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Nivolumab in Combination With Chemotherapy Pre-Surgery in Treating Patients With Borderline Resectable Pancreatic Cancer

Primary Purpose

Borderline Resectable Pancreatic Adenocarcinoma, Resectable Pancreatic Ductal Adenocarcinoma

Status
Recruiting
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Fluorouracil
Irinotecan
Irinotecan Hydrochloride
Leucovorin
Leucovorin Calcium
Nivolumab
Oxaliplatin
Therapeutic Conventional Surgery
Sponsored by
Jonsson Comprehensive Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Borderline Resectable Pancreatic Adenocarcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • UCLA / Jonsson Comprehensive Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (nivolumab, mFOLFIRINOX)

Arm Description

Patients receive nivolumab 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.

Outcomes

Primary Outcome Measures

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
Descriptive statistics with frequency and proportion will be used.
Pathologic complete response after nivolumab and mFFX treatment
Descriptive statistics with frequency and proportion will be used.

Secondary Outcome Measures

Percent change of CA 19-9 response rate
Descriptive statistics with frequency and proportion will be used to analyze the CA19-9 response rate.
R0 resection rate
Overall response rate (ORR)
Descriptive statistics with frequency and proportion will be used to analyze ORR.
Disease free survival (DFS)
Kaplan-Meier methods will be used to analyze DFS with median and 95% confidence interval (CI).
Incidence of adverse events
Will be categorized and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.3.
Delayed wound healing
Wound dehiscence
Wound infection

Full Information

First Posted
May 29, 2019
Last Updated
May 5, 2023
Sponsor
Jonsson Comprehensive Cancer Center
Collaborators
Bristol-Myers Squibb, NovoCure Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT03970252
Brief Title
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

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
July 24, 2019 (Actual)
Primary Completion Date
April 15, 2024 (Anticipated)
Study Completion Date
April 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Jonsson Comprehensive Cancer Center
Collaborators
Bristol-Myers Squibb, NovoCure Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Borderline Resectable Pancreatic Adenocarcinoma, Resectable Pancreatic Ductal Adenocarcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
36 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (nivolumab, mFOLFIRINOX)
Arm Type
Experimental
Arm Description
Patients receive nivolumab 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.
Intervention Type
Drug
Intervention Name(s)
Fluorouracil
Other Intervention Name(s)
5-Fluoro-2,4(1H, 3H)-pyrimidinedione, 5-Fluorouracil, 5-Fluracil, 5-FU, AccuSite, Carac, Fluoro Uracil, Fluouracil, Flurablastin, Fluracedyl, Fluracil, Fluril, Fluroblastin, Ribofluor, Ro 2-9757, Ro-2-9757
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Irinotecan
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Irinotecan Hydrochloride
Other Intervention Name(s)
Campto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440E
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Leucovorin
Other Intervention Name(s)
Folinic acid
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Leucovorin Calcium
Other Intervention Name(s)
Adinepar, Calcifolin, Calcium (6S)-Folinate, Calcium Folinate, Calcium Leucovorin, Calfolex, Calinat, Cehafolin, Citofolin, Citrec, citrovorum factor, Cromatonbic Folinico, Dalisol, Disintox, Divical, Ecofol, Emovis, Factor, Citrovorum, Flynoken A, Folaren, Folaxin, FOLI-cell, Foliben, Folidan, Folidar, Folinac, Folinate Calcium, folinic acid, Folinic Acid Calcium Salt Pentahydrate, Folinoral, Folinvit, Foliplus, Folix, Imo, Lederfolat, Lederfolin, Leucosar, leucovorin, Rescufolin, Rescuvolin, Tonofolin, Wellcovorin
Intervention Description
Given IV
Intervention Type
Biological
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Oxaliplatin
Other Intervention Name(s)
1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
Therapeutic Conventional Surgery
Intervention Description
Undergo surgery
Primary Outcome Measure Information:
Title
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
Description
Descriptive statistics with frequency and proportion will be used.
Time Frame
Up to 3 years
Title
Pathologic complete response after nivolumab and mFFX treatment
Description
Descriptive statistics with frequency and proportion will be used.
Time Frame
Up to 3 years
Secondary Outcome Measure Information:
Title
Percent change of CA 19-9 response rate
Description
Descriptive statistics with frequency and proportion will be used to analyze the CA19-9 response rate.
Time Frame
Baseline up to 3 years
Title
R0 resection rate
Time Frame
Up to 3 years
Title
Overall response rate (ORR)
Description
Descriptive statistics with frequency and proportion will be used to analyze ORR.
Time Frame
Up to 3 years
Title
Disease free survival (DFS)
Description
Kaplan-Meier methods will be used to analyze DFS with median and 95% confidence interval (CI).
Time Frame
Up to 3 years
Title
Incidence of adverse events
Description
Will be categorized and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.3.
Time Frame
Up to 28 days after last dose of study drug
Title
Delayed wound healing
Time Frame
Up to 3 years
Title
Wound dehiscence
Time Frame
Up to 3 years
Title
Wound infection
Time Frame
Up to 3 years
Other Pre-specified Outcome Measures:
Title
Changes in immune cell infiltrates and cancer cell IFNgamma signaling in response to FOLFIRINOX and nivolumab treatment
Description
Will examine the tissue from baseline to post-therapy at the time of surgery or at the time of progression. Will use descriptive statistics and graphical displays to compare the percent change in stromal depletion overall and to describe the association with cell proliferation and death. In addition, will graphically explore the percent change in stromal depletion for patients who undergo surgery compared to those who have disease progression.
Time Frame
Baseline up to 3 years
Title
Signaling and metabolomic changes in pancreatic ductal adenocarcinoma (PDAC) cancer cells that respond to IFNgamma
Description
Will examine the tissue from baseline to post-therapy at the time of surgery or at the time of progression. Will use descriptive statistics and graphical displays to compare the percent change in stromal depletion overall and to describe the association with cell proliferation and death. In addition, will graphically explore the percent change in stromal depletion for patients who undergo surgery compared to those who have disease progression.
Time Frame
Baseline up to 3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Zev A Wainberg
Organizational Affiliation
UCLA / Jonsson Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA / Jonsson Comprehensive Cancer Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zev A. Wainberg
Phone
310-829-5471
Email
zwainberg@mednet.ucla.edu
First Name & Middle Initial & Last Name & Degree
Zev A. Wainberg

12. IPD Sharing Statement

Learn more about this trial

Nivolumab in Combination With Chemotherapy Pre-Surgery in Treating Patients With Borderline Resectable Pancreatic Cancer

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