Futibatinib and Pembrolizumab for the Treatment of Advanced or Metastatic FGF19 Positive BCLC Stage A, B, or C Liver Cancer
Futibatinib and Pembrolizumab for the Treatment of Advanced or Metastatic FGF19 Positive BCLC Stage A, B, or C Liver Cancer
This phase II trial studies the effect of futibatinib and pembrolizumab in treating patients
 with FGF19 positive BCLC stage A, B, or C liver cancer that has spread to other parts of the
 body (advanced or metastatic). Futibatinib may stop the growth of cancer cells by blocking
 some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as
 pembrolizumab, may help the body's immune system attack the cancer, and may interfere with
 the ability of tumor cells to grow and spread. Giving futibatinib and pembrolizumab may help
 treat patients with FGF19 positive liver cancer.
PRIMARY OBJECTIVE:

 I. Determine the efficacy of combination of futibatinib and pembrolizumab in patients with
 advanced hepatocellular carcinoma (HCC) and high FGF19 expression who has received at least
 one line of therapy using progression free survival (PFS) at 6 months.

 SECONDARY OBJECTIVES:

 I. Assess the safety and tolerability of futibatinib and pembrolizumab combination through
 adverse event monitoring.

 II. Determine the overall objective response rate (ORR) and overall survival (OS) of patients
 with advanced HCC treated with futibatinib and pembrolizumab combination.

 III. Assess change in overall health-related quality of life, as measured by the global
 health domain of the European Organization for Research and Treatment of Cancer Quality of
 Life Questionnaire (EORTC-QLQ-C30) between baseline and at time of first-restaging scan.

 EXPLORATORY OBJECTIVES:

 I. To evaluate the prognostic effect of baseline number of circulating tumor cells (CTCs).

 II. To determine whether the change in number of CTCs post 2 months of treatment from
 baseline is associated with PFS and OS.

 III. To evaluate the prognostic effect of baseline circulating cell-free deoxyribonucleic
 acid (cfDNA).

 IV. To determine whether the change in cfDNA at 2 months of treatment from baseline is
 associated with PFS and OS.

 V. To compare prostate-specific membrane antigen (PSMA) positron emission tomography/magnetic
 resonance imaging (PET/MR) or PET/computed tomography (CT) with conventional MRI or CT for
 evaluation of treatment response.

 VI. To correlate drug response in patient derived organoids with clinical response and
 characterize the tumor microenvironment.

 OUTLINE:

 Patients receive futibatinib orally (PO) once daily (QD) on days 1-21 for cycles 1-9, and
 days 1-42 for subsequent cycles and pembrolizumab intravenously (IV) over 30 minutes on day
 1. Cycles repeat every 21 days for cycles 1-9 and every 42 days for subsequent cycles for up
 to 2 years in the absence of disease progression or unacceptable toxicity.

 After completing study treatment, patients are followed up at 30 days, every 9 weeks for up
 to 18 months, and then every 6 months for up to 5 years.
Inclusion Criteria:

 -  PRE-REGISTRATION: Age >= 18 years

 -  PRE-REGISTRATION: Disease characteristics:

 -  Radiologically confirmed hepatocellular carcinoma (HCC) that is not eligible for
 curative resection, transplantation, or ablative therapies

 -  Received at least one prior systemic treatment for HCC

 -  NOTE: Prior radiation, chemoembolization, radioembolization or other local
 ablative therapies or hepatic resection are permitted

 -  PRE-REGISTRATION: Measurable disease by any imaging modality as defined by Response
 Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in at least one site not
 previously treated with radiation or liver directed therapy (including bland, chemo-
 or radio-embolization, or ablation)

 -  NOTE: Tumor lesions in a previously irradiated area are not considered measurable
 disease; disease that is measurable by physical examination only is not eligible

 -  PRE-REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0,
 1 or 2

 -  PRE-REGISTRATION: Child-Pugh scores of =< 7 (Child-Pugh A or B7)

 -  PRE-REGISTRATION: Barcelona Clinic Liver Cancer Stage (BCLC) stage A, B, or C

 -  PRE-REGISTRATION: Able to swallow oral medication

 -  PRE-REGISTRATION: Willingness to provide mandatory tissue specimens for correlative
 research

 -  REGISTRATION: Tumor tissue must be FGF19 positive by messenger ribonucleic acid (mRNA)
 or immunohistochemistry (IHC)

 -  REGISTRATION: Measurable disease by any imaging modality as defined by RECIST 1.1
 criteria in at least one site not previously treated with radiation or liver directed
 therapy (including bland, chemo- or radio-embolization, or ablation

 -  REGISTRATION: ECOG performance status (PS) 0, 1 or 2

 -  REGISTRATION: Absolute neutrophil count (ANC) >= 1500/mm^3 (=< 15 days prior to
 registration)

 -  REGISTRATION: Hemoglobin >= 9.0 g/dL (=< 15 days prior to registration)

 -  REGISTRATION: Platelet count >= 75,000/mm^3 (=< 15 days prior to registration)

 -  REGISTRATION: Albumin >= 2.5 g/dL (=< 15 days prior to registration)

 -  REGISTRATION: Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 2.5 x
 upper limit of normal (ULN) (or =< 5 x ULN for patients with liver metastasis) (=< 15
 days prior to registration)

 -  REGISTRATION: Total bilirubin =< 1.5 x ULN (=< 15 days prior to registration)

 -  REGISTRATION: Phosphorus =< 1.5 x ULN (=< 15 days prior to registration)

 -  REGISTRATION: Calcium =< 1.5 x ULN (=< 15 days prior to registration)

 -  REGISTRATION: Prothrombin time/international normalized ratio/activated partial
 thromboplastin time (PT/INR/aPTT) =< 1.5 x ULN OR if patient is receiving
 anticoagulant therapy then INR or aPTT is within target range of therapy (=< 15 days
 prior to registration)

 -  REGISTRATION: Serum creatinine =< 1.5 x ULN (=< 15 days prior to registration)

 -  REGISTRATION: Calculated creatinine clearance >= 40 ml/min using the Cockcroft-Gault
 formula (=< 15 days prior to registration)

 -  REGISTRATION: Child-Pugh scores of =< 7 (Child-Pugh A or B7)

 -  REGISTRATION: Negative pregnancy test done =< 7 days prior to registration, for
 persons of childbearing potential only

 -  REGISTRATION: Willing to use an adequate method of contraception from registration
 through 120 days after the last dose of study medication

 -  NOTE: Only for persons of childbearing potential or persons able to father a
 child with partners of childbearing potential

 -  REGISTRATION: Able to swallow oral medication

 -  REGISTRATION: Provide written informed consent

 -  REGISTRATION: Willingness to provide mandatory blood specimens for correlative
 research

 -  REGISTRATION: Willingness to provide mandatory tissue specimens for correlative
 research

 -  REGISTRATION: Willingness and the ability to comply with scheduled visits (including
 geographical proximity), treatment plans, laboratory tests, and other study procedures

 -  REGISTRATION: Ability to complete questionnaires by themselves or with assistance

 Exclusion Criteria:

 -  PRE-REGISTRATION: Known standard therapy for the patient's disease that is potentially
 curative or definitely capable of extending life expectancy

 -  PRE-REGISTRATION: Prior organ transplantation

 -  PRE-REGISTRATION: History of untreated brain metastasis

 -  PRE-REGISTRATION: History of hepatitis B (HBV) and viral load >=100 IU/mL

 -  NOTE: Patients who have received antiviral therapy and have viral load < 100
 IU/mL are eligible

 -  PRE-REGISTRATION: History and/or current evidence of any of the following disorders:

 -  Non-tumor related alteration of the calcium-phosphorus homeostasis that is
 considered clinically significant in the opinion of the Investigator

 -  Ectopic mineralization/calcification, including but not limited to soft tissue,
 kidneys, intestine, or myocardia and lung, considered clinically significant in
 the opinion of the Investigator

 -  Retinal or corneal disorder confirmed by retinal/corneal examination and
 considered clinically significant in the opinion of the Investigator

 -  PRE-REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease
 which, in the judgment of the investigator, would make the patient inappropriate for
 entry into this study or interfere significantly with the proper assessment of safety
 and toxicity of the prescribed regimens

 -  PRE-REGISTRATION: History or risk of autoimmune disease, including, but not limited
 to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
 vascular thrombosis associated with antiphospholipid syndrome, Wegener's
 granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis,
 autoimmune thyroid disease, vasculitis, or glomerulonephritis. Notes:

 -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
 replacement hormone are eligible

 -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are
 eligible

 -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
 dermatologic manifestations only (e.g., patients with psoriatic arthritis would
 be excluded) are permitted provided that they meet the following conditions:

 -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
 ocular manifestations

 -  Rash must cover less than 10% of body surface area (BSA)

 -  Disease is well controlled at baseline and only requiring low potency
 topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
 flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

 -  No acute exacerbations of underlying condition within the last 6 months (not
 requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
 retinoids, biologic agents, oral calcineurin inhibitors; high potency or
 oral steroids)

 -  PRE-REGISTRATION: Known active human immunodeficiency virus (HIV) infection (defined
 as patients who are not on anti-retroviral treatment and have detectable viral load
 and CD4+ < 500/ml). NOTE: HIV positive patients who are well controlled on
 anti-retroviral therapy are allowed to enroll

 -  PRE-REGISTRATION: Uncontrolled intercurrent illness including, but not limited to:

 -  Ongoing or active severe infection. NOTE: Must be afebrile > 7 days to be
 eligible. Patient may be eligible if fever is present and infection has been
 ruled out or fever is related to tumor

 -  Psychiatric illness/social situations that would limit compliance with study
 requirements

 -  PRE-REGISTRATION: Receiving any other investigational agent which would be considered
 as a treatment for the primary neoplasm

 -  PRE-REGISTRATION: Other active malignancy < 6 months prior to registration

 -  EXCEPTIONS: Non-melanotic skin cancer, papillary thyroid cancer, or
 carcinoma-in-situ of the cervix, or others curatively treated and now considered
 to be at less than 30% risk of relapse are eligible

 -  PRE-REGISTRATION: Clinically significant or uncontrolled cardiac disease, including
 unstable angina, acute myocardial infarction within 6 months from day 1 of study
 treatment administration, New York Heart Association class III and IV congestive heart
 failure, and uncontrolled arrhythmia

 -  NOTE: Participants with pacemaker or with atrial fibrillation and well controlled
 heart rate are allowed

 -  PRE-REGISTRATION: History of pneumonitis or interstitial lung disease within =< 3
 years prior to pre-registration

 -  REGISTRATION: Known standard therapy for the patient's disease that is potentially
 curative or definitely capable of extending life expectancy

 -  REGISTRATION: Any of the following because this study involves an investigational
 agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and
 newborn are unknown:

 -  Pregnant persons

 -  Nursing persons

 -  Persons of childbearing potential who are unwilling to employ adequate
 contraception

 -  REGISTRATION: Any of the following prior therapies:

 -  Surgery =< 4 weeks prior to registration

 -  Radiotherapy for extended field =< 4 weeks prior to registration or limited field
 radiotherapy =< 2 weeks prior to registration

 -  Systemic anticancer therapy =< 2 weeks prior to registration

 -  NOTE: Prior immunotherapy is allowed unless patient discontinued due to
 grade 4 adverse event (AE)

 -  Live vaccine =< 30 days prior to registration

 -  Prior treatment with FGFR inhibitor

 -  Received strong inhibitors and inducers and sensitive substrates of CYP3A4 =< 2
 weeks prior to registration

 -  Received a drug that has not received regulatory approval for any indication as
 follows:

 -  =< 2 weeks prior to registration for nonmyelosuppressive agents or

 -  =< 4 weeks prior to registration for myelosuppressive agents

 -  REGISTRATION: History and/or current evidence of any of the following disorders:

 -  Retinal or corneal disorder confirmed by retinal/corneal examination and
 considered clinically significant in the opinion of the Investigator

 -  REGISTRATION: Active central nervous system (CNS) metastasis and/or carcinomatous
 meningitis

 -  NOTE: Patients with previously treated brain metastases that are clinically and
 radiologically stable (for at least 4 weeks prior to enrollment) are eligible

 -  REGISTRATION: History of hepatitis B (HBV) and viral load >= 100 IU/ml

 -  NOTE: Patients who have received antiviral therapy and have viral load < 100
 IU/ml are eligible

 -  REGISTRATION: Corrected QT interval using Fridericia's formula (QTcF) > 480 msec

 -  NOTE: Patients with an atrioventricular pacemaker or other condition (for
 example, right bundle branch block) that renders the QT measurement invalid are
 an exception and the criterion does not apply

 -  REGISTRATION: Co-morbid systemic illnesses or other severe concurrent disease which,
 in the judgment of the investigator, would make the patient inappropriate for entry
 into this study or interfere significantly with the proper assessment of safety and
 toxicity of the prescribed regimens

 -  REGISTRATION: Receiving any other investigational agent which would be considered as a
 treatment for the primary neoplasm

 -  REGISTRATION: History or risk of autoimmune disease, including, but not limited to,
 systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,
 vascular thrombosis associated with antiphospholipid syndrome, Wegener's
 granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis,
 autoimmune thyroid disease, vasculitis, or glomerulonephritis. Notes:

 -  Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
 replacement hormone are eligible.

 -  Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are
 eligible.

 -  Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
 dermatologic manifestations only (e.g., patients with psoriatic arthritis would
 be excluded) are permitted provided that they meet the following conditions:

 -  Patients with psoriasis must have a baseline ophthalmologic exam to rule out
 ocular manifestations

 -  Rash must cover less than 10% of body surface area (BSA)

 -  Disease is well controlled at baseline and only requiring low potency
 topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%,
 flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)

 -  No acute exacerbations of underlying condition within the last 12 months
 (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
 retinoids, biologic agents, oral calcineurin inhibitors; high potency or
 oral steroids)

 -  REGISTRATION: Known active human immunodeficiency virus (HIV) infection (defined as
 patients who are not on anti-retroviral treatment and have detectable viral load and
 CD4+ < 500/ml)

 -  NOTE: HIV-positive patients who are well controlled on anti-retroviral therapy
 are allowed to enroll

 -  REGISTRATION: Currently taking strong CYP3A inhibitors/inducers and unable to
 discontinue =< 7 days prior to registration