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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Pancreatic Cancer
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilimumab; Drug: KRAS peptide vaccine

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Joann Santmyer, RN; Phone Number: 410-614-3644; Email: GIClinicalTrials@jhmi.edu
• Study Contact Backup: Name: Colleen Apostol, RN; Phone Number: 410-614-3644; Email: GIClinicalTrials@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Recruiting
      • Sidney Kimmel Comprehensive Cancer Center
      • Contact: Joann Santmyer, RN; Phone Number: 410-614-3644; Email: GIClinicalTrials@jhmi.edu
      • Contact: Colleen Apostol, RN; Phone Number: 410-614-3644; Email: GIClinicalTrials@jhmi.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Phase; KRAS Vaccine Peptide, Nivolumab and Ipilimumab	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 Names: 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 Names: YERVOY®; 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 Names: Hiltonol® (Poly-ICLC)
Experimental: Reinduction Treatment Phase; KRAS Vaccine Peptide, Nivolumab and Ipilimumab	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 Names: 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 Names: YERVOY®; 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 Names: Hiltonol® (Poly-ICLC)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants experiencing study drug-related toxicities	Number of participants experiencing study drug-related adverse events Grade 3 or higher as defined by CTCAE v5.0	2 years
Fold change in interferon-producing mutant-KRAS-specific cytotoxic (CD8) and helper (CD4) T cells at 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.	Baseline, 16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Free Survival (DFS)	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.	4 years
Overall Survival (OS)	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	4 years
Percentage change of interferon (IFN)-γ-producing mutant-KRAS-specific CD8 and CD4 T cells	Percent change of IFN-γ-producing mutant-KRAS-specific CD8 and CD4 T cells at any time after vaccination.	2 years
Objective Response Rate (ORR) per RECIST 1.1	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 years
Progression-free Survival (PFS) for RECIST 1.1	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.	4 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Bristol-Myers Squibb; National Cancer Institute (NCI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Neeha Zaidi, MD, Johns Hopkins Medical Institution

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2020
• Primary Completion (Estimated): August 8, 2025
• Study Completion (Estimated): August 8, 2025

Study Registration Dates

• First Submitted: October 3, 2019
• First Submitted That Met QC Criteria: October 3, 2019
• First Posted (Actual): October 7, 2019

Study Record Updates

• Last Update Posted (Estimated): March 1, 2024
• Last Update Submitted That Met QC Criteria: February 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Nivolumab; Cancer Vaccines; Immunotherapy; Anti-PD-1; Ipilimumab; Colon Cancer; Pancreatic Ductal Adenocarcinoma (PDAC); Anti-CTLA-4; Neoantigen Vaccines; KRAS Peptide Vaccine; Resected MMR-p Colorectal Cancer; Resected MMR-p Pancreatic Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Pancreatic Diseases; Colorectal Neoplasms; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Interferon Inducers; Nivolumab; Poly ICLC; Ipilimumab
• Other Study ID Numbers: J1994; 5P01CA247886 (U.S. NIH Grant/Contract); IRB00210915 (Other Identifier: Johns Hopkins Medical Institution); K08CA248624 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No