Urothelial Cancer
Conditions
Keywords
Urothelial carcinoma, FGFR inhibitor, Pemigatinib
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.
Interventions
DRUGPemigatinib
At Day 1, prior to the start of treatment, results from screening visit evaluations are reviewed to determine eligibility requirements. Subsequent visits during treatment phase will take place at Day 8, Day 15 and Day 21 and subsequently at 3 week intervals. Timing of subsequent visits can be prolonged to max. 9 week intervals if no problems exist during the first 12 weeks of therapy. Subjects will self-administer study drug using an oral QD regimen in a continuous dosing schedule. Each dose of Pemigatinib should be taken first thing in the morning upon waking or after a 2-hour fast; subjects should then fast for an additional 1 hour after taking study drug. The starting dose is 13.5 mg Pemigatinib. Study treatment will continue until 12 months, or until the evidence of disease relapse or onset of unacceptable toxicity.
Sponsors
Incyte Biosciences International Sàrl
AMS Advanced Medical Services GmbH
High Research s.r.l.
European Association of Urology Research Foundation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, single-arm
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Relapse-free Survival (RFS) After Start of Treatment With Pemigatinib. | Mean Relapse-free survival rate from start of treatment through premature study-end with a maximal follow-up of 62 weeks. | In the protocol, RFS at Year 2 was defined as the time from the start of treatment until disease relapse by Investigator determination, study-end or lost to follow-up, or death due to any cause. Due to the Covid-19 crisis causing significant delay of recruitment and the fact that we needed much more patients to identify patients with FGFR3 alterations, the study recruitment was prematurely stopped in November 2021 when 46 patients were screened and only 4 among 42 tested (9.5%) patients were identified with FGFR3 alterations. Two of the FGFR3 positive patients started treatment and the others were ineligible for the study. Since patients withdrawing from the study before completing the study period of 2 years cannot be included in the calculation of the 2-year RFS rate, the outcome results through premature study-end are presented. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Overall Survival After Start of Treatment With Pemigatinib. | Mean Overall Sturvival from start of treatment through premature study-end with a maximal follow-up of 62 weeks. | Mean Overall Survival of patients who started treatment with Pemigatinib is defined as the time from the start of treatment until the last date known alive, or death due to any cause through premature study-end. |
Countries
Italy
Participant flow
Recruitment details
In 2020, the study was started in 5 Italian centers and recruitment commenced. The first patient was screened in July 2020.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm Treatment with Pemigatinib at the protocol-defined dose administered orally once daily as continuous therapy schedule until 12 months.
Pemigatinib: At Day 1, prior to the start of treatment, results from screening visit evaluations are reviewed to determine eligibility requirements. Subsequent visits during treatment phase will take place at Day 8, Day 15 and Day 21 and subsequently at 3 week intervals. Timing of subsequent visits can be prolonged to max. 9 week intervals if no problems exist during the first 12 weeks of therapy. Subjects will self-administer study drug using an oral QD regimen in a continuous dosing schedule. Each dose of Pemigatinib should be taken first thing in the morning upon waking or after a 2-hour fast; subjects should then fast for an additional 1 hour after taking study drug. The starting dose is 13.5 mg Pemigatinib. Study treatment will continue until 12 months, or until the evidence of disease relapse or onset of unacceptable toxicity. | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Treatment Arm | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 2 Participants | — |
| Age, Categorical Between 18 and 65 years | 0 Participants | — |
| Age, Continuous | 73.5 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Italy | 2 participants | — |
| Sex: Female, Male Female | 0 Participants | — |
| Sex: Female, Male Male | 2 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
Mean Relapse-free Survival (RFS) After Start of Treatment With Pemigatinib.
In the protocol, RFS at Year 2 was defined as the time from the start of treatment until disease relapse by Investigator determination, study-end or lost to follow-up, or death due to any cause. Due to the Covid-19 crisis causing significant delay of recruitment and the fact that we needed much more patients to identify patients with FGFR3 alterations, the study recruitment was prematurely stopped in November 2021 when 46 patients were screened and only 4 among 42 tested (9.5%) patients were identified with FGFR3 alterations. Two of the FGFR3 positive patients started treatment and the others were ineligible for the study. Since patients withdrawing from the study before completing the study period of 2 years cannot be included in the calculation of the 2-year RFS rate, the outcome results through premature study-end are presented.
Time frame: Mean Relapse-free survival rate from start of treatment through premature study-end with a maximal follow-up of 62 weeks.
Population: 2 patients started treatment with Pemigatinib and were followed-up according to protocol through premature study-end.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mean RFS for Patients Treated With Pemigatinib. | Mean Relapse-free Survival (RFS) After Start of Treatment With Pemigatinib. | 26.6 weeks |
Secondary
Mean Overall Survival After Start of Treatment With Pemigatinib.
Mean Overall Survival of patients who started treatment with Pemigatinib is defined as the time from the start of treatment until the last date known alive, or death due to any cause through premature study-end.
Time frame: Mean Overall Sturvival from start of treatment through premature study-end with a maximal follow-up of 62 weeks.
Population: 2 patients started treatment with Pemigatinib and were followed-up according to protocol through premature study-end with a maximal follow-up of 62 weeks.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Mean RFS for Patients Treated With Pemigatinib. | Mean Overall Survival After Start of Treatment With Pemigatinib. | 34.2 weeks |