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

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.