| 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 | No |
| 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.
To compare the efficacy, as measured by PFS (determined by 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)
 OS
 SD at 12, 24, and 36 weeks
 Duration of response
 Best/maximum tumor shrinkage in target lesions |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of mRCC (regardless of 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 a minimum of 1 six-week cycle of sunitinib therapy.
2. At least 2 weeks since prior treatment with sunitinib, palliative radiation therapy, and/or surgery and resolution of all toxic effects of prior therapy according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE, version 3.0) Grade 1.
3. At least 1 measurable lesion that can be accurately measured in at least 1 dimension with the longest diameter (LD)  10 mm when measured by spiral computerized tomography (CT) (5-mm slice thickness contiguous) or  20 mm when measured by conventional CT (10-mm slice thickness contiguous). The lesion must be  2 times the size of the slice thickness per RECIST criteria.
4. Age ≥ 18 years.
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) without transfusion within 28 days before randomization
 Serum creatinine  2.0 x upper limit of normal (UNL)
 Total bilirubin  1.5 x ULN
 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)  3 x ULN (5  ULN if liver metastases are present)
 Fasting serum cholesterol  2.0 x ULN (therapy permitted)
 Fasting serum triglycerides  2.0 x ULN (therapy permitted)
 Fasting glycosolated hemoglobin A1c (HbA1c) ≤ 9% (therapy permitted)
 Corrected serum calcium  1.5 x ULN (corrected calcium = total calcium – 0.707 [albumin – 3.4 g/dL]. If a laboratory reports total calcium in mmol/L, results should be converted to mg/dL using 0.249 as conversion factor
 Partial thromboplastin time within normal limits (WNL)and international normalized ratio or prothrombin time or prothrombin activity < 1.3 x ULN
 Amylase and lipase  1.5 x ULN
 Sensitive thyroid stimulating hormone (sTSH)  5 x ULN
 Serum magnesium  0.41 mmol/L (1.0 mg/dL) (therapy permitted)
 Serum phosphorus  0.78 mmol/L (2.5 mg/dL) (therapy permitted)
 Serum uric acid  588 mcmol/L (10 mg/dL) (therapy permitted)

6. Adequate cardiac function (left ventricular ejection fraction ≥ 40%) as assessed by electrocardiogram (ECG), and either echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan as judged by the investigator and the sponsor’s medical monitor if abnormal.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
8. Ability to swallow whole sorafenib tablets.
9. Life expectancy of at least 3 months.
10. Signed and dated institutional review board (IRB) or independent ethics committee (IEC) approved informed consent form (ICF). |
|
| E.4 | Principal exclusion criteria |
1. History of a central nervous system (CNS) malignancy or metastatic disease to the CNS and subjects with a known, active CNS malignancy (primary or metastatic).
2. Subjects who do not have clear evidence of PD while receiving at least 1 six-week cycle of sunitinib therapy, but who discontinued therapy due to intolerance.
3. Bone only/non-measurable bone lesions as target lesions.
4. Any prior systemic therapy for 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 4 weeks before screening.
6. Not recovered from prior biopsy, surgery, traumatic injury, and/or radiation therapy, as judged by the investigator.
7. Nonhealing wound or ulcer.
8. Grade  3 hemorrhage within the past month.
9. Systolic blood pressure of > 160 mm Hg and/or diastolic pressure > 100 mm Hg (antihypertensive medications are permitted).
10. Unstable coronary artery disease, as judged by the investigator, or recent myocardial infarction (< 180 days).
11. American Heart Association class 3/4 heart disease.
12. QTc interval > 450 ms for men and > 470 ms for women and/or any ventricular arrhythmia and/or any uncontrolled atrial arrhythmia.
13. Receiving anticoagulation with warfarin (low dose warfarin for catheter patency is permitted). Low molecular weight (LMW) heparin is permitted.
14. HbA1c > 9% despite therapy.
15. Active ketonuria, urinary tract infection, or gross hematuria
 Urinalysis with  2+ proteinuria (approximately equivalent to 1 g/L or 100 mg/dL), any ketones, any leukocyte esterase, any nitrites, gross hematuria, or  1+ glucosuria (approximately equivalent to 1.46 mmol/L or 250 mg/dL)
16. Untreated, symptomatic hypothyroidism.
17. History of pulmonary hypertension or interstitial lung disease.
18. Receiving immunosuppressive agents within 4 weeks of the screening visit. Replacement doses of corticosteroids and topical/inhaled steroids are permitted.
19. Chronic viral/bacterial/fungal illnesses such as human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection. Subjects may be included if they are hepatitis B and/or hepatitis C antibody positive as long as they are hepatitis surface antigen negative and/or hepatitis C RNA negative, respectively.
20. Active infection(s), receiving active systemic antimicrobial therapy or serious intercurrent illness.
21. A “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 considered by their physician to be at less than 30% risk of relapse.
22. 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.
23. Refusal to use medically acceptable contraceptive methods for 3 months after the last dose of temsirolimus or sorafenib therapy.
24. Any other major illness that, in the investigator’s judgment, will substantially increase the risk associated with the subject’s participation in this study.
25. Known hypersensitivity to any of the components in the temsirolimus infusion or sorafenib product or other medical reasons for not being able to receive adequate premedication (antihistamine agents). |
|
| 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 | 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) | 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.8.3 |
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.8.6 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 | 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
| |
| 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 | 8 |
| 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 | 8 |
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