E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Renal Cell Carcinoma |
|
E.1.1.1 | Medical condition in easily understood language |
|
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 | PT |
E.1.2 | Classification code | 10050513 |
E.1.2 | Term | Metastatic renal cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 compare the progression-free survival (PFS) of subjects with refractory advanced renal cell carcinoma (RCC) randomized to treatment with tivozanib hydrochloride (tivozanib) or sorafenib as assessed by blinded independent radiological review (IRR) of computerized tomography (CT) or magnetic resonance imaging (MRI). |
|
E.2.2 | Secondary objectives of the trial |
To compare the overall survival (OS) of subjects randomized to treatment with tivozanib or sorafenib. To compare objective response rate (ORR) and duration of response (DoR) of subjects randomized to treatment with tivozanib or sorafenib. To compare the safety and tolerability of tivozanib and sorafenib. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. ≥ 18-years of age. 2. Subjects with recurrent metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib. 3. Subjects must have recovered from the AEs of prior therapy or returned to baseline. Controlled AEs such as hypothyroidism or hypertension are permitted. 4. Histologically or cytologically confirmed RCC with a clear cell component (subjects with pure papillary cell tumor or other non-clear cell histologies, including collecting duct, medullary, chromophobe and unclassified RCC are excluded). 5. Measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Life expectancy ≥ 3 months. 8. If female and of childbearing potential, documentation of negative pregnancy test prior to enrollment. 9. Ability to give written informed consent and comply with protocol. |
|
E.4 | Principal exclusion criteria |
1. Prior treatment with sorafenib or tivozanib. 2. More than 3 prior regimens for metastatic RCC. 3. Known central nervous system (CNS) metastases other than stable, treated brain metastases. Subjects with previously treated brain metastasis will be allowed if the brain metastasis has been stable by neuroimaging without steroid treatment for at least 3 months following prior treatment (radiotherapy or surgery). 4. Significant cardiovascular disease 5. Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug 6. Significant bleeding disorders 7. Currently active second primary malignancy 8. Pregnant or lactating females.
Participation in another interventional protocol. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
• To compare the PFS of subjects dosed with tivozanib with those subjects dosed with sorafenib. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analysis will be done at the time of the final PFS analysis. |
|
E.5.2 | Secondary end point(s) |
• To compare the OS between the 2 treatment arms by using stratified Log-rank test and the stratification factors included in the primary analysis. • To analyze OS, ORR, and DoR using the investigator and independent radiological review assessments. (Starting with version 5 of the protocol, all clinical response decisions will be based on local radiological review.)
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The first interim OS analysis (conducted in October 2018) occurred at the Primary PFS analysis with 183 OS events (70% information fraction) observed with alpha spending of 0.007. The second interim analysis occurred when all subjects had been on-study for at least two years (August 15, 2019), with 86% information fraction observed with 0.014 cumulative alpha spent at this time. The final OS analysis will occur on May 1, 2020 based on an estimate of approximately 4 OS events occurring per month (or approximately 263 OS events at that time). |
|
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 128 |
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 |
Belgium |
Canada |
Czech Republic |
Denmark |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
United Kingdom |
United States |
|
E.8.7 | Trial has a data monitoring committee | No |
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
|
End of the trial - when all subjects have been lost to follow-up, have withdrawn consent, or have died, or when all subjects in follow-up have been on-study for at least 2 years, whichever occurs first. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |