 years]
Descriptive statistics will be provided. Group comparisons of CD8+ T cell frequencies will be performed.
Estimate the effect of combined neoadjuvant therapy on relapse-free survival, time to recurrence and overall survival. [3 years]
Survival outcomes will be summarized with related 95% confidence interval.
Report of safety profile [3 years]
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting, with the exception of skin- or nail-related toxicities, which will be graded using CTCAE version 5.0 with modifications.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient is ≥18 years of age and has histologically or cytologically confirmed localized adenocarcinoma of the pancreas that is potentially resectable. Patients with islet cell or other neuroendocrine neoplasms are excluded.
Definition of localized, potentially resectable disease:
Staging by intravenous contrast-enhanced thin section helical abdominal computed tomography (2.5 mm cuts or less) or MRI (for patients with an IV contrast allergy) using pancreatic protocol. Endoscopic ultrasound is required for tissue acquisition and staging confirmation.
No extension to superior mesenteric artery (SMA) and hepatic artery. Patent superior mesenteric vein/portal vein (SMV/PV) with < 180-degree abutment and no evidence of invasion.
Clear fat plane between the SMA and celiac axis.
No extension to celiac axis and hepatic artery.
Patent superior mesenteric vein and portal vein.
No evidence of distant disease by additional imaging of the chest (CT with or without contrast or PET/CT) and pelvis (CT with contrast, PET/CT, or MRI with contrast).
No other evidence of distant disease 3. If a female patient is of childbearing potential, she must have a negative serum pregnancy test (β hCG) documented within 72 hours of the first administration of study drug.
If sexually active, the patient must agree to use contraception considered adequate and appropriate by the Investigator.
Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least [X days/weeks, corresponding to time needed to eliminate any study treatment(s) (e.g. 5 terminal half-lives for pembrolizumab and/or any active comparator/combination) plus an additional 90 days (a spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose] after the last dose of study treatment and refrain from donating sperm during this period.
Patient must not have received prior chemotherapy or radiation for pancreatic cancer.
Patient has an ECOG performance status PS 0-1. 8. Patient has been informed about the nature of the study, and has agreed to participate in the study, and signed the Informed Consent Form prior to participation in any study-related activities.
A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least [X days/weeks (corresponding to time needed to eliminate any study treatment(s) (pembrolizumab and/or any active comparator/combination) plus 30 days (a menstruation cycle) for study treatments with risk of genotoxicity] after the last dose of study treatment.

Have adequate organ function as defined in the following table (Table 4). Specimens must be collected within 10 days prior to the start of study intervention.

Hematological Absolute neutrophil count (ANC) ≥1500/μL Platelets ≥100 000/μL Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La Renal Creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

Patient has borderline resectable, locally advanced unresectable or advanced metastatic disease. Patients with neuroendocrine tumors, adenosquamous cancer, lymphoma of the pancreas, or ampullary cancer are also ineligible.
Patient has active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
Patient has known infection with HIV.
Patient has undergone major surgery, other than diagnostic surgery (-e.g. diagnostic laparoscopy or placement of a central venous catheter), within 4 weeks prior to Day 1 of treatment in this study.
Patient has a history of allergy or hypersensitivity to the study drugs.
Patient has serious medical risk factors involving any of the major organ systems such that the Investigator considers it unsafe for the patient to receive chemotherapy and/or radiation therapy.
Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
Patient has had clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before randomization.
Patient is unwilling or unable to comply with study procedures.
Patient is enrolled in any other therapeutic clinical protocol or investigational trial.
Patients aged ≥ 80 are not excluded. However, candidates in this age group should be thoroughly evaluated before enrollment in the study, to ensure they are fit to receive chemotherapy, and to potentially undergo pancreaticoduodenectomy. In addition to meeting all of the baseline patient selection criteria, clinical judgment on their susceptibility to infection and expected stability of their performance status and suitability to receive intensive chemotherapy cycles, should be paid special attention to. Patients should not be enrolled in the study should there be any hesitation on any of these considerations. Baseline criteria for all patients enrolled on the study must be carefully evaluated and all criteria followed appropriately.
Patient has evidence of peripheral neuropathy Grade 2 or higher.
Pregnant or lactating women who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In the event that 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug.
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as detectable HCV by RNA) infection. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Has had an allogenic tissue/solid organ transplant.