Screening success and patient recruitment was much lower than projected and a clinical/scientific interpretation will not be possible.

The purpose of this clinical trial is to demonstrate the benefit of Pemigatinib, a drug that has indicated promising effects for relapse free survival in molecularly-selected, high-risk patients with urothelial carcinoma (UC) who have received radical surgery. Patients will receive Pemigatinib at a once-daily dose on a continuous schedule, continued until 12 months.

This is an open-label, single-arm, Phase II study, evaluating safety and efficacy of INCB054828 (Pemigatinib) as adjuvant therapy for molecularly-selected, high-risk patients with urothelial carcinoma (UC) who have received radical surgery. Patients will receive Pemigatinib at a once-daily (QD) dose of 13.5 mg on a continuous schedule. Treatment will be continued until 12 months, or until the evidence of disease relapse or onset of unacceptable toxicity.

Hyperphosphatemia can be managed with diet modification, phosphate binders, or dose modification. Since mineralization of the cornea and retinal changes consisting of serous retinal detachment have been reported in humans, ophthalmic exams are done at baseline and once every 12 weeks during treatment and should include a visual acuity test, slit-lamp examination and fundoscopy. Additional assessments (e.g. Orbital computerized tomography (CT) should be done if clinically relevant retinal findings are observed on ophthalmologic exams and in participants with reported visual adverse events (AEs) or change in visual acuity, if the events or changes are suspected to be of retinal origin.

Inclusion Criteria:

• Histological evidence of pT3-4 and/or pN1-3 UC of the urinary bladder or upper urinary tract after radical cystectomy / radical nephroureterectomy. Patients with mixed histologies are required to have a dominant (i.e. at least 50%) urothelial cell carcinoma pattern.
• Previous administration of at least 3 cycles of neoadjuvant cisplatin-based chemotherapy OR, if neoadjuvant chemotherapy was not administered, ineligibility to receive cisplatin-based adjuvant chemotherapy based on Galsky's criteria, that include at least one of the following: (1) WHO performance status ≥ 2 and/or (2) creatinine-clearance < 60 ml/min and/or (3) CTCAE Gr ≥ 2 hearing loss and/or (4) CTCAE Gr ≥ 2 neuropathy.
• Evidence of FGFR alterations (mutations or translocations as specified in protocol) as assessed by a centralized Foundation Medicine test (Foundation One).
• Recovered with no evidence of disease confirmed by radiological images, prior to start of adjuvant therapy within 13 weeks after radical surgery.
• Willingness to avoid pregnancy or fathering children
• Written informed consent.

Exclusion Criteria:

• Any previous receipt of a selective FGFR inhibitor.

• Presence of primary CIS only.

• Presence of another malignancy in the 3 years before enrolment except for basal cell carcinoma or squamous cell carcinoma of the skin, cis of cervix, localised prostate cancer in active surveillance or other non invasive or other indolent malignancy that has undergone potentially curative therapy.

• Presence of pregnancy or lactation.

• Distant metastases (M1 disease).

• Treatment with other investigational drugs, receipt of anticancer medications (except for neoadjuvant cisplatin-based chemotherapy, see second inclusion criterion) or radiotherapy after radical surgery.

• Use of any potent CYP3A4 inhibitors or inducers within 14 days or 5 half lives (whichever is longer) before the first dose of study treatment.

• Abnormal laboratory parameters:

  • Total bilirubin ≥ 1.5 × upper limit of normal (ULN; ≥ 2.5 × ULN if Gilbert syndrome).
  • AST and/or ALT > 2.5 × ULN
  • Creatinine clearance ≤ 30 mL/min based on Cockroft-Gault.
  • Serum phosphate > institutional ULN.
  • Serum calcium outside of the institutional normal range or serum albumin-corrected calcium outside of the institutional normal range when serum albumin is outside of the institutional normal range.

• History of human immunodeficiency virus infection or active tuberculosis infection.

• Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (exceeding > 10 mg daily of prednison equivalent; inhalation steroids are permitted).

• Evidence of hepatitis B virus or hepatitis C virus active infection or risk of reactivation.

• Severe hepatic impairment

• Known prior severe hypersensitivity to investigational products or its excipients

• History of clinically significant or uncontrolled cardiac disease, including unstable angina, acute myocardial infarction within 6 months of enrolment, New York Heart Association Class III or IV.

• Current evidence of corneal disorder/keratopathy (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivitis, etc) or retinal disorder (including but not limited to, central serous retinopathy, macular/retinal degeneration, diabetic retino-pathy, retinal detachment, etc) as confirmed by ophthalmologic examination.

• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits.

From start of treatment to premature study end with a maximal follow-up of 62 weeks.

In 2020, we started in 5 Italian centers. We expected that 30% of the screened patients (pts) had FGFR3 alterations (F3). Due to the Covid-19 crisis (recruitment delay) and the fact that we needed more pts to identify F3, recruitment prematurely stopped in Nov. 2021 with 42 pts screened and only 4/42 tested identified with F3 (9%). Two out of 4 pts were ineligible and only 2 started treatment and were followed until Study-End in Nov. 2022 resulting in a limited follow-up of maximal 62 weeks.