dnajb1-prkaca fusion kinase peptide vaccine combined with nivolumab and ipilimumab for patients with fibrolamellar hepatocellular carcinoma

Conditions: Fibrolamellar Hepatocellular Carcinoma (FLC)

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 with non-flc solid tumors and to assess the t-cell response.


Eligibility criteria:
inclusion criteria: * 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. * 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: * 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.

Keywords: 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)