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

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ClinicalTrials.gov Identifier: NCT02451982
Recruitment Status : Recruiting
First Posted : May 22, 2015
Last Update Posted : May 3, 2022
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

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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 : June 30, 2023
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine


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




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



Information from the National Library of Medicine

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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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02451982


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

Locations
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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
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Principal Investigator: Lei Zheng, MD, PhD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University
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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    Key Record Dates
Last Update Posted: May 3, 2022
Last Verified: May 2022
Additional relevant MeSH terms:
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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