E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Renal cell carcinoma stage IV |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10038414 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10038414 |
E.1.2 | Term | Renal cell carcinoma stage IV |
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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 |
Phase 1: To assess the safety and tolerability of increasing doses of recombinant human Interleukin-21 (rIL-21), administered s.c. in a thrice weekly regimen, in combination with sunitinib 50 mg once daily (OD) p.o. administered according to manufacturer’s instructions (“4 weeks on 2 weeks off” schedule); to determine the maximum tolerated dose (MTD) in subjects with stage IV renal cell carcinoma (RCC). Phase 2a: To estimate the response rate of s.c. rIL-21 and sunitinib in combination, with reference to sunitinib alone, measured according to RECIST in subjects with stage IV RCC.
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E.2.2 | Secondary objectives of the trial |
Phase 1: to: -describe the pharmacokinetic responses in subjects treated with this regimen (rIL-21 and sunitinib).-assess if antibodies against recombinant human IL-21 are induced during therapy.-describe the pharmacodynamic responses in subjects treated with this regimen.-measure effects of this treatment regimen on tumour size according to Response Evaluation Criteria In Solid Tumours (RECIST) (if applicable). Phase 2a: to:-compare the safety profile of the combination treatment with that of sunitinib alone in terms of frequency of adverse events (incidence and severity).-describe the pharmacokinetic response in subjects treated with these regimens at steady state (rIL-21 and sunitinib).-describe the pharmacodynamic responses in subjects treated with these regimens.-estimate progression free survival in both treatment arms.-describe Health Related Quality of Life in both treatment arms.-assess if antibodies against recombinant human IL-21 are induced during therapy with rIL-21.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject.) 2. Histologically verified and surgically incurable stage IV RCC of clear cell type (clear cell type only required for phase 2a) 3.18 years of age or above 4.ECOG performance status of 0 or 1. Please refer to Appendix F. 5.Life expectancy of at least 3 months 6.0-2 risk factors according to Motzer criteria (favourable or intermediate risk) (1). Please be referred to Appendix D. 7.Prior resection of the primary tumour required 8.Full recovery from surgery for stage IV disease 9.Remaining measurable disease (according to RECIST) required for phase 2a only. Haematopoietic parameters: 10.White blood cell (WBC) higher/equal than 2.5 x 10 superscript 9/L 11.Absolute neutrophil count (ANC) higher/equal than 1.5 x 10 superscript 9/L 12.Platelet count higher/equal than 100 x 10 superscript 9/L 13.Haemoglobin higher/equal than 6.2 mmol/L 14.No signs of haemolytic anaemia 15.Serum creatinine less/equal than 177 μmol/L Hepatic parameters: 16.Bilirubin less/equal than 1.25 x upper limit of normal (ULN) 17.AST/SGOT less/equal than 2.5 x ULN 18.LDH less/equal than 2x upper limit of normal 19.Negative serologic testing for Hepatitis B and C 20. ALT ≤ 2.5 x ULN
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E.4 | Principal exclusion criteria |
1.Previous systemic treatment for stage IV disease 2. Rare histological subtypes of RCC (true papillary, collecting duct, sarcomatoid features), applies for phase 2a only 3.History of or active presence of auto-immune diseases (except vitiligo and treated pernicious anaemia) 4.History of any other active malignancy (except basal cell carcinoma of the skin and cervical cancer in situ) within five years prior to enrolment 5.Known chronic infectious disease including human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS) related illness 6.Any significant systemic disease which according to the Investigator could compromise the safety of the subject or interfere with the trial objectives 7.Concurrent treatment with systemic corticosteroids (topical or inhaled corticosteroid treatment is permitted) 8.Known or suspected allergy to trial products or related products 9.Previous participation in this trial (re-screening is allowed when agreed with the Local Trial Manager or the International Trial Manager) 10.Pregnant, breast-feeding, or the intention of becoming pregnant or not using adequate contraceptive measures (including country-specific adequate measures, if any). In Germany adequate contraception is: implants, injectables, combined oral contraceptives, hormonal IUD, sexual abstinence, or vasectomised partner. No specific requirements in the Netherlands. 11.The receipt of any investigational drug within 3 months prior to start on this trial (day 1) 12.The receipt of concomitant anti-coagulation therapy Low Molecular Weight (LMW) heparins allowed). 13.Cerebrovascular accident or transient ischemic attack within the last 12 months 14.Deep venous thrombosis or pulmonary embolism within the last 12 months Cardiac events within the last 12 months, such as: 15.Myocardial infarction 16.Severe/unstable angina 17.Coronary/peripheral artery bypass graft 18.Symptomatic congestive heart failure (CHF) Radiotherepy: 19. Radiotherapy within the last 4 weeks prior to start of treatment
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1: The primary endpoint for safety is observed toxicity to the combination of rIL-21 and sunitinib assessed using the US National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. DLT and MTD will be determined according to the criteria described in Section 11.11. Phase 2a: The primary endpoint for tumour response will be Objective Response Rate (ORR) as determined according to RECIST. An analysis will be performed when the last subject has completed the Main Trial (Week 28). Objective responses (CR and PR) will be confirmed after additionally 4 weeks and evaluated by independent and blinded radiologists. |
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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 | No |
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) | Yes |
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) | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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.8.3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
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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 | 1 |
E.8.9.1 | In the Member State concerned days | |
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 | 1 |