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Futibatinib and Pembrolizumab Combination in the Treatment of Advanced or Metastatic Urothelial Carcinoma

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ClinicalTrials.gov Identifier: NCT04601857
Recruitment Status : Recruiting
First Posted : October 26, 2020
Last Update Posted : January 25, 2021
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Taiho Oncology, Inc.

Brief Summary:
The purpose of the trial is to evaluate a response to combination of Fibroblast Growth Factor Receptor (FGFR) inhibitor futibatinib and anti-programmed cell death-1 (PD-1) antibody pembrolizumab in patients with advanced or spreading urothelial cancer who are not candidates to receive a platinum-based treatment regimens. It also will help us to learn about the side effects of this combination therapy. This study will also help us to find the futibatinib and pembrolizumab predictive markers of response (i.e. benefit from specific treatment; helps to select particular treatment over another). Another objective is to evaluate the supposed futibatinib and pembrolizumab combination's immunomodulatory effects (i.e. Drug that modifies the immune response or the functioning of the immune system as by the stimulation of antibody formation or the inhibition of white blood cell activity). By conducting this study, we will learn about the variability in drug concentrations within a patient population receiving clinically relevant doses of a futibatinib and pembrolizumab. Pharmacokinetics allows us to examine how the body processes a drug.

Condition or disease Intervention/treatment Phase
Advanced and Metastatic Urothelial Cancer Drug: Futibatinib and Pembrolizumab Phase 2

Detailed Description:

This study is an open-label, nonrandomized, multicenter Phase 2 study evaluating the combination of futibatinib and pembrolizumab in patients with advanced or metastatic UC who are not candidates to receive a platinum-based treatment regimen.

Approximately 46 subjects advanced or metastatic Urothelial Cancer (UC) will be enrolled in the trial at approximately 15-17 sites worldwide:

  • 6 patients in the safety lead-in
  • 20 patients with tumors characterized by specific genetic abnormalities (Cohort A)
  • 20 patients with tumors not characterized by specific genetic abnormalities (Cohort B).

A treatment cycle is defined as 21 days. All enrolled participants will receive the same treatment

  • Futibatinib at an oral (PO) dose of 20 mg daily (5 tablets) (QD); and
  • Pembrolizumab at an intravenous (I.V.) dose of 200 mg every 3 weeks (Q3W).

Treatment will continue until disease progression, unacceptable side effects, or any other of the criteria for treatment discontinuation is met; of note, pembrolizumab may be administered for a maximum of 35 doses or a maximum duration of 2 years, whichever is earlier. The study will begin with a safety lead-in period. During this period, a total of 6 patients with advanced or metastatic urothelial carcinoma will be enrolled and treated for at least one 21-day cycle. Patients will be enrolled into this initial safety lead-in period without regard for FGFR alteration status.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study Evaluating Futibatinib (TAS 120) Plus Pembrolizumab in the Treatment of Advanced or Metastatic Urothelial Carcinoma
Actual Study Start Date : January 21, 2021
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Futibatinib and Pembrolizumab (Cohort A)
Patients with UC and FGFR3 mutation or FGFR1-4 fusion/rearrangement.
Drug: Futibatinib and Pembrolizumab
All enrolled patients will receive the same treatment regimen of Futibatinib at an oral dose of 20 mg daily and Pembrolizumab at an intravenous dose of 200 mg every 3 weeks.
Other Name: TAS120 and MK3475

Experimental: Futibatinib and Pembrolizumab (Cohort B)
All other patients than in Cohort A with UC (including patients with other FGFR or non-FGFR genetic aberrations and patients with wild-type [non-mutated] tumors).
Drug: Futibatinib and Pembrolizumab
All enrolled patients will receive the same treatment regimen of Futibatinib at an oral dose of 20 mg daily and Pembrolizumab at an intravenous dose of 200 mg every 3 weeks.
Other Name: TAS120 and MK3475




Primary Outcome Measures :
  1. To evaluate the objective response rate (ORR) of futibatinib in combination with pembrolizumab in patients with advanced or metastatic UC who are not candidates to receive a platinum-based treatment regimen [ Time Frame: Approximately 12 months ]
    Objective response rate (ORR), defined as the proportion of patients experiencing a best overall response of partial response (PR) or complete response (CR).


Secondary Outcome Measures :
  1. Disease control rate (DCR) in both Cohorts A and B [ Time Frame: Approximately 8 months ]
    DCR defined as the proportion of patients experiencing a best overall response of stable disease (SD), PR, or CR.

  2. Duration of response (DOR)in both Cohorts A and B [ Time Frame: Approximately 8 months ]
    DOR defined as the time from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.

  3. Progression-free survival (PFS) in both Cohorts A and B [ Time Frame: Approximately 8 months ]
    PFS defined as the time from the first dose of study therapy to the date of death (any cause) or disease progression, whichever occurs first.

  4. Overall survival (OS) in both Cohorts A and B [ Time Frame: Approximately 18 months ]
    OS defined as the time from the date of the first dose to the death date.

  5. Incidence of treatment-emergent Adverse Events (AE)[Safety and Tolerability]in both Cohorts A and B [ Time Frame: Approximately 8 months ]
    Safety and tolerability of the futibatinib and pembolizumab combination therapy based on reported AEs, graded according to the NCI-CTCAE, Version 5.0


Other Outcome Measures:
  1. Explore predictive markers of response to futibatinib and pembrolizumab [ Time Frame: Approximately 18 months ]
    Relationship between FGFR aberrations, PD-L1 status, and status of other biomarkers in the tumor and clinical outcome.

  2. Evaluate the immunomodulatory effects of the combination of futibatinib and pembrolizumab [ Time Frame: Approximately 12 months ]
    Assess the effect of the combination on T-cells and other biomarkers.

  3. Estimate maximum plasma concentration [Cmax] of futibatinib at steady-state [ Time Frame: Approximately 12 months ]
    Steady-state Cmax of futibatinib will be estimated using the population pharmacokinetic [PK] analysis. Relationship between Cmax and clinical outcome will be explored.

  4. Estimate area under the plasma concentration-time curve over the dose interval [AUC] of futibatinib at steady-state [ Time Frame: Approximately 12 months ]
    Steady-state AUC of futibatinib will be estimated using the population PK analysis. Relationship between AUC and clinical outcome will be explored.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  1. Histologically confirmed advanced or metastatic urothelial carcinoma who have not received systemic treatment for advanced metastatic disease. For patients who received prior adjuvant/neoadjuvant chemotherapy or chemo-radiation for urothelial carcinoma, a treatment-free interval >12 months between the last treatment administration and the date of recurrence is required in order to be considered treatment-naïve in the metastatic setting.

    1. Cohort A: must have an FGFR3 mutation or FGFR1-4 fusion/rearrangement.
    2. Cohort B: all other patients with UC (including patients with other FGFR or non-FGFR genetic aberrations and patients with wild-type [non-mutated] tumors)
  2. Unfit for or intolerant to standard platinum-based chemotherapy as defined by any one of the following criteria:

    a. Chronic kidney disease characterized by the estimated creatinine clearance rate (eCCr) per Cockcroft-Gault formula of <60 mL/min or estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, corresponding to NCI-CTCAE v.5.0 Grade ≥2

    b. Impaired hearing (measured by audiometry) of >25 decibel (dB) at two contiguous test frequencies in at least one ear, corresponding to NCI-CTCAE v.5.0 Grade ≥2

    c. Peripheral sensory neuropathy Grade ≥2 by NCI-CTCAE v.5.0

    e. In the opinion of the Investigator, the patient is considered ineligible to receive any platinum-based chemotherapy

  3. Be willing and able to provide written informed consent for the trial.
  4. Be ≥ 18 years of age.
  5. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1.
  6. Adequate organ function as defined by the following criteria:

    1. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
    2. Platelet count ≥ 100,000/mm3
    3. Hemoglobin ≥ 9.0 g/dL
    4. Alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × upper limit of normal (ULN); if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5.0 × ULN.
    5. Total bilirubin ≤ 1.5 × ULN, or ≤ 3.0 × ULN for patients with Gilbert's syndrome.
    6. Creatinine clearance (Ccr) (calculated or measured value): ≥30 mL/min. For calculated Ccr, use the Cockcroft-Gault formula.
    7. International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or Activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
    8. Phosphorus <1.5 ULN
  7. Have a measurable disease per RECIST 1.1, as assessed by the local site Investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

Exclusion Criteria:

  1. Have received prior therapy with anti-PD-1, anti-PD-L1/L2 agent or FGFR inhibitor.
  2. History and/or current evidence of any of the following disorders:

    1. Non-tumor related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the Investigator
    2. 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
    3. Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator.
  3. Has received major surgery within the previous 4 weeks.
  4. Has received any non-investigational anticancer therapy within the previous 3 weeks (mitomycin within the previous 5 weeks).
  5. Is currently participating in a study of an investigational agent/device, or has participated in a study of an investigational agent or used an investigational device within 4 weeks prior to the first dose of study treatment.
  6. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
  7. Have an active autoimmune disease that has required systemic treatment in the past 2 years (that is, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (for example, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
  8. Have a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis.
  9. Have had an allogenic tissue/ organ transplant.
  10. Has known human immunodeficiency virus (HIV) and/or history of Hepatitis B or C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative Hepatitis C virus (HCV) RNA results greater than the lower limits of detection of the assay.
  11. Have known active central nervous system metastases and/or carcinomatous meningitis.
  12. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
  13. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years
  14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients

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): NCT04601857


Contacts
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Contact: Maciej Gil, MD 609-555-1212 clinicaltrialinfo@taihooncology.com

Locations
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United States, California
UCSF Helen Diller Family Not yet recruiting
San Francisco, California, United States, 94158
Contact: Vadim Koshkin, Dr    415-514-3878      
United States, Michigan
Henry Ford Hospital Recruiting
Detroit, Michigan, United States, 48202
Contact: Klara Hwang, Dr    415-514-3878      
United States, New York
Dana-Farber Cancer Institute Not yet recruiting
Boston, New York, United States, 02215
Contact: Guru Sonpavde, Dr    617-632-3993      
Sponsors and Collaborators
Taiho Oncology, Inc.
Merck Sharp & Dohme Corp.
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Responsible Party: Taiho Oncology, Inc.
ClinicalTrials.gov Identifier: NCT04601857    
Other Study ID Numbers: TAS-120-203
First Posted: October 26, 2020    Key Record Dates
Last Update Posted: January 25, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Taiho Oncology, Inc.:
Futibatinib
Pembrolizumab
Urothelial cancer
FGFR
TAS120
MK3475 B04
Additional relevant MeSH terms:
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Carcinoma, Transitional Cell
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents