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

Official title

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

Overview

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.

Interventions

• Drug DNAJB1-PRKACA peptide vaccine
  1. 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. 2. Drug: 0.3 mg DNAJB1-PRKACA peptide vaccine + 0.5mg Poly-ICLC
• Drug Nivolumab
  1. 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. 2. Drug: 3mg/kg and 480mg IV
• Drug Ipilimumab
  1. 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. 2. Drug: 1mg/kg IV

Primary outcome measures

• All Cohorts: Number of participants experiencing study drug-related toxicities [Time frame: 4 years]
• All Cohorts: Fold change in interferon-producing DNAJB1-PRKACA-specific CD4 and CD8 T cells at 10 weeks [Time frame: Baseline and 10 weeks]
• Cohort A only: Progression-free survival (PFS) [Time frame: 6 months]

Secondary outcome measures (5)

• Objective response rate (ORR) [Time frame: 4 years]
• Duration of response (DoR) [Time frame: 4 years]
• Disease control rate (DCR) [Time frame: 4 years]
• Progression-free survival (PFS) [Time frame: 4 years]
• Overall survival (OS) [Time frame: 4 years]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• Sidney Kimmel Comprehensive Cancer Center — Baltimore

Publications

• 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 M PMID 41286513
• 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 PMID 35561331
• 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. PMID 34272087

Identifiers

NCT: NCT04248569 · J19140 · IRB00222681

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗