E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients With Advanced Renal Cell Carcinoma Who Have Failed First-Line Sunitinib Therapy |
|
MedDRA Classification |
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 | 10050513 |
E.1.2 | Term | Metastatic renal cell carcinoma |
|
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 |
To compare the safety and tolerability of temsirolimus and sorafenib when used as single agents in the second-line setting in subjects with advanced RCC who have failed prior first-line treatment with sunitinib due to progressive disease (PD). To compare the efficacy, as measured by PFS (determined by a centralized independent assessment), of temsirolimus and sorafenib when used as single agents in the second-line setting in subjects with advanced RCC who have failed prior first-line treatment with sunitinib. |
|
E.2.2 | Secondary objectives of the trial |
To examine additional efficacy endpoints including: - PFS by investigator assessment - Response rate (complete response [CR] and partial response [PR]) by Response Evaluation Criteria in Solid Tumors (RECIST) by independent assessment - OS - Proportion of subjects with PFS at 12, 24 and 36 weeks by independent assessment - Duration of response |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects ≥ 18 years. 2. Histologically confirmed diagnosis of mRCC (regardless of histologic or nephrectomy status) with well documented radiological progressive disease (PD) by RECIST criteria or clinical PD, as judged by the investigator while receiving first-line sunitinib therapy. Subjects must have received at least 1 cycle of sunitinib therapy (minimum of 4 weeks of continuous sunitinib therapy regardless of dose). 3. At time of randomization there must be at least 2 weeks since prior treatment with sunitinib, palliative radiation therapy, and/or surgery. 4. At the time of randomization there must be at least 1 measurable lesion per RECIST criteria. Lesions that have been previously irradiated or embolized cannot be selected as target lesions. Irradiated and embolized lesions can be monitored to assess progression as non-target lesions. 5. Screening laboratory values within the following limits: Absolute neutrophil count ≥1.5 x 109/L (1500/mL) Platelet count ≥100 x 109/L (100,000/mL) Leukocyte count ≥3 x 109/L (3000/μL) Hemoglobin ≥80g/L (8.0g/dL) within two weeks of randomization Serum creatinine less than or equal to 2.0 x ULN Total bilirubin less than or equal to 1.5 x ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 x ULN (less than or equal to 5 x ULN if liver metastases are present) Glycosylated hemoglobin A1c (HbA1c) ≤ 9% (hyperglycemia therapy permitted) Prothrombin time (PT) or international normalized ratio (INR), or prothrombin activity and partial thromboplastin time (PTT) ≤ 1.5 x ULN (Anticoagulation is allowed if the subject is on a stable dose of coumarin type anticoagulant or LMW heparin prior to randomization.) 6. Adequate cardiac function (left ventricular ejection fraction ≥ 40%) as assessed by either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan as judged by the investigator. 7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 8. Ability to swallow whole sorafenib tablets. 9. Life expectancy of at least 12 weeks. 10. Signed and dated institutional review board (IRB) or independent ethics committee (IEC) approved informed consent form (ICF) before any protocol specific screening procedures. |
|
E.4 | Principal exclusion criteria |
1. Metastatic CNS from RCC. 2. Subjects who discontinued therapy due specifically to intolerance. 3. Bone only lesions as target lesions. 4. Any prior systemic therapy for RCC/mRCC other than sunitinib. 5. Receiving known strong CYP3A4 isoenzyme inhibitors and/or inducers. Subjects taking CYP3A4 isoenzyme inhibitors and/or inducers not classified as strong are eligible, provided the subject has been on a stable regimen for at least one week prior to randomization. 6. Not recovered from prior biopsy, surgery, traumatic injury, radiation therapy and/or has a non-healing wound or ulcer, as judged by the investigator. 7. Grade ≥ 3 hemorrhage and/or treatment with transfusions within 2 weeks of randomization. 8. Inadequately controlled hypertension (defined as a blood pressure of > 150 mm Hg systolic and/or > 100 mm Hg diastolic on treatment. 9. Unstable coronary artery disease, as judged by the investigator, or recent myocardial infarction (< 180 days). 10. American Heart Association class 3/4 heart disease. 11. ECG QTc interval findings > 450 msec for men and > 470 msec for women and/or any uncontrolled clinically significant cardiac arrhythmia. 12. Active ketonuria, secondary to poorly controlled diabetes mellitus. 13. History of pulmonary hypertension or interstitial lung disease. 14. Receiving immunosuppressive agents within 28 days prior to randomization. Replacement doses of corticosteroids and topical/inhaled steroids are permitted. 15. Immunocompromised subjects, including known seropositivity for human immunodeficiency virus (HIV), or current or chronic hepatitis B and /or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus [anit HCV] with confirmatory testing). (Note: testing is not mandatory to be eligible for the study.) 16. Active infection(s), receiving active systemic antimicrobial therapy or serious intercurrent illness. 17. Currently active second malignancy other than non-melanoma skin cancers. Subjects are not considered to have a currently active malignancy if they have completed anticancer therapy and are disease-free at least 5 years. 18. Pregnant or nursing women, women who are of childbearing potential (biologically capable of becoming pregnant) who are not using a medically acceptable contraceptive method, or men who are not using a medically acceptable contraceptive method with partners of childbearing potential. 19. Refusal to use medically acceptable contraceptive methods for 3 months after the last dose of temsirolimus or sorafenib therapy. 20. Any other significant illness residual sunitinib toxicity or medically significant abnormal laboratory finding that would, in the investigator’s judgment, make the subject inappropriate for this study, or would increase the risk associated with the subject’s participation in this study. 21. Known hypersensitivity to any of the components of the test articles or documented medical condition that would prohibit adequate premedication with antihistamine. 22. Patients currently receiving and /or have received prior investigational drugs of vaccines (except sunitinib) within the past 30 days. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
PFS by independent assessment |
|
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 | No |
E.6.7 | Pharmacodynamic | No |
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 | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 | Information not present in EudraCT |
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 |
|
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
| |
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 | 2 |
E.8.9.1 | In the Member State concerned days | |
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 | 2 |