DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma

• ClinicalTrials.gov Identifier: NCT04248569
• Recruitment Status: Recruiting
• First Posted: January 30, 2020
• Last Update Posted: March 30, 2021
• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Bristol-Myers Squibb; Fibrolamellar Cancer Foundation
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Description

Brief Summary:

The primary objective of the trial is the safety and tolerability of administering a vaccine targeting the DNAJB1-PRKACA fusion kinase, in combination with nivolumab and ipilimumab in patients with unresectable or metastatic FLC and to assess the T-cell response.

Condition or disease	Intervention/treatment	Phase
Fibrolamellar Hepatocellular Carcinoma (FLC)	Drug: DNAJB1-PRKACA peptide vaccine; Drug: Nivolumab; Drug: Ipilimumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma
• Actual Study Start Date: April 21, 2020
• Estimated Primary Completion Date: March 2024
• Estimated Study Completion Date: March 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: DNAJB1-PRKACA peptide vaccine, Nivolumab, and Ipilimumab

Drug: DNAJB1-PRKACA peptide vaccine; Patient 1-3: DNAJB1-PRKACA peptide vaccine will be administered on Day 1, 8, 15 of cycle 1 and on Day 1 of cycle 2, 3, 4 and 5 (priming phase). Boost vaccinations will be administered every 3 cycles beginning from C6D1.; Patient 4-12: DNAJB1-PRKACA peptide vaccine will be administered on Day 1, 8, 15 of cycle 1 and on Day 1 of cycle 2, 3 and 4 (priming phase). Boost vaccinations will be administered every 3 cycles beginning from C5D1.; Drug: 0.3 mg DNAJB1-PRKACA peptide vaccine + 0.5mg Poly-ICLC; Other Names: Hiltonol® (Poly-ICLC); Other Name: Hiltonol® (Poly-ICLC); Drug: Nivolumab; Patient 1-3: Nivolumab 3mg/kg will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycle 2-5 during the priming phase. Boost/maintenance vaccinations will be administered as a flat dose of 480mg every 4 weeks starting on Day 1 of Cycle 6.; Patient 4-12: Nivolumab 3mg/kg will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycle 1-4 during the priming phase. Boost/maintenance vaccinations will be administered as a flat dose of 480mg every 4 weeks starting on Day 1 of Cycle 5.; Drug: 3mg/kg and 480mg IV; Other Name: OPDIVO; Other Name: OPDIVO; Drug: Ipilimumab; Patient 1-3: Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycles 2, 3, 4 and 5 of the study, every 3 weeks of the priming phase.; Patient 4-12: Ipilimumab (1 mg/kg) will be administered as a 30 minute IV infusion (-10/+15min) on Day 1 of Cycles 1, 2, 3 and 4 of the study, every 3 weeks of the priming phase.; Drug: 1mg/kg IV; Other Name: YERVOY®; Other Name: YERVOY®

Outcome Measures

Primary Outcome Measures :

1. Number of participants experiencing study drug-related toxicities [ Time Frame: 4 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 DNAJB1-PRKACA-specific cluster of differentiation 8 (CD8) T cells at 12 weeks [ Time Frame: Baseline and 12 weeks ]
   Evaluated by the fold change in interferon-producing DNAJB1-PRKACA-specific CD8 cells after vaccination at 12 weeks compare to pre-vaccination baseline.
3. Fold change in interferon-producing DNAJB1-PRKACA-specific cluster of differentiation 4 (CD4) T cells at 12 weeks [ Time Frame: Baseline and 12 weeks ]
   Evaluated by the fold change in interferon-producing DNAJB1-PRKACA-specific CD4 T cells after vaccination at 12 weeks compare to pre-vaccination baseline.

Secondary Outcome Measures :

1. Objective response rate (ORR) [ Time Frame: 4 years ]
   ORR is defined as the number of patients achieving a complete response (CR) or 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% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.
2. iRECIST Objective response rate (iRORR) [ Time Frame: 4 years ]
   iRORR is defined as the number of patients achieving a complete response (CR) or partial response (PR) based on the Response Evaluation Criteria in Solid Tumors (iRECIST 1.1) at any time during the study. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.
3. Duration of response (DoR) [ Time Frame: 4 years ]
   Number of weeks from the start date of PR or CR (whichever response is recorded first) and subsequently confirmed to the first date of disease progression or death is documented per RECIST 1.1. CR = disappearance of all target lesions, PR is =>30% decrease in sum of diameters of target lesions.
4. Disease control rate (DCR) [ Time Frame: 4 years ]
   DCR is defined as the number of patients achieving a complete response (CR) or partial response (PR) and stable disease (SD) 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% decrease in sum of diameters of target lesions, progressive disease (PD) is >20% increase in sum of diameters of target lesions, stable disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions.
5. Progression-free survival (PFS) [ Time Frame: 4 years ]
   PFS is defined as the number of patients with disease progression (progressive disease [PD] or death due to any cause. Per RECIST 1.1 criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in sum of diameters of target lesions, Progressive Disease (PD) is >20% increase in sum of diameters of target lesions, Stable Disease (SD) is <30% decrease or <20% increase in sum of diameters of target lesions. Estimation based on the Kaplan-Meier curve.
6. Immune progression-free survival (irPFS) [ Time Frame: 4 years ]
   irPFS rate is defined as the number of patients with disease progression (PD or death due to any cause. Per immune-related response (irRC) criteria, CR = disappearance of all target lesions, Partial Response (PR) is =>30% decrease in tumor burden compared with baseline, Progressive Disease (PD) is >20% increase in tumor burden compared with nadir, Stable Disease (SD) is <30% decrease in tumor burden compared with baseline or <20% increase in tumor burden compared to nadir. Estimation based on the Kaplan-Meier curve.
7. Overall survival (OS) [ Time Frame: 4 years ]
   OS will be measured from date of first 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: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Must have histologically confirmed FLC (fibrolamellar hepatocellular cancer) that is metastatic or unresectable.
• Presence of DNAJB1-PRKACA fusion transcript, assessed by RNA-sequencing in the archival tissue.
• Age ≥12 years. Note: Subjects age ≥ 12 years but <18 are eligible to enroll only after 6 adult patients have enrolled on the study.
• Patients < 18 years old must have a body weight ≥40 kg.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Patients must have adequate organ and marrow function defined by study-specified laboratory tests prior to initial study drug.
• Patients must have measurable disease per RECIST 1.1.
• Patients ≥ 18 years old must have an accessible non-bone tumor lesion from which serial core biopsy specimens can be obtained.
• Must be willing to provide tissue and blood samples for mandatory translational research.
• 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:

• Have had chemotherapy or other systemic therapy or radiotherapy, as follows:

  • Have had chemotherapy, biological cancer therapy, or radiation 14 days prior to the first dose of study drug.
  • Have had surgery within 28 days of dosing of investigational agent, excluding minor procedures (dental work, skin biopsy, etc.), celiac plexus block, and biliary stent placement.
  • Have received other approved or investigational agents or device within 28 days of the first dose of study drug.
  • Have not recovered from acute adverse events to grade ≤1 or baseline due to agents administered
• Prior treatment with immunotherapy agents (including, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, etc.).
• Have received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment
• Known sensitivity to or history of allergic reactions to investigational drug (s).
• Hypersensitivity reaction to any monoclonal antibody.
• 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.
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoeitic stem cell transplant will be excluded.
• Has a diagnosis of immunodeficiency.
• Systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of study drug administration.
• Symptomatic interstitial lung disease.
• Has a pulse oximetry of <92% on room air or is on supplemental home oxygen.
• Active or untreated brain metastases or leptomeningeal metastases.
• 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.
• Are pregnant or breastfeeding.
• Infection with HIV or hepatitis B or C.
• Have had evidence of active or acute diverticulitis, intra-abdominal abscess, or GI obstruction.
• Unwilling or unable to follow the study schedule for any reason.
• Any other sound medical, psychiatric, and/or social reason as determined by the Investigator.
• Any illicit drugs or other substance abuse.
• Clinically meaningful ascites.

Contacts and Locations

Contacts

Contact: Anna Ferguson, RN; 410-614-7186; afergus1@jhmi.edu

Contact: Marina Baretti, MD; 410-614-1058; mbarett1@jhu.edu

Locations

United States, Maryland

Sidney Kimmel Comprehensive Cancer Center; Recruiting

Baltimore, Maryland, United States, 21231

Contact: Anna Ferguson, RN 410-614-3644 afergus1@jhmi.edu

Contact: Marina Baretti, MD 410-614-1058 mbarett1@jhu.edu

Principal Investigator: Mark Yarchoan, MD

Sub-Investigator: Marina Baretti, MD

Sponsors and Collaborators

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Bristol-Myers Squibb

Fibrolamellar Cancer Foundation

Investigators

• Principal Investigator: Mark Yarchoan, MD; Johns Hopkins Medical Institution

More Information

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT04248569
• Other Study ID Numbers: J19140; IRB00222681 ( Other Identifier: Johns Hopkins Medicine Institutional Review Board )
• First Posted: January 30, 2020
• Last Update Posted: March 30, 2021
• Last Verified: March 2021

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:

DNAJB1-PRKACA Peptide Vaccine; Nivolumab; Ipilimumab; Anti-PD-1 (receptor blocking antibody); Anti-CTLA-4 (receptor blocking antibody); Neoantigen Vaccines; Cancer Vaccines; Immunotherapy; Fibrolamellar Hepatocellular Cancer (FLC)

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Nivolumab; Ipilimumab; Poly ICLC; Antineoplastic Agents, Immunological; Antineoplastic Agents; Interferon Inducers; Immunologic Factors; Physiological Effects of Drugs