Clinical trial NCT03970252: Nivolumab in Combination With Chemotherapy Pre-Surgery in Treating Patients With Borderline Resectable Pancreatic Cancer
Official title: A Pilot and Feasibility Study of PD-1 Blockade With Nivolumab in Combination With Chemotherapy in Patients With Borderline Resectable Pancreatic Adenocarcinoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Borderline Resectable Pancreatic Adenocarcinoma
Resectable Pancreatic Ductal Adenocarcinoma
Lead sponsor: Jonsson Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
name: NovoCure Ltd.
First posted: 2019-05-31
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This pilot and feasibility study studies how well nivolumab and combination chemotherapy work before surgery in treating patients with pancreatic cancer that could possibly be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab in combination with chemotherapy before surgery may work better in treating patients with pancreatic cancer compared to chemotherapy alone.

Detailed description: PRIMARY OBJECTIVES:

I. To evaluate development of clinically relevant pancreatic fistula in the post-operative period after neoadjuvant treatment with nivolumab and fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (FOLFIRINOX) (FFX).

II. To evaluate pathologic complete response after neoadjuvant nivolumab and FOLFIRINOX (FFX).

SECONDARY OBJECTIVES:

I. To evaluate early efficacy measured by percent change of CA 19-9 response rate, R0 resection rate, overall response rate (ORR) and disease free survival (DFS).

EXPLORATORY OBJECTIVES, OTHER ASSESSMENTS:

I. To determine degree of changes in the tumor microenvironment (TME) of nivolumab and modified (m) FFX on cell proliferation and apoptosis.

OUTLINE:

Patients receive nivolumab intravenously (IV) over 60 minutes on day 1. Patients also receive fluorouracil IV over 10 minutes and over 46 hours, irinotecan hydrochloride IV over 90-120 minutes, leucovorin calcium IV over 120 minutes, and oxaliplatin IV over 120 minutes on days 1 and 15. Treatments repeat every 28 days for 3-6 cycles in the absence of disease progression or unacceptable toxicity. Within 2-4 weeks after treatment, patients with resectable disease undergo surgery. Within 8-12 weeks after surgery, patients with successful resection may receive 6 additional cycles of fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2-3 months.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed pancreatic adenocarcinoma
* One of the following:

  * Borderline resectable disease. There are multiple definitions of borderline resectable pancreatic ductal adenocarcinoma (PDAC) including the MD Anderson definition and the criteria developed during the Consensus Conference sponsored by the American Hepato-Pancreato-Biliary Association, Society of Surgical Oncology, and Society for Surgery of the Alimentary Tract. Borderline resectable PDAC cases will be identified per the definition developed in the currently running inter-group pilot trial for borderline resectable pancreatic cancer (NCT01821612). Per this trial, borderline resectable PDAC is defined as the presence of any one or more of the following on computed tomography (CT):

    * An interface between the primary tumor and the superior mesenteric vein or portal vein (SMV-PV) measuring \>= 180 degrees of the circumference of the vessel wall
  * Short-segment occlusion of the SMV-PV with normal vein above and below the level of obstruction that is amenable to resection and venous reconstruction
  * Short segment interface (of any degree) between tumor and hepatic artery with normal artery proximal and distal to the interface that is amenable to resection and reconstruction
  * An interface between the tumor and superior mesenteric artery (SMA) measuring \< 180 degrees of the circumference of the vessel wall
* Performance status of Eastern Cooperative Oncology Group (ECOG) of 0-1
* Therapy naive
* Absolute neutrophil count (ANC) \>= 1500/mm\^3
* Platelets \>= 100,000/mm\^3
* Hemoglobin \>= 9 g/dl
* Serum total bilirubin =\< 1.5 x upper limit of normal (ULN)
* Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) and aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]) =\< 2.5 x ULN
* Alkaline phosphatase =\< 2.5 x ULN
* Serum creatinine (sCr) =\< 1.5 x ULN or creatinine clearance (Ccr) \>= 40 mL/min as calculated by the modified Cockcroft-Gault formula
* Peripheral neuropathy \< grade 2

Exclusion Criteria:

* Locally advanced (clearly unresectable) or metastatic disease
* Known status of human immunodeficiency virus (HIV) which is not well-controlled at the time of study eligibility
* Untreated hepatitis B infection
* Active infection or antibiotics within 48 hours prior to study
* Currently active second primary malignancy or history of malignancy less than 5 years prior to the time of study eligibility (patients with history of skin cancers excluding melanoma will be eligible for participation)
* Serious medical comorbidities such as New York Heart Association class III/IV cardiac disease, uncontrolled cardiac arrhythmias, myocardial infarction over the past 12 months
* Known, existing uncontrolled coagulopathy. Patients who have had a venous thromboembolic event (e.g., pulmonary embolism or deep vein thrombosis) requiring anticoagulation are eligible IF: they are appropriately anticoagulated and have not had a grade 2 or greater bleeding episode in the 3 weeks before day 1
* Prior history of cerebrovascular accident or transient ischemic attack, or pre-existing carotid artery disease
* Known pregnancy, nursing women or positive pregnancy test. Requirement for women of childbearing potential (WOCBP) must have a pregnancy test every 4 weeks and WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) within 24 hours prior to the start of nivolumab
* Any prisoners, or subjects who are compulsory detained are excluded
* Any condition that would preclude informed consent, consistent follow-up and compliance for the study participation

Primary outcomes:
measure: Clinically relevant pancreatic fistula in the post-operative period after neoadjuvant treatment with nivolumab and fluorouracil, irinotecan hydrochloride, leucovorin calcium and oxaliplatin (FOLFIRINOX) (mFFX) chemotherapy
timeFrame: Up to 3 years
measure: Pathologic complete response after nivolumab and mFFX treatment
timeFrame: Up to 3 years
Secondary outcomes:
measure: Percent change of CA 19-9 response rate
timeFrame: Baseline up to 3 years
measure: R0 resection rate
timeFrame: Up to 3 years
measure: Overall response rate (ORR)
timeFrame: Up to 3 years
measure: Disease free survival (DFS)
timeFrame: Up to 3 years
measure: Incidence of adverse events
timeFrame: Up to 28 days after last dose of study drug
measure: Delayed wound healing
timeFrame: Up to 3 years
measure: Wound dehiscence
timeFrame: Up to 3 years
measure: Wound infection
timeFrame: Up to 3 years
Other outcomes:
measure: Changes in immune cell infiltrates and cancer cell IFNgamma signaling in response to FOLFIRINOX and nivolumab treatment
timeFrame: Baseline up to 3 years
measure: Signaling and metabolomic changes in pancreatic ductal adenocarcinoma (PDAC) cancer cells that respond to IFNgamma
timeFrame: Baseline up to 3 years
Locations:
city: Los Angeles
country: United States
facility: UCLA / Jonsson Comprehensive Cancer Center
state: California
Study officials:
affiliation: UCLA / Jonsson Comprehensive Cancer Center
name: Zev A Wainberg
role: PRINCIPAL_INVESTIGATOR
References: