E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male and female participants at least 18 years of age who have untreated metastatic or unresectable urothelial carcinoma. |
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E.1.1.1 | Medical condition in easily understood language |
Male and female participants at least 18 years of age who have bladder cancer. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10005003 |
E.1.2 | Term | Bladder cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate and compare PFS in participants treated with pemigatinib in combination with pembrolizumab (Treatment Group A) and pemigatinib alone (Treatment Group B) versus SOC (Treatment Group C).
Differences in PFS will be evaluated hierarchically, and the comparison between pemigatinib in combination with pembrolizumab (Treatment Group A) and SOC (Treatment Group C) will be evaluated first, and if significant difference is detected, a second comparison will be made in PFS between pemigatinib alone (Treatment Group B) and SOC (Treatment Group C). Hypothesis: The combination of pembrolizumab plus pemigatinib has superior PFS as compared with SOC. Contribution of pemigatinib alone to combination will be assessed by comparing Treatment Groups A and C and Treatment Groups B and C. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate and compare the efficacy of the 3 treatment groups with respect to OS. - To evaluate and compare the efficacy of the 3 treatment groups with respect to overall tumor response and DOR. - To evaluate the safety of the 3 treatment groups. - To evaluate changes from baseline in patient-reported outcomes. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female participants aged 18 years and older at the time of signing the informed consent; a legally minor participant from Japan needs written parental or legal guardian's consent. 2. Histologically documented metastatic or unresectable UC; may include primary site from bladder, ureters, upper tract, renal pelvis, urethra, or urachus. Both transitional cell and mixed transitional cell histologies are allowed, provided urothelial component is ≥ 50%. Note: Participants with non-UC of the urinary tract are not allowed. 3. Have at least 1 measurable target lesion per RECIST v1.1 as assessed by the local site investigator/radiologist. Eligibility for chemotherapy is defined as meeting either criterion #4 OR #5 as described below. 4. Cisplatin ineligibility, defined by the presence of one of the following criteria: a. Creatinine clearance of < 60 mL/min but ≥ 30 mL/min (measured by the Cockcroft-Gault formula or 24-hour urine). b. ECOG performance status 2 (within 7 days prior to randomization). c. ≥ Grade 2 audiometric hearing loss (25 db in 2 consecutive wave ranges; CTCAE v5.0). d. New York Heart Association Class III heart failure. e. ≥ Grade 2 peripheral neuropathy (CTCAE v5.0). OR 5. Ineligibility to receive any platinum-based chemotherapy (ie, ineligible for cisplatin and carboplatin), defined as ECOG performance status 2 (within 7 days prior to randomization) AND at least one of the following: a. Documented visceral metastatic disease(due to poor prognosis and lack of benefit). b. Creatinine clearance of < 60 mL/min but ≥ 30 mL/min (measured by the Cockcroft-Gault formula or 24-hour urine). c. ≥ Grade 2 audiometric hearing loss (25 db in 2 consecutive wave ranges; CTCAE v5.0). d. ≥ Grade 2 peripheral neuropathy (CTCAE v5.0). e. Other reason, identified on the eCRF, for the participant being unable to receive carboplatin safely. Additional criteria for platinum ineligibility will be considered and allowed on a case-by-case basis, following consultation with the sponsor. 6. Must have known FGFR3 mutation or rearrangement (participant can be randomized based on a local report, but this will need to be retrospectively confirmed by the sponsor's central laboratory; see Appendix E). See Section 8.7.1 for details on tumor tissue requirements. Note: Participants with gene amplifications only are excluded. 7. Local or central laboratory test result of PD-L1 is mandatory at screening. Participants can be randomized based on a local genomics report, but this will need to be retrospectively confirmed by the sponsor's central laboratory. If local result is not available, formalinfixed, paraffin-embedded tissue blocks or slides must be sent to the sponsor's central laboratory. Formalin-fixed, paraffin-embedded tissue blocks are preferred to slides. If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 30 days from the date slides are cut (see Section 8.7.1 for details on tumor tissue requirements). Note: In the event the participant does not have local PD-L1 results or the sample is not evaluable for PD-L1, the participant will not be eligible. If a local result is available and the participant is randomized, but the sample fails or the local result is not confirmed by the central laboratory, the site should contact the medical monitor. 8. Have received no prior systemic chemotherapy for metastatic or unresectable UC except: a. Adjuvant platinum-based chemotherapy, following radical cystectomy, with recurrence > 12 months from completion of therapy. b. Neo-adjuvant platinum-based chemotherapy, with recurrence > 12 months since completion of therapy. Note: Low-dose chemotherapy (eg, low-dose cisplatin, cisplatin + 5-FU, mitomycin + 5-FU, or cisplatin + paclitaxel) given concurrently with radiation to the primary tumor site is not considered as systemic therapy. A washout period of 3 weeks before the first dose of study treatment is required. In the clinical setting, chemotherapy is given with the sole purpose of sensitizing the tumor to local radiation. It is not administered at doses with any systemic efficacy. Surgery is not considered first-line therapy following diagnosis of advanced/metastatic disease. 9. ECOG performance status 0 to 2. For remaining points 10 and 11 please refer to Protocol Amendment 1, section 5.1.
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E.4 | Principal exclusion criteria |
1. Prior receipt of a selective FGFR inhibitor (eg, erdafitinib, rogaratinib,infigratinib,dovitinib, vofatamab) for any indication or reason. 2. Completion of prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent, or with an agent directed to another co-inhibitory T-cell receptor ≤ 18 months prior to the start of treatment for this study. 3. Receipt of anticancer medications or investigational drugs for unresectable and/or metastatic disease (not including adjuvant/neo-adjuvant treatment with platinumcontaining chemotherapy completed ≥ 12 months prior to the start of treatment for this study). 4. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, tumor embolization), except for treatment allowed per protocol. 5. Has disease that is suitable for local therapy administered with curative intent. 6. Has tumor with any neuroendocrine or small cell component. 7. Current evidence of clinically significant corneal (including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and keratoconjunctivitis, etc) or retinal disorder (including but not limited to macular/retinal degeneration, diabetic retinopathy, retinal detachment, etc) as confirmed by ophthalmologic examination. 8. Has received prior radiotherapy to a metastatic site within 3 weeks of the first dose of study treatment, with the exception of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks before the start of study treatment. Participants must have recovered from all radiation-related toxicities and must not require corticosteroids. 9. Has CNS metastases, unless the participant has completed local therapy (eg, whole brain radiation therapy, surgery, radiosurgery) and has discontinued use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks before starting study treatment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival, defined as the time from randomization date until the date of disease progression (as measured by BICR per RECIST v1.1) or death due to any cause, whichever occurs first. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The schedule for efficacy assessments will be at screening (this will be considered the baseline scan), every 9 weeks (every 3 cycles) from date of randomization until 1 year, then every 12 weeks (every 4 cycles) thereafter, and then at EOT (if applicable). Please refer to the schedule of activities reported in table 4 of the protocol. |
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E.5.2 | Secondary end point(s) |
- Overall survival, defined the time from the date of randomization until death due to any cause. - Objective response rate, defined as the proportion of participants with best overall response of CR or PR determined by BICR per RECIST v1.1. - Duration of response, defined as the time from the date of the first assessment of CR or PR until the date of the first disease progression per BICR per RECIST v1.1 or death, whichever occurs first. - Safety and tolerability of pemigatinib with or without pembrolizumab and SOC will be assessed by evaluating the frequency, duration and severity of AEs, physical examination findings, vital sign changes, and clinical laboratory assessments. - Patient-reported outcome scales (ie, EORTC QLQ-C30, EQ-5D-5L) at each timepoint and change from baseline to each timepoint. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The schedule for efficacy assessments will be at screening (this will be considered the baseline scan), every 9 weeks (every 3 cycles) from date of randomization until 1 year, then every 12 weeks (every 4 cycles) thereafter, and then at EOT (if applicable). Adverse events (CTCAE v4.03) will be monitored from the time the participant signs the ICF until at least 30 days for after the last dose of study treatment. A comprehensive eye examination should be performed by a qualified ophthalmologist at screening on all participants, once every 3 cycles (± 7 days) for participants randomized to Treatment Groups A and B only, at EOT for all participants, and as clinically indicated. Please refer to the schedule of activities reported in table 4 of the protocol. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 76 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
Belgium |
Canada |
Finland |
France |
Germany |
Ireland |
Israel |
Italy |
Japan |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |