Platform Study of Neoadjuvant and Adjuvant Immunotherapy for Patients With Resectable Adenocarcinoma of the Pancreas

A Platform Study of Combination Immunotherapy for the Neoadjuvant and Adjuvant Treatment of Patients With Surgically Resectable Adenocarcinoma of the Pancreas

This platform trial will evaluate various immunotherapy combinations given in the neo-adjuvant and adjuvant setting in patients with surgically resectable pancreatic ductal adenocarcinoma.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: Cyclophosphamide; Biological: GVAX pancreatic cancer; Drug: Nivolumab; Drug: Urelumab; Drug: BMS-986253

Detailed Description

Immunotherapy is an innovative approach being developed for the treatment of pancreatic cancer, a lethal and relatively chemotherapy-resistant disease. However, the tumor and its environment have developed a number of ways in which they inhibit the function of the immune system preventing it from recognizing and killing the cancer. In addition, the investigators still do not understand how T cells, the cells in the immune system that have the potential to recognize cancer as different and kill cancer cells, traffic into the tumor to accomplish their task. The investigators are currently testing an immune system activating pancreatic cancer vaccine (known as GVAX) in combination with immune boosting doses of the chemotherapy agent, cyclophosphamide, as preoperative and postoperative treatments for pancreatic cancer. The investigators have discovered tertiary lymphoid aggregates, a unique lymph node-like structure formed within resected tumors from the patients who received the vaccine two weeks prior to the surgery. This discovery demonstrates that the immune system can get into the tumor and provides the investigators with the opportunity to better understand how these immune cells traffic into the tumor and function once they arrive. The investigators also found that the vaccine causes an increase in signals that would suppress the immune system's ability to fight off cancer cells, including signals involving PD-1. In this novel study, the investigators will test the effects of blocking PD-1 in combination with the vaccine in patients with pancreatic cancer. The investigators will specifically isolate these immune cells and evaluate at both the genetic and protein level, the types of signals expressed by these aggregates. The investigators will compare aggregates from patients with long term survival versus patients who succumb to their cancer early. In this way, the investigators will be able to determine how safe this novel treatment is, how effective it is at changing the immune system in pancreatic cancer, and how it impacts the health and survival of pancreatic cancer patients who undergo surgery to remove the cancer.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Carol Judkins, RN; Phone Number: 410-614-5241; Email: judkica@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Recruiting
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
      • Contact: Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce; Phone Number: 410-955-8804; Email: jhcccro@jhmi.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Newly diagnosed or clinically-suspected adenocarcinoma of the head, neck, or uncinate process of the pancreas
• Tumor must be surgically resectable
• ECOG Performance Status of 0 to 1
• Adequate organ function as defined by study-specified laboratory tests
• Must agree to use acceptable form of birth control

Exclusion Criteria:

• Received any type of anti-cancer treatment or immunotherapy for pancreas cancer
• History of autoimmune disease (Graves or Hashimoto's disease, vitiligo, and type I diabetes are allowed)
• Systemically steroid use within 14 days
• Evidence of active infection
• Pregnant or lactating
• Diagnosed with another cancer or myeloproliferative disorder (some exceptions)
• History of severe hypersensitivity reaction to any monoclonal antibody or known component of the study drugs
• Known history of infection with HIV, hepatitis B, or hepatitis C
• Oxygen saturation of <92% on room air by pulse oximetry
• On home oxygen

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: CY/GVAX alone; Patients receive low-dose cyclophosphamide IV on day 0 and GVAX pancreatic cancer vaccine ID on day 1. Patients undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive low-dose cyclophosphamide IV on day 0 and the vaccine on day 1. Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive low-dose cyclophosphamide IV on day 0 and the vaccine on day 1. Treatment with cyclophosphamide and the vaccine repeats every 28 days for 4 courses. Patients will then enter the extended treatment phase where they will receive cyclophosphamide on day 0, and GVAX on day 1 every 12 weeks for another 2 treatments.	Drug: Cyclophosphamide; 200 mg/m2 IV; Other Names: Cytoxan, CY; Biological: GVAX pancreatic cancer; 5x10^8 cells intradermal injection; Other Names: GVAX, pancreatic tumor vaccine
Experimental: Arm B: CY/GVAX with nivolumab; Patients receive low-dose cyclophosphamide and nivolumab IV on day 0 and GVAX pancreatic cancer vaccine ID on day 1. Patients undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive low-dose cyclophosphamide and nivolumab IV on day 0 and the vaccine on day 1. Beginning approximately 1 month after vaccination, patients receive standard adjuvant chemoradiotherapy. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive low-dose cyclophosphamide and nivolumab IV on day 0 and the vaccine on day 1. Treatment with cyclophosphamide, nivolumab, and the vaccine repeats every 28 days for 4 courses. Patients will then enter the extended treatment phase where they will receive nivolumab every 4 weeks for another 6 treatments as well as cyclophosphamide on day 0, and GVAX on day 1 every 12 weeks for another 2 treatments.	Drug: Cyclophosphamide; 200 mg/m2 IV; Other Names: Cytoxan, CY; Biological: GVAX pancreatic cancer; 5x10^8 cells intradermal injection; Other Names: GVAX, pancreatic tumor vaccine; Drug: Nivolumab; 480 mg IV; Other Names: OPDIVO; BMS-936558; anti-PD1
Experimental: Arm C: CY/GVAX with nivolumab and urelumab; Patients receive low-dose cyclophosphamide, nivolumab, and urelumab on day 0 and GVAX pancreatic cancer vaccine on day 1. Patients undergo pancreaticoduodenectomy on day 15. Approximately 6-10 weeks after surgery, patients receive low-dose cyclophosphamide, nivolumab, and urelumab on day 0 and the vaccine on day 1. Beginning approximately 28 days after vaccination, patients receive standard adjuvant chemoradiotherapy. Beginning approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive low-dose cyclophosphamide, nivolumab, and urelumab on day 0 and GVAX on day 1. Treatment with cyclophosphamide, nivolumab, urelumab, and the vaccine repeats every 28 days for 4 courses. Patients will then enter the extended treatment phase where they will receive nivolumab and urelumab every 4 weeks for another 6 treatments as well as cyclophosphamide on day 0, and GVAX on day 1 every 12 weeks for another 2 treatments.	Drug: Cyclophosphamide; 200 mg/m2 IV; Other Names: Cytoxan, CY; Biological: GVAX pancreatic cancer; 5x10^8 cells intradermal injection; Other Names: GVAX, pancreatic tumor vaccine; Drug: Nivolumab; 480 mg IV; Other Names: OPDIVO; BMS-936558; anti-PD1; Drug: Urelumab; 8 mg IV; Other Names: BMS-663513; anti-CD137 Agonist
Experimental: Arm D: BMS-986253 and Nivolumab; Patients receive BMS-986253 and nivolumab on day 0 (Cycle 1), 15 days prior to surgery. 6-10 weeks after surgery, patients receive Cycle 2, with nivolumab on day 0 and BMS-986253 on days 0 and 14. Patients then receive standard adjuvant chemoradiotherapy. Approximately 4-8 weeks after the completion of chemoradiotherapy, patients receive 4 additional 28-day cycles of immunotherapy, with Nivolumab on Day 0 and BMS-986253 on Days 0 and 14. Patients will then enter the extended treatment phase where they will receive nivolumab alone every 4 weeks for another 6 treatments.	Drug: Nivolumab; 480 mg IV; Other Names: OPDIVO; BMS-936558; anti-PD1; Drug: BMS-986253; 2400 mg IV; Other Names: anti-IL8 antibody; HuMax-IL8

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IL17A expression	median IL17A expression in lymphoid aggregates from resected tumor (Arms A and B only)	4 years
Intratumoral CD8+CD137+cells	Fold change of intratumoral CD8+CD137+cells before and after neoadjuvant therapy (Arms B and C only)	4 years
Intratumoral granzyme B+PD-1+CD137+ cells	Percent change of intratumoral granzyme B+PD-1+CD137+ cells in surgical (post-treatment) tissue compared to baseline (pre-treatment) biopsy (Arm D only)	4 years
Pathologic Response	Percent of patients with a response grade of 0-2 (0=complete response 1=marked response, 2=moderate response) at time of surgery	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drug-Related Adverse Events	Number of participants experiencing study drug-related toxicities	4 years
Overall Survival	Overall Survival is defined as the time from surgery to death from any cause	4 years
Disease Free Survival	Disease Free Survival is defined as the time from surgery until evidence of disease recurrence or death from any cause	4 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Bristol-Myers Squibb; National Cancer Institute (NCI)
• Investigators: Principal Investigator: Lei Zheng, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2016
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: May 20, 2015
• First Submitted That Met QC Criteria: May 20, 2015
• First Posted (Estimated): May 22, 2015

Study Record Updates

• Last Update Posted (Actual): August 28, 2023
• Last Update Submitted That Met QC Criteria: August 25, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Cyclophosphamide; Nivolumab
• Other Study ID Numbers: J1568; IRB00050517 (Other Identifier: JHMIRB); R01CA197296 (U.S. NIH Grant/Contract)