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

• ClinicalTrials.gov Identifier: NCT02451982
• Recruitment Status: Recruiting
• First Posted: May 22, 2015
• Last Update Posted: August 28, 2023
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI); Bristol-Myers Squibb
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: May 20, 2015
• First Posted Date: May 22, 2015
• Last Update Posted Date: August 28, 2023
• Actual Study Start Date: March 28, 2016
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 20, 2021)

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

• Original Primary Outcome Measures (submitted: May 20, 2015): Median IL17A expression in vaccine-induced lymphoid aggregates found in surgically resected pancreatic tumors [ Time Frame: 4 years ]

Current Secondary Outcome Measures (submitted: October 20, 2021)

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

Original Secondary Outcome Measures (submitted: May 20, 2015)

• Number of participants experiencing immune-related toxicities (IRAEs) [ Time Frame: 4 years ]
• Overall Survival [ Time Frame: 4 years ]
• Disease Free Survival [ Time Frame: 4 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Platform Study of Neoadjuvant and Adjuvant Immunotherapy for Patients With Resectable Adenocarcinoma of the Pancreas
• Official Title: A Platform Study of Combination Immunotherapy for the Neoadjuvant and Adjuvant Treatment of Patients With Surgically Resectable Adenocarcinoma of the Pancreas
• Brief Summary: This platform trial will evaluate various immunotherapy combinations given in the neo-adjuvant and adjuvant setting in patients with surgically resectable pancreatic ductal adenocarcinoma.
• 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
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pancreatic Cancer

Intervention

• Drug: Cyclophosphamide
  200 mg/m2 IV
  Other Name: Cytoxan, CY
• Biological: GVAX pancreatic cancer
  5x10^8 cells intradermal injection
  Other Name: GVAX, pancreatic tumor vaccine
• Drug: Nivolumab
  480 mg IV
  Other Name: OPDIVO; BMS-936558; anti-PD1
• Drug: Urelumab
  8 mg IV
  Other Name: BMS-663513; anti-CD137 Agonist
• Drug: BMS-986253
  2400 mg IV
  Other Name: anti-IL8 antibody; HuMax-IL8

Study Arms

• 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.
  Interventions:

  • Drug: Cyclophosphamide
  • Biological: GVAX pancreatic cancer
• 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.
  Interventions:

  • Drug: Cyclophosphamide
  • Biological: GVAX pancreatic cancer
  • Drug: Nivolumab
• 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.
  Interventions:

  • Drug: Cyclophosphamide
  • Biological: GVAX pancreatic cancer
  • Drug: Nivolumab
  • Drug: Urelumab
• 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.
  Interventions:

  • Drug: Nivolumab
  • Drug: BMS-986253

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 20, 2021): 76
• Original Estimated Enrollment (submitted: May 20, 2015): 50
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Carol Judkins, RN; 410-614-5241; judkica@jhmi.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02451982
• Other Study ID Numbers: J1568; IRB00050517 ( Other Identifier: JHMIRB ); R01CA197296 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Responsible Party: Same as current
• Current Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Original Study Sponsor: Same as current

Collaborators

• National Cancer Institute (NCI)
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Lei Zheng, MD, PhD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: August 2023