| 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)
Tertiary objectives are:
-Patient-reported outcome (PRO)
-Evaluate biomarkers to investigate the drug (i.e. mode-of-action-related effect and/or safety) and/or the pathomechanism of the disease.
-Pharmacokinetics |
|
| 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. Mandatory FGFR testing of patients will be performed prior to start of screening (signing of ICF 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.
-Ability to understand and signing of the written patient information/informed consent form (PI/ICF) for FGFR testing
-Male or female patients ≥ 18 yrs 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:
-Histologically confirmed. Patients with mixed histologies are required to have a dominant transitional cell pattern.
-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 / 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 mths 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.
-Adequate laboratory and organ function:
- Absolute neutrophil count (ANC) ≥ 1,500/mm3
- Platelet count ≥100,000/mm3
- Hemoglobin ≥9.0 g/dL (without transfusion or erythropoietin within 4 weeks before randomization).
- Total bilirubin ≤1.5 times the upper limit of normal (ULN). Known Gilbert syndrome is allowed if total bilirubin is ≤ 3 x ULN.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN for patients with liver involvement of their cancer).
- Alkaline phosphatase limit ≤2.5 x ULN (≤5 x ULN for patients with liver and bone involvement of their cancer).
- Lipase <2 x ULN
- Glomerular filtration rate (GFR) ≥30 mL/min/1.73 m2 according to MDRD abbreviated formula.
- International normalized ratio (INR) ≤1.5 x ULN, and partial thromboplastin time (PTT) or activated PTT (aPTT) ≤1.5 x ULN. Patients being treated with anticoagulant, e.g. warfarin or heparin, will be allowed to participate provided no prior evidence of an underlying abnormality in these parameters exists. Close monitoring of at least weekly evaluations will be performed until INR is stable based on a pre-dose measurement as defined by the local standard of care.
-Women of childbearing potential (WOCBP) and fertile men must agree to use adequate contraception when sexually active from signing of ICF for study treatment eligibility until at least 6 months after the last study drug administration of rogaratinib or vinflunine and until at least 6 mths for docetaxel or paclitaxel. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control. Highly effective (failure rate of less than 1% per year) contraception methods include:
- Combined (estrogen and progesterone containing: oral, intravaginal, transdermal) and progesterone-only (oral, injectable, implantable) hormonal contraception associated with inhibition of ovulation.
- Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
- Bilateral tubal occlusion or vasectomized partner (provided that partner is the sole sexual partner and has received medical assessment of the surgical success).
- Sexual abstinence (reliability to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient).
- Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Male patients with a female partner of childbearing potential must use a condom and ensure that an additional form of contraception is also used during treatment and until at least 6 months after last study drug administration.
Genetic consultation is recommended if the patient wishes to have children after ending the treatment with chemotherapy or rogaratinib. These treatments could affect male fertility; therefore fertility preservation (sperm conservation) should be considered before starting treatment with the study drug.
-Negative serum pregnancy test in women of childbearing potential (performed within 7 days before randomization). Negative results must be available prior to study drug administration. |
|
| E.4 | Principal exclusion criteria |
•Previous or concurrent cancer except cervical carcinoma in situ, treated basal-cell or squamous cell skin carcinoma, any cancer curatively treated >3 yrs before randomization or curatively treated incidental prostate cancer (T1/T2a)
•Active symptomatic or untreated brain metastases as determined by CT / MRI evaluation during screening & prior radiographic assessment. Patients with treated asymptomatic CNS metastases are eligible, provided they meet all following criteria:
-evaluable / measurable disease outside CNS
-no metastases to midbrain, pons, medulla, cerebellum or within 10mm of optic apparatus (optic nerves & chiasm)
-no history of intracranial or spinal cord hemorrhage
-no evidence of significant vasogenic edema
-anticonvulsants at stable dose are allowed
-no stereotactic radiation, whole-brain radiation or neurosurgical resection within 12 wks before the first study drug administration
-radiographic demonstration of interim stability between completion of CNS-directed therapy & screening radiographic study
-screening CNS radiographic study ≥4 wks since completion of radiotherapy / surgical resection
Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that dose is stable for 1 mth prior to and following screening radiographic studies)
•Known HIV infection
•Renal dialysis
•Any malabsorption condition
•Breast-feeding
•Ongoing / previous treatment with anti-FGFR directed therapies or with taxanes / vinflunine
•More than 2 prior lines of systemic anti-cancer therapy for urothelial carcinoma given for advanced unresectable/metastatic disease
•Ongoing / previous anti-cancer treatment within 4 wks before randomization:
-Patients who have received prior treatment with anti-CTLA-4 may be enrolled provided at least 5 half-lives (approx. 75 days) have elapsed before randomization
-Prior cancer vaccines and cellular immunotherapy are permitted
-Previous radiotherapy is acceptable under the following conditions:
-Therapeutic radiotherapy ≥3 wks before the baseline tumor scan
-Palliative radiotherapy for bone metastases / soft tissue lesions allowed & should be completed >7 days prior to baseline tumor scan
-Lesions at site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease
•Anti-cancer therapy: any agent / combination of agents with clinically proven anti-tumor activity, including immunotherapy administered by any route with the purpose of affecting the malignancy, either directly or indirectly, including palliative and therapeutic endpoints
•Use of strong inhibitors and inducers of CYP3A4 should have been stopped 2 wks before randomization
•Concomitant therapies that are known to increase serum calcium or phosphate levels and cannot be discontinued or switched to different medication before randomization
•Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in study / evaluation of study results.
•Major surgery / significant trauma within 4 wks before randomization
•Unresolved toxicity higher than National Cancer Institute’s CTCAE v.4.03 Grade 1 attributed to any prior therapy/procedure excluding alopecia, anemia and/or hypothyroidism
•History / current condition of uncontrolled cardiovascular disease including any of the following conditions:
-CHF NYHA > Class 2
-Unstable angina (symptoms of angina at rest) or new-onset angina
-MI within past 6 mths before randomization
-Unstable cardiac arrhythmias requiring anti-arrhythmic therapy. Patients with arrhythmia under control with anti-arrhythmic therapy such as beta-blockers /digoxin are eligible
•Arterial or venous thrombotic events or embolic events e.g cerebrovascular accident (including transient ischemic attacks), DVT or pulmonary embolism within 3 mths before randomization
•Current evidence of endocrine alteration of calcium phosphate homeostasis
•Current diagnosis of any retinal detachment, RPED, serous retinopathy / retinal vein occlusion
•Active infection with hep. B or C, requiring treatment. Note: prophylactic antiviral treatment against reactivation of chronic hep. B (e.g. entecavir) is allowed
•Active infections (≥ CTCAE v.4.03 Grade 3)
•Evidence or history of bleeding diathesis / coagulopathy
•Any hemorrhage / bleeding event ≥ CTCAE v.4.03 Grade 3 within 4 wks before randomization.
•Seizure disorder requiring therapy
•Serious, non-healing wound, ulcer / bone fracture
•Any condition that is unstable or could jeopardize the safety of the patient and his/her compliance in the study
•Inability to swallow oral medications
•Known hypersensitivity to any of the study drugs, study drug classes or excipients in formulation
•Previous assignment to study treatment during this study
•Investigational drug treatment outside of this study during or within 4 wks before randomization
•Close affiliation with investigational site
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall survival (defined as the time from randomization until death from any cause) will be considered an exploratory efficacy variable for the Phase 2, since the Phase 3 part of the study will no longer be conducted.
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 casue. Patients alive at the date of data cut-off for analysis will be censored at the last date knwn to be alive.
he primary efficacy variable of Phase 2 is ORR, and will be analyzed based on central review assessment. Although OS is the primary variable originally planned for the Phase 3 part of this study, it is considered an exploratory efficacy variable for the Phase 2 part. The analysis will be performed when survival data is considered adequate for analysis by the
sponsor. |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy variables include PFS, DCR and DOR based on independent central review assessments.
Secondary efficacy variables including progression-free survival (PFS), disease control rate (DCR) and duration of response (DOR) will be analyzed based on final database.
Summary of adverse events (AEs) is considered as a secondary variable objective for the study.
PRO data as measured by the EORTC QLQ-C30 and EQ-5D will be analyzed to assess differences in health-related Quality of Life (HRQoL) and health utility values between treatment arms based on time-adjusted Area Under the Curve (AUC) using all available data.
Patients’ biomarker status at baseline will be correlated with treatment effect in OS, PFS and response to explore which biological targets may be particularly important in defining the appropriate therapeutic population for the agent. Biomarker analyses and results will be provided in a separate report.
Pharmacokinetic variables
The samples collected on Day 1 of Cycles 1 through 5 at pre-dose and between 0.5 and 1.5 hours post-dose will document a longitudinal exposure under steady state condition. The longitudinal exposure data will be used in exposure-response modelling of adverse events and clinical responses. Evaluation of the data described above will be presented in a separate report. In the clinical study report, only plasma concentration data for all analytes will be listed. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy variables 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 | 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 | 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.
LPLV is the last patient's last active follow-up visit |
|
| 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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