| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Urothelial Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced Urothelial 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077840 |
| E.1.2 | Term | Urothelial cancer of renal pelvis |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
The primary objective of this study is to evaluate efficacy of erdafitinib versus chemotherapy or pembrolizumab in subjects with advanced urothelial cancer harboring selected FGFR aberrations who have progressed after 1 or 2 prior treatments, at least 1 of which includes an anti-programmed death-ligand 1 (PD-[L]1) agent (cohort 1), or 1 prior treatment not containing an anti-PD-(L)1 agent (cohort 2).
The primary endpoint of overall survival will be evaluated in 2 cohorts:
- Cohort 1: erdafitinib versus chemotherapy (docetaxel or vinflunine) [subjects who have received prior anti-PD(L)1 agent]
- Cohort 2: erdafitinib versus pembrolizumab [subjects who have not received prior anti-PD(L)1 agent]
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| E.2.2 | Secondary objectives of the trial |
- To evaluate progression-free survival (PFS) of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
- To evaluate the objective response rate (ORR) of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
- To evaluate the health-related quality of life (HRQOL) of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
- To evaluate the duration of response (DOR) for subjects treated with erdafitinib versus chemotherapy or pembrolizumab
- To characterize the safety profile of subjects treated with erdafitinib versus chemotherapy or pembrolizumab
- To evaluate the population PK of erdafitinib |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥18yrs of age (or the legal age of consent in the jurisdiction in which the study is taking place)
2. Histologic demonstration of transitional cell carcinoma of the urothelium. Minor components (<50% overall) of variant histology such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable
3. Metastatic or surgically unresectable urothelial cancer
4. Documented PD, defined as any progression that requires a change in treatment, prior to randomization.
5.3 Cohort 1: Prior treatment with an anti-PD-(L)1 agent as monotherapy or as combination therapy; no more than 2 prior lines of systemic treatment. Prior treatment with an anti-PD-(L)1 agent could have been given as neo-adjuvant, adjuvant, or in metastatic line of treatment as frontline or maintenance therapy, as follows:
-Together with chemotherapy or as maintenance therapy
-Together with chemotherapy in metastatic setting
-For superficial cancer (early disease/non-muscle invasive bladder cancer), OR in neo-adjuvant OR adjuvant setting. If these subjects did not relapse within a year of their last dose of anti-PD-(L)1, this will not be counted as a prior line of systemic treatment. These subjects will however still be eligible only for Cohort 1.
Cohort 2: No prior treatment with an anti-PD-(L)1 agent; only 1 line of prior systemic treatment. Note: Subjects who received neoadjuvant or adjuvant chemotherapy or immunotherapy and showed PD within 12m of the last dose are considered to have received systemic therapy in the metastatic setting.
6.1 Subjects must meet appropriate molecular eligibility criteria (as determined by central laboratory screening or by local historical test results (from tissue or blood) performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified or regional equivalent laboratory using the following methods: local next-generation sequencing (NGS), direct digital counting methods, or the Qiagen Therascreen FGFR Rotor-Gene Q (RGQ) reverse transcription polymerase chain reaction (RT-PCR) test.
Tumors must have at least 1 of the following translocations: FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1; or 1 of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C
7. ECOG performance status Grade 0, 1, or 2
8.4. Adequate bone marrow, liver, and renal function:
a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding 2wks):
Absolute neutrophil count (ANC) >1,500/mm3
Platelet count >75,000/mm3 (≥100,000/mm3 for Cohort 1 subjects at sites choosing vinflunine chemotherapy)
Hemoglobin >8.0 g/dL (without transfusion or demonstrate stability, i.e., no significant decline in hemoglobin, for 2wks after transfusion)
b. Liver function:
-Total bilirubin <1.5 x ULN OR direct bilirubin ≤ULN for subjects with total bilirubin levels >1.5xULN [≤1xULN for Cohort 1 subjects at sites choosing docetaxel chemotherapy]
-Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x institutional ULN or ≤5x institutional ULN for subjects with liver metastases (For subjects in Cohort 1 at sites choosing docetaxel chemotherapy, both the ALT and AST values must be ≤1.5×ULN concomitant with alkaline phosphatase of ≤2.5×ULN)
c. Renal function: Creatinine clearance >30 mL/min either directly measured via 24hr urine collection or calculated using Cockcroft-Gaultd
d.Criterion deleted per amdt 3.
e. Phosphate: <ULN within 14 days of treatment and prior to Cy1 D1 (medical management allowed)
9.1 Must sign an ICF (or legally acceptable representative) indicating that he or she understands the nature, significance, purpose of, procedures for, and consequences of the study and willing to participate in the study.
10. A woman of childbearing potential who is sexually active must have a negative pregnancy test (ß-hCG) at Screening (urine or serum)
11.2 Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for subject participating in clinical studies For women of childbearing potential (defined as: fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy):
• practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly)
Please refer to Protocol pages 45 for remaining text for inclusion criteria.
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| E.4 | Principal exclusion criteria |
For All Subjects
1. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30d prior to randomization
2.1 Active malignancies (ie, requiring treatment change in the last 24m). The only allowed exceptions are:
•urothelial cancer
•skin cancer treated within the last 24m that is considered completely cured
•localized prostate cancer with a Gleason score of 6 (treated within the last 24m or untreated and under surveillance)
•localized prostate cancer with a Gleason score of 3+4 that has been treated more than 6m prior to full study screening and considered to have a very low risk of recurrence.
3. Symptomatic central nervous system metastases
4. Received prior FGFR inhibitor treatment
5. Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients
6.2 Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade
7. History of uncontrolled cardiovascular disease including:
a. unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive heart failure Class III-V (Attachment 3) within the preceding 3m; cerebrovascular accident or transient ischemic attack within the preceding 3m
b. QTc prolongation as confirmed by triplicate assessment at screening (Fridericia; QTc >480 milliseconds)
c. Pulmonary embolism or other venous thromboembolism (VTE) within the preceding 2m
8. Known active AIDS (human immunodeficiency virus (HIV) infection), unless the subject has been on a stable anti retroviral therapy regimen for the last 6m or more, has had no opportunistic infections in the last 6m, and has CD4 count >350
9.1 Known active hepatitis B or C infection (unless polymerase chain reaction[PCR]-negative [according to local laboratory range] on all available tests for the past 6m).
10.1 Not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, neuropathy, hearing loss)
11. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions
12. Major surgery within 4wks before randomization
13.2 Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being)or that could prevent, limit, or confound the protocol-specified assessments. Examples include ongoing active infection requiring systemic therapy and uncontrolled ongoing medical conditions.
For Cohort 1 Subjects
14.2Criterion modified per Amendment 4.
14.3 For those participating , at sites using docetaxel:has a history of severe hypersensitivity reaction (eg, generalized rash/erythema, hypotension, bronchospasm, angioedema or anaphylaxis) to either docetaxel or to other drugs formulated with polysorbate and paclitaxel. At sites using docetaxel, subjects with evidence of interstitial lung disease or active non-infectious pneumonitis are excluded.
For Cohort 2 Subjects
15. Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic or immunosuppressive agents. Subjects with vitiligo, diabetes Type I, or resolved childhood asthma/atopy would be an exception to this rule. Subjects who require intermittent use of bronchodilators, inhaled steroids, or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjøgren's syndrome will not be excluded from the study
16. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor
17. Evidence of interstitial lung disease or active non-infectious pneumonitis
18. Active infection requiring systemic therapy
19. Received a live virus vaccine within 30 days of first dose
20. Known allergies, hypersensitivity, or intolerance to pembrolizumab or its excipients |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is overall survival (OS). Overall survival is measured from the date of randomization to the date of the subject’s death. If the subject is alive or the vital status is unknown, the subject will be censored at the date the subject was last known to be alive
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
- PFS: duration in days from the date of randomization to the date of disease progression (assessed per RECIST v1.1 by the investigator) or relapse from CR or death, whichever is reported first. For subjects who do not have disease progression and are alive, as well as for subjects with unknown disease progression or unknown survival status as of the clinical cutoff date, PFS will be censored at the date of the last adequate disease assessment. If there is no postbaseline tumor assessment for a subject, PFS will be censored on the date of randomization. Refer to the Statistical Analysis Plan (SAP) for further details regarding censoring rules. Adequate disease assessment is defined as having sufficient evidence to indicate correctly that progression has or has not occurred
- ORR: the proportion of subjects who achieve complete response or partial response, as assessed per RECIST v1.1 by the investigator
- Change from baseline in patient-reported health status and physical functioning scales of the Functional Assessment of Cancer Therapy – Bladder Cancer (FACT-Bl),Time Until Symptom Deterioration (subset of FACT-Bl items), Patient-Global Impression of Severity (PGIS), and utility and visual analog scale of the European Quality of Life-5 Dimensions-5 Levels Questionnaire (EQ-5D-5L)
- DOR: for responders, duration in days from the date of initial documentation of a response to the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death. The censoring is similar to PFS
- Safety: collection of adverse event, clinical laboratory values, electrocardiograms, vital signs, ophthalmologic evaluations, physical examinations
- Oral clearance, area under the plasma concentration-time curve (and other parameters, as needed and as data permits) will be estimated using a population approach
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 143 |
| 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 |
| Argentina |
| Switzerland |
| Ukraine |
| Taiwan |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| China |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Turkey |
| 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 | 5 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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