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

• ClinicalTrials.gov Identifier: NCT04117087
• Recruitment Status: Recruiting
• First Posted: October 7, 2019
• Last Update Posted: March 1, 2024
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Bristol-Myers Squibb; National Cancer Institute (NCI); National Institutes of Health (NIH)
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

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 colorectal cancer who have exposure to 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

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel 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 28, 2020
• Estimated Primary Completion Date: August 8, 2025
• Estimated Study Completion Date: August 8, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment Phase; KRAS Vaccine Peptide, Nivolumab and Ipilimumab	Drug: KRAS peptide vaccine; KRAS peptide vaccine will be administered on cycle 1 (days 1, 8, 15) and R-Cycle 2 Day 1 (R-C2D1). Boost vaccinations with will be administered every 28 days at Reinduction cycle 5, 7, 9, 13. Extended vaccinations will be administered on Reinduction cycles 15 to 18, 19 and beyond (180 days ± 30 days for a total of 5 years on study.; Drug: up to 1.8 mg KRAS peptide vaccine + 0.5mg Poly-ICLC; Other Name: Hiltonol® (Poly-ICLC); Drug: Nivolumab; Nivolumab will be administered as a 30 minute IV infusion (-10min/+15min) on Day 1 of each 21 day cycle. Boost Phase will be administered every 28 days on cycles 5 thru 14.; Drug: 3mg/kg IV, 480 mg IV; Other Name: OPDIVO; Drug: Ipilimumab; Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10min/+15min) on Day 1 of Cycles 1 and 3 of the study.; Drug: 1mg/kg IV; Other Name: YERVOY®
Experimental: Reinduction Treatment Phase; KRAS Vaccine Peptide, Nivolumab and Ipilimumab	Drug: KRAS peptide vaccine; KRAS peptide vaccine will be administered on cycle 1 (days 1, 8, 15) and R-Cycle 2 Day 1 (R-C2D1). Boost vaccinations with will be administered every 28 days at Reinduction cycle 5, 7, 9, 13. Extended vaccinations will be administered on Reinduction cycles 15 to 18, 19 and beyond (180 days ± 30 days for a total of 5 years on study.; Drug: up to 1.8 mg KRAS peptide vaccine + 0.5mg Poly-ICLC; Other Name: Hiltonol® (Poly-ICLC); Drug: Nivolumab; Nivolumab will be administered as a 30 minute IV infusion (-10min/+15min) on Day 1 of each 21 day cycle. Boost Phase will be administered every 28 days on cycles 5 thru 14.; Drug: 3mg/kg IV, 480 mg IV; Other Name: OPDIVO; Drug: Ipilimumab; Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10min/+15min) on Day 1 of Cycles 1 and 3 of the study.; Drug: 1mg/kg IV; Other Name: YERVOY®

Outcome Measures

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 cytotoxic (CD8) and helper (CD4) T cells at 16 weeks [ Time Frame: Baseline, 16 weeks ]
   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: 2 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 microsatellite stable (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. 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 Metastatic Colorectal Cancer (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.
5. 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

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:

PDAC or metastatic MSS CRC Cohort:

• 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 exposure to 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.

Reinduction Treatment Cohort:

• Have a single site of locoregional recurrence or distant metastasis noted on imaging > 12 months after the first dose of the mutant KRAS peptide vaccine with poly-ICLC adjuvant.
• Have completed definitive treatment for solitary recurrence per standard-of-care (e.g. surgical resection, radiation, and/or chemotherapy) <6 months prior to screening for reinduction treatment.

Both Cohorts:

*Age ≥18 years.

• 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.
• PDAC or metastatic MSS CRC Cohort: 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 and Reinduction Treatment Cohorts, any peritoneal involvement by the tumor.
• For metastatic MSS CRC and Reinduction Treatment Cohorts, any radiological or clinical pleural effusions or ascites.
• For metastatic MSS CRC and Reinduction Treatment Cohorts, patients on parenteral nutrition.
• For metastatic MSS CRC and Reinduction Treatment Cohorts, patients with any single liver metastases greater than 5 cm or greater > 50% liver involvement.
• For metastatic MSS CRC and Reinduction Treatment Cohorts, history of malignant bowel obstruction.

Contacts and Locations

Contacts

Contact: Colleen Apostol, RN; 410-614-3644; GIClinicalTrials@jhmi.edu

Contact: Joann Santmyer, RN; 410-614-3644; GIClinicalTrials@jhmi.edu

Locations

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center; Recruiting

Baltimore, Maryland, United States, 21231

Contact: Colleen Apostol, 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

National Cancer Institute (NCI)

National Institutes of Health (NIH)

Investigators

• Principal Investigator: Neeha Zaidi, MD; Johns Hopkins Medical Institution

More Information

• 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 ); 5P01CA247886 ( U.S. NIH Grant/Contract ); K08CA248624 ( U.S. NIH Grant/Contract )
• First Posted: October 7, 2019
• Last Update Posted: March 1, 2024
• Last Verified: February 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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