Clinical trial NCT04294277: Safety and Efficacy of Pemigatinib in Patients With High-risk Urothelial Cancer After Radical Surgery
Official title: 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 Who Have Received Radical Surgery
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Urothelial Cancer
Keywords: Urothelial carcinoma
FGFR inhibitor
Pemigatinib
Lead sponsor: European Association of Urology Research Foundation
Sponsor class: OTHER
Collaborators: name: Incyte Biosciences International Sàrl
name: AMS Advanced Medical Services GmbH
name: High Research s.r.l.
First posted: 2020-03-04
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label, single-arm
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Mean Relapse-free Survival (RFS) After Start of Treatment With Pemigatinib.
timeFrame: Mean Relapse-free survival rate from start of treatment through premature study-end with a maximal follow-up of 62 weeks.
Secondary outcomes:
measure: Mean Overall Survival After Start of Treatment With Pemigatinib.
timeFrame: Mean Overall Sturvival from start of treatment through premature study-end with a maximal follow-up of 62 weeks.
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
city: Bologna
country: Italy
facility: Policlinico Sant'Orsola-Malpighi - Azienda Ospedaliero-Univeristaria di Bologna
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
city: Milano
country: Italy
facility: IRCCS San Raffaele Hospital
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario A. Gemelli, IRCCS
Study officials:
affiliation: IRCCS San Raffaele Hospital
name: Andrea Necchi, Dr.
role: PRINCIPAL_INVESTIGATOR
References: