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.
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
- 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.
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
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
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.
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
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