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

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ClinicalTrials.gov Identifier: NCT04828486
Recruitment Status : Recruiting
First Posted : April 2, 2021
Last Update Posted : November 10, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced Hepatocellular Carcinoma BCLC Stage A Hepatocellular Carcinoma BCLC Stage B Hepatocellular Carcinoma BCLC Stage C Hepatocellular Carcinoma Metastatic Hepatocellular Carcinoma Drug: Futibatinib Biological: Pembrolizumab Other: Quality-of-Life Assessment Phase 2

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of FGFR Inhibitor Futibatinib in Combination With Anti-PD-1 Antibody Pembrolizumab in Patients With Advanced or Metastatic Hepatocellular Carcinoma With FGF19 Expression After First Line Therapy
Actual Study Start Date : May 7, 2021
Estimated Primary Completion Date : May 6, 2023
Estimated Study Completion Date : May 6, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (futibatinib, pembrolizumab)
Patients receive futibatinib PO QD on days 1-21 for cycles 1-9, and days 1-42 for subsequent cycles and pembrolizumab 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.
Drug: Futibatinib
Given PO
Other Name: TAS-120

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: At 6 months ]
    PFS will be calculated using the Kaplan-Meier method.


Secondary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 5 years ]
    ORR defined as the number of evaluable patients achieving a response (partial response or complete response per Response Evaluation Criteria in Solid Tumors v1.1) during treatment with study therapy divided by the total number of evaluable patients. Point estimates will be generated for objective response rates along with 95% binomial confidence intervals.

  2. Overall survival (OS) [ Time Frame: Time from registration to death due to any cause, assessed up to 5 years ]
    The distribution of survival time will be estimated using the method of Kaplan-Meier. OS medians will be estimated along with 95% confidence intervals.

  3. Incidence of adverse events [ Time Frame: Up to 5 years ]
    Adverse events will be evaluated, per Common Terminology Criteria for Adverse Events version 5.0, for each patient.

  4. Change in quality of life (QOL) [ Time Frame: Up to 5 years ]
    As measured by the global health domain of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The median QOL change from baseline along with a 95% confidence interval will be estimated using the Hodges-Lehmann method.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRE-REGISTRATION: Age >= 18 years
  • PRE-REGISTRATION: Radiologically confirmed hepatocellular carcinoma (HCC)
  • PRE-REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
  • 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: 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
  • 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
  • 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: Barcelona Clinic Liver Cancer Stage (BCLC) stage A, B, or C
  • 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 a) persons of childbearing potential or b) 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: Prior organ transplantation
  • PRE-REGISTRATION: History of untreated brain metastasis
  • 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:

      • 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: 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: 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:

      • 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 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
  • 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
  • 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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04828486


Locations
Layout table for location information
United States, Minnesota
Mayo Clinic in Rochester Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015    mayocliniccancerstudies@mayo.edu   
Principal Investigator: Nguyen H. Tran, M.D.         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Nguyen H Tran Mayo Clinic in Rochester
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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT04828486    
Other Study ID Numbers: MC200402
NCI-2021-02444 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC200402 ( Other Identifier: Mayo Clinic in Rochester )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: April 2, 2021    Key Record Dates
Last Update Posted: November 10, 2021
Last Verified: October 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Pembrolizumab
Futibatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents