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

• ClinicalTrials.gov Identifier: NCT03970252
• Recruitment Status: Recruiting
• First Posted: May 31, 2019
• Last Update Posted: July 23, 2020
• Sponsor: Jonsson Comprehensive Cancer Center
• Collaborators: Bristol-Myers Squibb; NovoCure Ltd.
• Information provided by (Responsible Party): Jonsson Comprehensive Cancer Center

Study Description

Brief Summary:

This phase I/II trial 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.

Condition or disease	Intervention/treatment	Phase
Borderline Resectable Pancreatic Adenocarcinoma; Resectable Pancreatic Ductal Adenocarcinoma	Drug: Fluorouracil; Drug: Irinotecan; Drug: Irinotecan Hydrochloride; Drug: Leucovorin; Drug: Leucovorin Calcium; Biological: Nivolumab; Drug: Oxaliplatin; Procedure: Therapeutic Conventional Surgery	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 36 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot and Feasibility Study of PD-1 Blockade With Nivolumab in Combination With Chemotherapy in Patients With Borderline Resectable Pancreatic Adenocarcinoma
• Actual Study Start Date: July 24, 2019
• Estimated Primary Completion Date: April 15, 2021
• Estimated Study Completion Date: April 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (nivolumab, mFOLFIRINOX); 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.

Drug: Fluorouracil; Given IV; Other Names: 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; Drug: Irinotecan; Given IV; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto; Camptosar; Camptothecin 11; Camptothecin-11; CPT 11; CPT-11; Irinomedac; U-101440E; Drug: Leucovorin; Given IV; Other Name: Folinic acid; Drug: Leucovorin Calcium; Given IV; Other Names: 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; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Ai Heng; Aiheng; Dacotin; Dacplat; Diaminocyclohexane Oxalatoplatinum; Eloxatin; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Procedure: Therapeutic Conventional Surgery; Undergo surgery

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: Up to 3 years ]
   Descriptive statistics with frequency and proportion will be used.
2. Pathologic complete response after nivolumab and mFFX treatment [ Time Frame: Up to 3 years ]
   Descriptive statistics with frequency and proportion will be used.

Secondary Outcome Measures :

1. Percent change of CA 19-9 response rate [ Time Frame: Baseline up to 3 years ]
   Descriptive statistics with frequency and proportion will be used to analyze the CA19-9 response rate.
2. R0 resection rate [ Time Frame: Up to 3 years ]
3. Overall response rate (ORR) [ Time Frame: Up to 3 years ]
   Descriptive statistics with frequency and proportion will be used to analyze ORR.
4. Disease free survival (DFS) [ Time Frame: Up to 3 years ]
   Kaplan-Meier methods will be used to analyze DFS with median and 95% confidence interval (CI).
5. Incidence of adverse events [ Time Frame: Up to 28 days after last dose of study drug ]
   Will be categorized and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.3.
6. Delayed wound healing [ Time Frame: Up to 3 years ]
7. Wound dehiscence [ Time Frame: Up to 3 years ]
8. Wound infection [ Time Frame: Up to 3 years ]

Other Outcome Measures:

1. Changes in immune cell infiltrates and cancer cell IFNgamma signaling in response to FOLFIRINOX and nivolumab treatment [ Time Frame: Baseline up to 3 years ]
   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.
2. Signaling and metabolomic changes in pancreatic ductal adenocarcinoma (PDAC) cancer cells that respond to IFNgamma [ Time Frame: Baseline up to 3 years ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

UCLA / Jonsson Comprehensive Cancer Center; Recruiting

Los Angeles, California, United States, 90095

Contact: Zev A. Wainberg 310-829-5471 zwainberg@mednet.ucla.edu

Principal Investigator: Zev A. Wainberg

Sponsors and Collaborators

Jonsson Comprehensive Cancer Center

Bristol-Myers Squibb

NovoCure Ltd.

Investigators

• Principal Investigator: Zev A Wainberg; UCLA / Jonsson Comprehensive Cancer Center

More Information

• Responsible Party: Jonsson Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT03970252
• Other Study ID Numbers: 19-000290; NCI-2019-02886 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 19-000290 ( Other Identifier: UCLA / Jonsson Comprehensive Cancer Center )
• First Posted: May 31, 2019
• Last Update Posted: July 23, 2020
• Last Verified: July 2020

• 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

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Calcium, Dietary; Leucovorin; Folic Acid; Fluorouracil; Oxaliplatin; Irinotecan; Nivolumab; Camptothecin; Calcium; Levoleucovorin; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Bone Density Conservation Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Antineoplastic Agents, Immunological; Antidotes; Protective Agents