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Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected MMR-p Colorectal and Pancreatic Cancer

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ClinicalTrials.gov Identifier: NCT04117087
Recruitment Status : Recruiting
First Posted : October 7, 2019
Last Update Posted : May 26, 2022
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Brief Summary:
Phase 1 study for patients with resected PDAC after neoadjuvant and/ or adjuvant chemotherapy and/or radiation, as well as patients with metastatic MSS CRC who have progressed on 2 or more lines of chemotherapy, to evaluate safety and the immune response to pooled mutant-KRAS peptide vaccine (KRAS peptide vaccine) with poly-ICLC adjuvant in combination with nivolumab and ipilimumab.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Pancreatic Cancer Drug: KRAS peptide vaccine Drug: Nivolumab Drug: Ipilimumab Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected MMR-p Colorectal and Pancreatic Cancer
Actual Study Start Date : May 29, 2020
Estimated Primary Completion Date : June 1, 2024
Estimated Study Completion Date : June 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: KRAS peptide vaccine, Nivolumab, and Ipilimumab Drug: KRAS peptide vaccine
  1. KRAS peptide vaccine will be administered on days 1, 8, and 15. Five boost vaccinations with will be administered at 8 week intervals (on weeks 13, 21, 29, 37, and 45). There is an extended booster phase for Pancreatic Cancer patients with no evidence of disease. These patients have the option of receiving KRAS peptide vaccine every 90 days (± 30 days) for up to 4 additional doses.
  2. Drug: up to 1.8 mg KRAS peptide vaccine + 0.5mg Poly-ICLC
Other Name: Hiltonol® (Poly-ICLC)

Drug: Nivolumab
  1. Nivolumab 3mg/kg will be administered as a 30 minute IV infusion (-10min/+15min) every 3 weeks for four doses. In the boost phase 480 mg flat dose will be administered every 4 weeks beginning C5D1.
  2. Drug: 3mg/kg IV, 480 mg IV
Other Name: OPDIVO

Drug: Ipilimumab
  1. Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10min/+15min) every 6 weeks for two doses.
  2. Drug: 1mg/kg IV
Other Name: YERVOY®




Primary Outcome Measures :
  1. Number of participants experiencing study drug-related toxicities [ Time Frame: 2 years ]
    Number of participants experiencing study drug-related adverse events Grade 3 or higher as defined by CTCAE v5.0

  2. Fold change in interferon-producing mutant-KRAS-specific CD8 and CD4 T cells at 16 weeks [ Time Frame: 2 years ]
    Evaluated by the fold change in interferon-producing mutant-KRAS-specific CD8 and CD4 T cells after vaccination at 16 weeks compare to pre-vaccination baseline.


Secondary Outcome Measures :
  1. Disease Free Survival (DFS) [ Time Frame: 4 years ]
    DFS is defined as the number of months from cycle 1, day 1 of vaccination until the first documented disease recurrence or death due to any cause in patients with resected PDAC. Will be censored at the date of the last progressive disease evaluation if no event observed.

  2. Percentage change of interferon (IFN)-γ-producing mutant-KRAS-specific CD8 and CD4 T cells [ Time Frame: Baseline, 4 years ]
    Percent change of IFN-γ-producing mutant-KRAS-specific CD8 and CD4 T cells at any time after vaccination.

  3. Objective Response Rate (ORR) per RECIST 1.1 [ Time Frame: 4 years ]
    ORR is defined as the number of patients with metastatic MSS CRC who are administered at least one dose of KRAS achieving a complete response (CR) partial response (PR) based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) at any time during the study. CR = disappearance of all target lesions, PR is =>30 percent decrease in sum of diameters of target lesions, progressive disease (PD) is >20 percent increase in sum of diameters of target lesions, stable disease (SD) is <30 percent decrease or <20 percent increase in sum of diameters of target lesions.

  4. Objective Response Rate (ORR) per iRECIST [ Time Frame: 4 years ]
    ORR is defined as the number of patients with metastatic MSS CRC who are administered at least one dose of KRAS achieving a complete response (iCR) partial response (iPR) based on the Response Evaluation Criteria in Solid Tumors (iRECIST) at any time during the study. iCR = disappearance of all target lesions, iPR is =>30 percent decrease in sum of diameters of target lesions, progressive disease (iPD) is >20 percent increase in sum of diameters of target lesions, stable disease (iSD) is <30 percent decrease or <20 percent increase in sum of diameters of target lesions.

  5. Progression-free Survival (PFS) for RECIST 1.1 [ Time Frame: 4 years ]
    PFS is defined as the numbers of months from the date of the first vaccine dose to the date of disease progression or death due to any cause, which ever occurs first, for mCRC patients. Censored at the date of last scan for subjects without documentation of disease progression (PD) at the time of analysis or relapse from complete response [CR] as assessed using RECIST 1.1 criteria) or death due to any cause. Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30 percent decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20 percent increase in sum of diameters of target lesions, Stable Disease (SD) is <30 percent decrease or <20 percent increase in sum of diameters of target lesions.

  6. Progression-free Survival (PFS) for iRECIST [ Time Frame: 4 years ]
    PFS per iRECIST is defined as the numbers of months from the date of the first vaccine dose to the date of disease progression or death due to any cause, which ever occurs first, for mCRC patients. Censored at the date of last scan for subjects without documentation of disease progression (iPD) at the time of analysis or relapse from complete response [iCR] as assessed using RECIST 1.1 criteria) or death due to any cause. Per iRECIST (iPFS) criteria, iCR = disappearance of all target lesions, Partial Response (iPR) is =>30 percent decrease in sum of diameters of target lesions, Progressive Disease (iPD) is >20 percent increase in sum of diameters of target lesions, Stable Disease (iSD) is <30 percent decrease or <20 percent increase in sum of diameters of target lesions.

  7. Overall Survival (OS) [ Time Frame: 4 years ]
    OS will be measured as the number of months from the date of first vaccine dose until death or end of follow up. OS will be censored on the date the subject was last known to be alive for subjects without documentation of death at the time of analysis. Estimation based on the Kaplan Meier Curve



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:

  • Age ≥18 years.
  • Have histologically or cytologically - proven cancer of the pancreas (PDA) or MSS colorectal (CRC) in one of the following categories:

    • PDAC must have no evidence of disease and last dose of neoadjuvant and/or adjuvant chemotherapy/radiation therapy/or surgery must be < 6 months from study entry.
    • Metastatic MSS CRC after progression on 2 more lines of chemotherapy in the metastatic setting including 5-flurouracil, irinotecan, and oxaliplatin exposure. Patients treated with FOLFOXIRI may enroll after progression or intolerance to that regimen.
  • For metastatic MSS CRC cohort, must have tumor lesions amenable to repeated biopsy, and patient's acceptance to have a tumor biopsy of an accessible lesion at baseline and on treatment if the lesion can be biopsied with acceptable clinical risk (as judged by the Principal Investigator).
  • For metastatic MSS CRC patients, must have measurable disease per RECIST 1.1.
  • Have sufficient archival tumor tissue for next-generation sequencing (NGS) and immune-phenotyping.
  • Have one of the KRAS mutations included in the vaccine at the time of vaccination expressed in tumor.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Life expectancy of greater than 6 months.
  • Patients must have adequate organ and marrow function defined by study-specified laboratory tests prior to initial study drug.
  • Woman of childbearing potential must have a negative pregnancy test and follow contraceptive guidelines as defined per protocol.
  • Men must use acceptable form of birth control while on study.
  • Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria

  • If expected to require any other form of systemic or localized antineoplastic therapy while on study.
  • Within 2 weeks prior to first dose of study drug.

    • Systemic or topical steroids corticosteroids at immunosuppressive doses (> 10 mg/day of prednisone or equivalent). Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
    • Any palliative or adjuvant radiation or gamma knife radiosurgery.
    • Any chemotherapy.
  • Within 4 weeks prior to first dose of study drug.

    • Any investigational cytotoxic drug.
    • Any investigational device.
    • Has received a live vaccine.
    • Received any allergen hyposensitization therapy.
    • Received any growth factors, e.g. granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin.
    • Any major surgery.
  • Prior treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4), etc.).
  • Hypersensitivity reaction to any monoclonal antibody.
  • Known history or evidence of brain metastases.
  • Has active autoimmune disease that has required systemic treatment in the past 2 years, or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
  • Known history or concurrent interstitial lung disease.
  • Has a pulse oximetry < 92% on room air.
  • Requires the use of home oxygen.
  • Infection with HIV or hepatitis B or C.
  • Uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, symptomatic congestive heart failure, unstable angina, cardiac arrhythmia, metastatic cancer, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Has been diagnosed with another cancer or myeloproliferative disorder within the past 5 year.
  • Has a diagnosis of immunodeficiency.
  • Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded.
  • Any other sound medical, psychiatric, and/or social reason as determined by the Investigator.
  • Unwilling or unable to follow the study schedule for any reason.
  • Are pregnant or breastfeeding.
  • For metastatic MSS CRC cohort, any peritoneal involvement by the tumor.
  • For metastatic MSS CRC cohort, any radiological or clinical pleural effusions or ascites.
  • For metastatic MSS CRC cohort, patients on parenteral nutrition.
  • For metastatic CRC cohort, patients with any single liver metastases greater than 5 cm or greater > 50% liver involvement.
  • For metastatic MSS CRC cohort, history of malignant bowel obstruction.

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): NCT04117087


Contacts
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Contact: Trish Brothers, RN 410-614-3644 GIClinicalTrials@jhmi.edu
Contact: Joann Santmyer, RN 410-614-3644 GIClinicalTrials@jhmi.edu

Locations
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United States, Maryland
Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21231
Contact: Trish Brothers, RN    410-614-3644    GIClinicalTrials@jhmi.edu   
Contact: Joann Santmyer, RN    410-614-3644    GIClinicalTrials@jhmi.edu   
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Bristol-Myers Squibb
Investigators
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Principal Investigator: Neeha Zaidi, MD Johns Hopkins Medical Institution
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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT04117087    
Other Study ID Numbers: J1994
IRB00210915 ( Other Identifier: Johns Hopkins Medical Institution )
First Posted: October 7, 2019    Key Record Dates
Last Update Posted: May 26, 2022
Last Verified: May 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins:
KRAS Peptide Vaccine
Nivolumab
Ipilimumab
Anti-PD-1
Anti-CTLA-4
Neoantigen Vaccines
Cancer Vaccines
Immunotherapy
Colon Cancer
Pancreatic Ductal Adenocarcinoma (PDAC)
Resected MMR-p Colorectal Cancer
Resected MMR-p Pancreatic Cancer
Additional relevant MeSH terms:
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Colorectal Neoplasms
Pancreatic Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Nivolumab
Ipilimumab
Poly ICLC
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Interferon Inducers
Immunologic Factors
Physiological Effects of Drugs