FLC Peptide Vaccine Combined with Nivolumab and Ipilimumab for the Treatment of Patients with Fibrolamellar Cancer

Inclusion Criteria

• Patients must have histologically confirmed fibrolamellar carcinoma (FLC) that is metastatic or unresectable. Patients who are candidates for potentially curative interventions, including but not limited to surgical resection, radiofrequency ablation, or liver transplantation, are not eligible
• Presence of DNAJB1-PRKACA fusion transcript, assessed by ribonucleic acid (RNA)-sequencing, deoxyribonucleic acid (DNA)-sequencing, or in situ hybridization in the archival tissue. Note: Patients without sufficient archival tissue may undergo a screening biopsy, which will be used to confirm the presence of the fusion transcript and will also fulfill the requirements of the baseline biopsy. In cases where confirmation of the fusion transcript leads to significant patient delay (e.g. > 3 weeks from screening), patients may enroll and begin study therapy pending confirmation of the DNAJB1-PRKACA fusion transcript. Patients later found not to have the DNAJB1-PRKACA fusion transcript will be replaced on study for all efficacy analyses
• 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 of =< 1 (Karnofsky >= 70%)
• Hemoglobin (HgB) >= 9.0 g/dL. Patients transfused to a hemoglobin >= 9.0 g/dL must maintain this hemoglobin for at least 1 week
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 75,000/mcL
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN)
• Serum albumin >= 2.8 g/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 5.0 upper limit of normal (ULN). NOTE: For patients < 18 years old: AST/ALT: < 3.0 x ULN
• International normalized ratio (INR) =< 1.6. Note: INR prolongation due to anticoagulants for prophylaxis (e.g. atrial fibrillation) in patients without liver cirrhosis could be exception
• Serum creatinine =< 1.5 x ULN of normal based on age/gender or calculated creatinine clearance >= 40 mL/min using the modified Cockcroft-Gault: * Age: 12 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female) * Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female) * Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * Patients >= 18 years old must have an accessible non-bone tumor lesion from which serial core biopsy specimens can be obtained. NOTE: Patients with bone only disease are not eligible due to difficulties in obtaining serial bone biopsies for correlative analyses
• Willingness to provide tissue and blood samples for mandatory translational research. NOTE: In the event that baseline biopsy was unsuccessful or invaluable, the second biopsy, as well as the optional biopsy at the time of progression, will not be required and the subject will continue to be treated per study protocol
• Evidence of post-menopausal status or negative serum pregnancy test for women of childbearing potential (WOCBP) (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]). Post-menopausal women and WOCBP. NOTE: If a patient has a positive or indeterminate serum or urine pregnancy test, then an ultrasound must be done to rule out pregnancy to enroll on trial * WOCBP must agree to follow instructions for method(s) of contraception: hormonal or barrier method of birth control, including male condom, female condom, or diaphragm with spermicidal gel; abstinence) from the time of enrollment for the duration of treatment with study drugs plus 5 half-lives of study drug(s) plus 4 weeks (duration of ovulatory cycle) for a total of 23 weeks post treatment completion * Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug(s) plus 90 days (duration of sperm turnover) for a total of 31 weeks post-treatment completion * At least one barrier method of contraception must be employed by all sexually active patients (male and female), regardless of other methods, to prevent the transfer of body fluids
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• 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 investigational new drug (IND) sponsor
• Patients with a history of prior treatment with 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
• Patients who have received any non-oncology live vaccine therapy used for prevention of infectious diseases within 28 days of study treatment. Examples include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. NOTE: * Patients, if enrolled, should not receive live vaccine while receiving study drug(s) and up to 30 days after the last dose of study drug(s) * Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu-Mist) are liveattenuated vaccines, and are not allowed within 28 days of study treatment
• Known sensitivity to or history of allergic reactions attributed to compounds of similar chemical or biologic composition of nivolumab and/or ipilimumab and/or polyinosinicpolycytidylic acid (Poly-ICLC)
• History of severe hypersensitivity reaction to any monoclonal antibody
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) or is likely to interfere with the safety or efficacy of the trial therapy in the opinion of the treating investigator. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Presence of any tissue or organ allograft, regardless of need for immunosuppression, including corneal allograft. Patients with a history of allogeneic hematopoietic stem cell transplant will be excluded
• Has a diagnosis of immunodeficiency
• Patients requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of study drug administration. The following are exceptions to this criterion: * Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption) * Physiologic replacement doses of systemic corticosteroids are permitted, doses not to exceed 10 mg/day of prednisone or its equivalent * A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
• Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Patient has a pulse oximetry of < 92% on room air or is on supplemental home oxygen
• Patients with active or untreated brain metastases or leptomeningeal metastases * NOTE: Patients with previously treated brain metastases must have stable neurologic status and imaging following local therapy (surgery or radiation) for at least 4 weeks, with no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration (stable low dose dexamethasone allowed at discretion of IND sponsor)
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situation; or concurrent active malignancy requiring systemic therapy or expected to require active therapy within the clinical study period, or any other intercurrent illness that in the judgment of the investigator would limit compliance with study requirements or interfere with the interpretation of the therapy response
• Pregnant women are excluded from this study because the agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued
• Has a known history of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C
• Patients who have had evidence of active or acute diverticulitis, intra- abdominal abscess, or gastrointestinal (GI) obstruction which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
• Patient is unwilling or unable to follow the study schedule for any reason
• Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or other substance abuse (including alcohol) that could potentially interfere with adherence to study procedures or requirements
• Clinically meaningful ascites, defined as any ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 weeks prior to the first scheduled dose