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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pancreatic Cancer	Drug: Cyclophosphamide; Biological: GVAX pancreatic cancer; Drug: Nivolumab; Drug: Urelumab; Drug: BMS-986253	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 76 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Platform Study of Combination Immunotherapy for the Neoadjuvant and Adjuvant Treatment of Patients With Surgically Resectable Adenocarcinoma of the Pancreas
• Actual Study Start Date: March 28, 2016
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: December 31, 2025

Arms and Interventions

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 Name: Cytoxan, CY; Biological: GVAX pancreatic cancer; 5x10^8 cells intradermal injection; Other Name: 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 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
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 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
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 Name: OPDIVO; BMS-936558; anti-PD1; Drug: BMS-986253; 2400 mg IV; Other Name: anti-IL8 antibody; HuMax-IL8

Outcome Measures

Primary Outcome Measures :

1. IL17A expression [ Time Frame: 4 years ]
   median IL17A expression in lymphoid aggregates from resected tumor (Arms A and B only)
2. 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)
3. 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)
4. 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

Secondary Outcome Measures :

1. Drug-Related Adverse Events [ Time Frame: 4 years ]
   Number of participants experiencing study drug-related toxicities
2. Overall Survival [ Time Frame: 4 years ]
   Overall Survival is defined as the time from surgery to death from any cause
3. 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

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:

• 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

Contacts and Locations

Contacts

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

Locations

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Recruiting

Baltimore, Maryland, United States, 21231-2410

Contact: Clinical Trials Office - Sidney Kimmel Comprehensive Cancer Ce 410-955-8804 jhcccro@jhmi.edu

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

National Cancer Institute (NCI)

Bristol-Myers Squibb

Investigators

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

More Information

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT02451982
• Other Study ID Numbers: J1568; IRB00050517 ( Other Identifier: JHMIRB ); R01CA197296 ( U.S. NIH Grant/Contract )
• First Posted: May 22, 2015
• Last Update Posted: August 28, 2023
• Last Verified: August 2023

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Cyclophosphamide; Nivolumab; Immunologic Factors; Physiological Effects of Drugs; Immunosuppressive Agents; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors