Futibatinib and Pembrolizumab for the Treatment of Advanced or Metastatic FGF19 Positive BCLC Stage A, B, or C Liver Cancer

Overview

About this study

This is a single-arm, two-stage, phase II trial to assess the efficacy of futibatinib plus pembrolizumab in advanced hepatocellular carcinoma for patients with FGF19 expression after receiving at least 1 line of therapy. Patients will receive futibatinib 20 mg daily Days 1-21 and will receive pembrolizumab 200 mg Day 1 of each 21 day cycle per current clinical standard of care. Patient will receive treatment until disease progression or unacceptable toxicities. Patients will undergo restaging scans every 3 cycles. Subjects will be monitored for adverse events from the beginning of the study drug to 28 days after the last dose. We will collect blood samples for determination of cell free DNA and circulating tumor cells at baseline, after 3 and 6 cycles, and at progression. We will collect tumor biopsy specimens before treatment initiation to develop patient derived tumor organoid.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Pre-Registration – Inclusion Criteria

  • Age ≥ 18 years.
  • Radiologically or pathologically confirmed hepatocellular carcinoma (HCC).
  • Willingness to provide mandatory tissue specimens for correlative research.

Pre-Registration - Exclusion Criteria

  • Prior organ transplantation.

Registration – Inclusion Criteria:

  • Tumor tissue must be FGF19 positive by mRNA or IHC.
  • 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.
    • 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).
    • NOTE: Tumor lesions in a previously irradiated area are not considered measurable disease; disease that is measurable by physical examination only is not eligible.
  • ECOG Performance Status (PS) 0, 1 or 2.
  • The following laboratory values obtained ≤ 15 days prior to registration:
    • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
    • Hemoglobin ≥ 9.0 g/dL;
    • Platelet count ≥ 75,000/mm^3;
    • Albumin ≥ 2.5 g/dL;
    • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 × ULN (or ≤ 5 × ULN for patients with liver metastasis);
    • Total bilirubin ≤ 1.5 × ULN;
    • Phosphorus ≤ 1.5 × ULN;
    • Calcium ≤ 1.5 × ULN;
    • PT/INR/aPTT ≤ 1.5 × ULN OR if patient is receiving anticoagulant therapy then INR or aPTT is within target range of therapy;
    • Serum creatinine ≤ 1.5 × ULN;
    • Calculated creatinine clearance ≥ 40 ml/min using the Cockcroft-Gault formula
  • Child-Pugh scores of ≤ 7 (Child-Pugh A or B7).
  • BCLC stage A, B, or C.
  • Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
  • 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).
  • Able to swallow oral medication.
  • Provide written informed consent.
  • Willingness to provide mandatory blood specimens for correlative research .
  • Willingness to provide mandatory tissue specimens for correlative researchsee 
  • Willingness and the ability to comply with scheduled visits (including geographical proximity), treatment plans, laboratory tests, and other study procedures.
  • Ability to complete questionnaires by themselves or with assistance.

Registration - Exclusion Criteria:

  • Known standard therapy for the patient’s disease that is potentially curative or definitely capable of extending life expectancy.
  • 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.
  • 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 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.
  • 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.
    • History of pneumonitis or interstitial lung disease within ≤ 3 years prior to pre-registration.
  • Active 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.
  • 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..
  • 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.
  • 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.
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
  • 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, Sjögren’s syndrome, Guillain-Barré 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, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
    • Must not have 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).
  • 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.
  • Currently taking strong CYP3A inhibitors/inducers and unable to discontinue ≤ 7 days prior to 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.
  • 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.
  • 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.
  • Other active malignancy < 6 months prior to pre-registration.

Eligibility last updated 1/19/22 for Amendment 3. Questions regarding updates should be directed to the study team contact.

 

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Nguyen Tran, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

855-776-0015

More information

Publications

Publications are currently not available
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