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 | 20.0 |
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 one prior treatment. 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 antiPD-(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 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. ≥18 years 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. Stage IV disease (metastatic or surgically unresectable, cT4b, N+, or M+ cancer) 4. Documented progression of disease, defined as any progression that requires a change in treatment, prior to randomization 5. Only one line of prior treatment for metastatic urothelial cancer. Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression (as defined in criterion 4), within 12 months of the last dose are considered to have received chemotherapy in the metastatic setting Cohort 1: prior chemotherapy and anti-PD(L)1 [in combination or in maintenance setting] (anti-PD(L)1 alone is allowed only for subjects with documented cisplatin ineligibility) Cohort 2: prior chemotherapy (no prior anti-PD(L)1 treatment) 6. Subjects must meet appropriate molecular eligibility criteria (as determined by central laboratory screening): 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 (Attachment 1) 8. Adequate bone marrow, liver, and renal function: a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating agent in preceding 2 weeks): Absolute neutrophil count (ANC) >1,500/mm3 Platelet count >75,000/mm3 Hemoglobin >8.0 g/dL (without transfusion or demonstrate stability, i.e., no significant decline in hemoglobin, for 2 weeks after transfusion) b. Liver function: Total bilirubin <1.5 x institutional upper limit of normal (ULN), unless known to have Gilbert's disease [≤1xULN for Cohort 1 subjects at sites choosing docetaxel chemotherapy] Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x institutional ULN [ALT and AST both ≤1.5xULN and alkaline phosphatase ≤2.5xULN for Cohort 1 subjects at sites choosing docetaxel chemotherapy] c. Renal function: Creatinine clearance >30 mL/min/1.73 m2 either directly measured via 24-hour urine collection or calculated using Cockcroft-Gault (Attachment 2) d. Electrolytes: Potassium within institutional normal limits e. Phosphate: <ULN within 14 days of treatment and prior to Cycle 1 Day 1 (medical management allowed) 9. Must sign an informed consent form (ICF) (or their legally acceptable representative must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study 10. A woman of childbearing potential who is sexually active must have a negative pregnancy test (ß-human chorionic gonadotropin [ß-hCG]) at Screening (urine or serum) 11. 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: • practicing a highly effective method of contraception (failure rate of <1% per year when used consistently and correctly) Examples of highly effective contraceptives include - user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); vasectomized partner; sexual abstinence - user-dependent methods: combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable • agrees to remain on a highly effective method throughout the study and for at least 6 months after the last dose of study drug • agrees to not donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for at least 6 months after the last dose of study drug • not breast-feeding, not planning to become pregnant within 6 months after the last dose of study drug For men who are sexually active with women of childbearing potential: • agrees to use a barrier method of contraception (eg, condom with spermicidal foam/gel/film/cream/suppository) • agrees to not donate sperm during the study and for at least 6 months after the last dose of study drug • not planning to father a child during the study or within 6 months after the last dose of study drug
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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 30 days prior to randomization 2. Active malignancies (ie, requiring treatment change in the last 24 months) other than urothelial cancer (except skin cancers within the last 24 months that is considered completely cured) 3. Symptomatic central nervous system metastases 4. Received prior FGFR inhibitor treatment 5. Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients 6. Corneal or retinal abnormality likely to increase the risk of eye toxicity, i.e.: a. History of central serous retinopathy (CSR) or retinal vascular occlusion (RVO) b. Active wet, age-related macular degeneration (AMD) c. Diabetic retinopathy with macular edema (non-proliferative) d. Uncontrolled glaucoma (per local standard of care) e. Corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal abrasion, inflammation or ulceration. 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 3 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months 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 2 months 8. Known active AIDS (human immunodeficiency virus (HIV) infection), unless the subject has been on a stable anti retroviral therapy regimen for the last 6 months or more, has had no opportunistic infections in the last 6 months, and has CD4 count >350 9. Known active hepatitis B or C infection (subjects with history of hepatitis C infection but negative hepatitis C virus polymerase chain reaction[(PCR] test and subjects with JNJ42756493 (Erdafitinib) hepatitis B with positive hepatitis B surface antibody are allowed) 10. Not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, Grade 1 neuropathy, Grade 1-2 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 4 weeks before randomization 13. 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 poorly controlled diabetes (hemoglobin A1c >8), or ongoing active infection requiring intravenous antibiotics
For Cohort 1 Subjects 14. Depending on the chemotherapy regimen to be used at the participating site, 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 polyoxyethylated castor oil, or to vinflunine or other vinca alkaloids
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), 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Brazil |
Canada |
China |
France |
Germany |
Greece |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Netherlands |
Portugal |
Russian Federation |
Spain |
Taiwan |
Turkey |
Ukraine |
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 |