A Phase 2 Study Evaluating Futibatinib (TAS-120) Plus Pembrolizumab in the Treatment of Advanced or Metastatic bladder, urethra or pelvis cancer

Prior treatment

• Have received prior therapy with anti-PD-1, anti-PD-L1/L2 agent.
• Has received major surgery within the previous 4 weeks.
• Has received any non-investigational anticancer therapy within the previous 3 weeks (mitomycin within the previous 5 weeks).
• 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.
• 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.
• Have known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, that is, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable, and without steroid treatment requirement for at least 1 month prior to the first dose of study treatment.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
• Have received prior FGFR inhibitor treatment including futibatinib

Other illness

• 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 HCV RNA results greater than the lower limits of detection of the assay.
• Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
  • Criteria 16 and for Protected Persons, see Protocol Addendum 2, dated 3 May 2021 section 4.2 and 4.2.1

Lab values

• History and/or current evidence of any of the following disorders: a. Non-tumor related alteration of the calcium-phosphorus homeostasis that is considered clinically significant in the opinion of the Investigator b. 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 c. Retinal or corneal disorder confirmed by retinal/corneal examination and considered clinically significant in the opinion of the Investigator.
• Corrected QT interval using Fridericia's formula (QTcF) >470 msec. 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.
• A serious illness or medical condition(s) including, but not limited to, the following: a. Has an active infection requiring systemic therapy. b. Myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure within the previous 6 months c. History or current evidence of uncontrolled ventricular arrhythmia d. Chronic diarrhea diseases considered to be clinically significant in the opinion of the Investigator e. Congenital long QT syndrome, or any known history of torsade de pointes, or family history of unexplained sudden death f. 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. g. Have a history of (noninfectious) pneumonitis that required steroids or has current pneumonitis. h. Have had an allogenic tissue/ organ transplant.
  • Please refer to protocol for addition exclusion criteria.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating Investigator.

Other

• The patient is pregnant or breastfeeding.

• Histologically confirmed advanced or metastatic UC in patients 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. a. In safety lead-in: enrollment regardless of FGFR status b. Cohort A: must have an FGFR3 mutation or FGFR1-4 fusion/rearrangement c. Cohort B: all other patients with UC (including patients with other FGFR or nonFGFR genetic aberrations and patients with WT [nonmutated] tumors)
• A male patient must agree to use contraception during the treatment period and for at least 6 months following the last dose of study treatment.
• A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP). b. A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 6 months after the last dose of study treatment. c. A WOCBP who has a negative serum pregnancy test within 7 days prior to treatment.
• Ability to take medications orally (feeding tube is not permitted).
• Willing and able to comply with scheduled visits and study procedures.
• Unfit for or intolerant to cisplatin 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 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. Please refer to protocol for addition inclusion criteria.
• Be willing and able to provide written informed consent for the trial.
• Be ≥18 years of age.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1.
• Adequate organ function as defined by the following criteria: a. Absolute neutrophil count (ANC) ≥1.5 × 109 /L b. Platelet count ≥100,000/mm3 c. Hemoglobin ≥9.0 g/dL d. Alanine aminotransferase (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. e. Total bilirubin ≤1.5 × ULN, or ≤3.0 × ULN for patients with Gilbert's syndrome. f. Creatinine clearance (Ccr) (calculated or measured value): ≥30 mL/min. For calculated Ccr, use the Cockcroft-Gault formula. g. International normalized ratio (INR) OR prothrombin time ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as prothrombin time or aPTT is within therapeutic range of intended use of anticoagulants h. Phosphorus <1.5 ULN
• Adequate recovery from the side effects of any prior therapy for nonmetastatic disease (generally defined as recovery of all AEs due to ≤ Grade 1 or baseline; however, patients with ≤ Grade 2 neuropathy, anemia, alopecia, and skin pigmentation may be eligible).
• Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
• 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.