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

A Pilot Study of a DNAJB1-PRKACA Fusion Kinase Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Fibrolamellar Hepatocellular Carcinoma

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 with non-FLC solid tumors and to assess the T-cell response.

Study Overview

• Status: Recruiting
• Conditions: Fibrolamellar Hepatocellular Carcinoma (FLC)
• Intervention / Treatment: Drug: DNAJB1-PRKACA peptide vaccine; Drug: Nivolumab; Drug: Ipilimumab

• Study Type: Interventional
• Enrollment (Estimated): 56
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Marina Baretti, MD; Phone Number: 410-614-1058; Email: mbarett1@jhu.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: Marina Baretti, MD; Phone Number: 410-614-1058; Email: mbarett1@jhu.edu
      • Principal Investigator: Mark Yarchoan, MD
      • Sub-Investigator: Marina Baretti, MD
      • Contact: Colleen Apostol, RN; Phone Number: 410-614-3644; Email: GIClinicalTrials@jhmi.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria for Cohort A, B and C:

• Cohort A and B: Must have histologically confirmed FLC (fibrolamellar hepatocellular cancer) that is metastatic or unresectable.
• Cohort C: Patients with histologically proven metastatic or unresectable DNAJB1-PRKACA fusion transcript positive solid tumor malignancies, non-FLC solid tumors.
• Cohort A and B: Age > 12 years. Note: Subjects age > 12 years but <18 are eligible to enroll only after 6 adult patients have enrolled on the study.
• Cohort A and B: Patients < 18 years old must have a body weight ≥40 kg.
• Cohort C: Patients must be Age ≥ 18 years.

All Cohorts:

• Presence of DNAJB1-PRKACA fusion transcript, assessed by RNA-sequencing, DNA-sequencing, or in situ hybridization in the archival tissue.
• ECOG performance status of ≤2 (Karnofsky ≥60%)
• Patients must have adequate liver, kidney and marrow function defined by study-specified laboratory tests prior to initial study drug.
• Patients must have measurable disease per RECIST 1.1.
• 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 for Cohorts A, B and C:

• Cohort A and C: Patients with a history of prior treatment with checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40, anti-CD40, anti-CTLA-4, or anti-LAG-3 antibodies. NOTE: Prior therapy with interferon-alpha is allowed.
• Cohort B: Participants a with history of unacceptable, life-threatening toxicity related to prior immune therapy (eg, anti-CTLA-4 or anti-PD-1/PD-L1 treatment, any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (eg, hormone replacement after endocrinopathy).

All Cohorts:

• 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.
• 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.

Inclusion Criteria for Re-Enrolling Patients:

• Patients previously treated with the vaccine targeting the DNAJB1-PRKACA fusion kinase in combination with nivolumab and ipilimumab, who, in the opinion of the principal investigator, had clinical or radiological benefits.
• Patients < 18 years old must have a body weight ≥40 kg.
• ECOG performance status of ≤2 (Karnofsky ≥60%, see Appendix A).
• Patients must have adequate liver, kidney and marrow function defined by study-specified laboratory tests prior to initial study drug.
• Patients must have measurable disease per RECIST 1.1.
• Willingness 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 for Re-Enrolling Patients:

• Participants with a history of prior unacceptable and/or life-threatening toxicities.

• Patients who have had chemotherapy or other systemic therapy or radiotherapy, as follows:

  • Patients who have had chemotherapy, biological cancer therapy, or radiation 14 days prior to the first dose of study drug.
  • Patients who 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.
  • Patients who have received other approved or investigational agents or device within 28 days of the first dose of study drug.
  • Patients who have not recovered from acute adverse events to grade ≤1 or baseline due to agents administered, with exception of alopecia or stable neuropathy, unless approved by the IND Sponsor.
• Patients who 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.
• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DNAJB1-PRKACA peptide vaccine, Nivolumab, and Ipilimumab; Cohort A: Patients with FLC cancer with no prior checkpoint inhibitor treatment. Cohort B: Patients with FLC cancer with prior checkpoint inhibitor treatment. Cohort C: Patients with non-FLC cancer (solid tumors) with prior checkpoint inhibitor treatment eligible.	Drug: DNAJB1-PRKACA peptide vaccine; DNAJB1-PRKACA peptide vaccine: Day 1, 8, 15 of cycle 1 and on Day 1 of cycle 2, 3 and 4 (priming phase). Boost vaccinations: every 3 cycles beginning C5D1.; Drug: 0.3 mg DNAJB1-PRKACA peptide vaccine + 0.5mg Poly-ICLC; Other Names: Hiltonol® (Poly-ICLC); Drug: Nivolumab; 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 Names: OPDIVO; Drug: Ipilimumab; 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 Names: YERVOY®
Experimental: R- Enrollment: DNAJB1-PRKACA peptide vaccine, Nivolumab, and Ipilimumab; Re-enrolling patients: Patients previously treated with the vaccine targeting the DNAJB1-PRKACA fusion kinase in combination with nivolumab and ipilimumab, who, in the opinion of the principal investigator, had clinical or radiological benefits. Re-enrolling patients who come off treatment ≤ 12 months from last dose may resume therapy at the study timepoint that they stopped study therapy. Patients who came off study therapy > 12 months of last dose (i.e. to pursue alternative therapies (for example, surgical debulking), or after completion of the 2 years of study therapy), may restart study therapy at C1D1. In both cases, if the investigator assesses a drug-related toxicity to be related to anti-CTLA4 (ie. not anti-PD(L)1) therapy, patients can be enrolled in the study with nivolumab plus FLC peptide vaccine only.	Drug: DNAJB1-PRKACA peptide vaccine; DNAJB1-PRKACA peptide vaccine: Day 1, 8, 15 of cycle 1 and on Day 1 of cycle 2, 3 and 4 (priming phase). Boost vaccinations: every 3 cycles beginning C5D1.; Drug: 0.3 mg DNAJB1-PRKACA peptide vaccine + 0.5mg Poly-ICLC; Other Names: Hiltonol® (Poly-ICLC); Drug: Nivolumab; 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 Names: OPDIVO; Drug: Ipilimumab; 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 Names: YERVOY®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort A only: Progression-free survival (PFS)	PFS at 6 months, will be estimated as the proportion of subjects who remain alive and free of disease progression at 6 months from the start of treatment. Disease progression will be determined using RECIST 1.1 criteria. The proportion of subjects achieving PFS at 6 months will be estimated using the Kaplan-Meier method, and the corresponding 95% confidence interval will be reported.	6 months
All Cohorts: 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	4 years
All Cohorts: Fold change in interferon-producing DNAJB1-PRKACA-specific CD4 and CD8 T cells at 10 weeks	Evaluated by the fold change in interferon-producing DNAJB1-PRKACA-specific CD8 cells after vaccination at 10 weeks compare to pre-vaccination baseline.	Baseline and 10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	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.	4 years
Duration of response (DoR)	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 years
Disease control rate (DCR)	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.	4 years
Overall survival (OS)	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.	4 years
Progression-free survival (PFS)	PFS is defined as number of months from the date of first treatment until first documented local progression 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.	4 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Fibrolamellar Cancer Foundation
• Investigators: Principal Investigator: Mark Yarchoan, MD, Johns Hopkins Medical Institution

Publications and helpful links

General Publications

• Short SS, Kastenberg ZJ, Wei G, Bondoc A, Dasgupta R, Tiao GM, Watters E, Heaton TE, Lotakis D, La Quaglia MP, Murphy AJ, Davidoff AM, Mansfield SA, Langham MR, Lautz TB, Superina RA, Ott KC, Malek MM, Morgan KM, Kim ES, Zamora A, Lascano D, Roach J, Murphy JT, Rothstein DH, Vasudevan SA, Whitlock R, Lal DR, Hallis B, Butter A, Baertschiger RM, Lapidus-Krol E, Putra J, Tracy ER, Aldrink JH, Apfeld J, Le HD, Park KY, Rich BS, Glick RD, Fialkowski EA, Utria AF, Meyers RL, Riehle KJ. Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study. Cancer. 2022 Jul 15;128(14):2786-2795. doi: 10.1002/cncr.34256. Epub 2022 May 13.
• O'Neill AF, Church AJ, Perez-Atayde AR, Shaikh R, Marcus KJ, Vakili K. Fibrolamellar carcinoma: An entity all its own. Curr Probl Cancer. 2021 Aug;45(4):100770. doi: 10.1016/j.currproblcancer.2021.100770. Epub 2021 Jul 1.
• Baretti M, Kirk AM, Ladle BH, Kamdar Z, Bendinelli KJ, Ho WJ, Adhikari S, Clark NA, Sundararaman B, Wang H, Kung HC, Hernandez J, Qi H, Shin SM, Hernandez A, Nakazawa M, Schattgen SA, Crawford JC, Furth M, Anders RA, Thoburn C, Zaidi N, Huff AL, Nauroth J, Jaffee E, Pogorelyy MV, Thomas PG, Yarchoan M. A therapeutic peptide vaccine for fibrolamellar hepatocellular carcinoma: a phase 1 trial. Nat Med. 2025 Nov 24. doi: 10.1038/s41591-025-03995-y. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2020
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2034

Study Registration Dates

• First Submitted: January 28, 2020
• First Submitted That Met QC Criteria: January 28, 2020
• First Posted (Actual): January 30, 2020

Study Record Updates

• Last Update Posted (Estimated): December 3, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Nivolumab; Cancer Vaccines; Immunotherapy; Ipilimumab; DNAJB1-PRKACA Peptide Vaccine; Anti-PD-1 (receptor blocking antibody); Anti-CTLA-4 (receptor blocking antibody); Neoantigen Vaccines; Fibrolamellar Hepatocellular Cancer (FLC)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Fibrolamellar hepatocellular carcinoma; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; Ipilimumab; poly ICLC
• Other Study ID Numbers: J19140; IRB00222681 (Other Identifier: Johns Hopkins Medicine Institutional Review Board)

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