| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
mRNA FGF receptor 1 and 3 positive locally advanced or metastatic
urothelial carcinoma progressed after prior platinum-containing
chemotherapy |
|
| E.1.1.1 | Medical condition in easily understood language |
Locally advanced or metastatic bladder cancer with a high amount
of specific cell growth factor receptors 1 and 3 (FGFR1 and 3) in the
tumor
cells |
|
| 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 | 10064467 |
| E.1.2 | Term | Urothelial carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary objective of this trial is to demonstrate the superiority of rogaratinib over chemotherapy in
terms of prolonging overall survival of urothelial carcinoma patients with
FGFR positive tumors.
The objective for the Phase 2 part of the study is to demonstrate the efficacy of rogaratinib over chemotherapy in terms of objective response rate of urothelial carcinoma patients with FGFR positive tumors. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objective of this trial is to evaluate additional efficacy including the following variables:
Progression-free survival (PFS)
Objective response rate (ORR)
Disease control rate (DCR)
Duration of response (DOR)
and to evaluate the safety of rogaratinib (adverse events) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Existence of archival or fresh biopsy for FGFR testing. Mandatory FGFR testing of patients will be performed prior to start of screening (signing of informed consent for study treatment eligibility). The timing of the FGFR test is at the discretion of the investigator. Investigators should ensure all patients will be eligible in terms of disease status and lines of treatment.
- Male or female patients ≥ 18 years of age (at least age of legal maturity).
- Documented urothelial carcinoma (transitional cell carcinoma) including urinary bladder, renal pelvis, ureters, urethra, meeting all of the following criteria:
o Histologically confirmed. Patients with mixed histologies are required to have a dominant transitional cell pattern.
o Locally advanced (T4, any N; or any T, N 2−3) or metastatic disease (any T, any N and M1). Locally advanced bladder cancer must be unresectable i.e. invading the pelvic or abdominal wall (stage T4b) or presenting with bulky nodal disease (N2-3).
- ECOG Performance Status of 0 or 1.
- Disease progression during or following treatment with at least one platinum-containing regimen (patients should have been treated for at least 2 cycles). In patients who received prior adjuvant/neoadjuvant platinum-containing chemotherapy, progression had to occur within 12 months of treatment.
- High FGFR1 or 3 mRNA expression levels in archival or fresh tumor biopsy specimen quantified as outlined in the lab manual.
- At least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) in contrast enhanced (unless contraindicated) CT or MRI |
|
| E.4 | Principal exclusion criteria |
- Previous or concurrent cancer except
o cervical carcinoma in situ
o treated basal-cell or squamous cell skin carcinoma
o any cancer curatively treated > 3 years before randomization
o curatively treated incidental prostate cancer (T1/T2a)
- Ongoing or previous anti-cancer treatment within 4 weeks before randomization.
- More than two prior lines of systemic anti-cancer therapy for urothelial carcinoma given for advanced unresectable/metastatic disease.
- Ongoing or previous treatment with anti-FGFR directed therapies (e.g. receptor tyrosine kinase inhibitors including rogaratinib or FGFR-specific antibodies) or with taxanes or vinflunine
- Unresolved toxicity higher than National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.03 (CTCAE v.4.03) Grade 1 attributed to any prior therapy/procedure excluding alopecia, anemia and/or hypothyroidism.
- History or current condition of an uncontrolled cardiovascular disease including any of the following conditions:
o Congestive heart failure (CHF) NYHA > Class 2.
o Unstable angina (symptoms of angina at rest) or new-onset angina (within last 3 months before randomization).
o Myocardial infarction (MI) within past 6 months before randomization.
o Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers or digoxin are eligible.
- Arterial or venous thrombotic events or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before randomization.
- Current evidence of endocrine alteration of calcium phosphate homeostasis (e.g. parathyroid disorder, history of parathyroidectomy, tumor lysis, tumoral calcinosis, paraneoplastic hypercalcemia).
- Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 weeks before randomization.
- Current diagnosis of any retinal detachment, retinal pigment epithelial detachment (RPED), serous retinopathy or retinal vein occlusion.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall survival
Overall survival was the primary efficacy variable of the originally planned Phase 3 part. Due to the stop of enrollment, the study will not move forward to its Phase 3 and will remain as Phase 2. Objective response rate (ORR) is the primary efficacy variable for the Phase 2 part. The study will remain open until the survival data is considered adequate for analysis by the sponsor.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Overall Survival (OS): Defined as the time (days) from randomization to death due to any cause. Patients alive at the date of data cut-off for analysis will be censored at the last date known to be alive. |
|
| E.5.2 | Secondary end point(s) |
1. Progression-free survival (PFS)
2. Objective response rate (ORR)
3. Disease-control rate (DCR)
4. Duration of response (DOR)
5. Incidence of Adverse Events as a measure of safety and tolerability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary efficacy variables including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) will be analyzed based on final database. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | 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 | Yes |
| 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 | 2 |
| 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 | 107 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| 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 |
| China |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Hong Kong |
| Hungary |
| Ireland |
| Israel |
| Italy |
| Japan |
| Korea, Democratic People's Republic of |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Singapore |
| Slovakia |
| Spain |
| Sweden |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last patient for all centers in the respective country has occurred.
The end of the study as a whole will be reached when the last visit of the last patient has been achieved in all participating centers (EU and non-EU), or the primary completion event has been reached, whichever comes later. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 11 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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