| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First-Line Treatment in Subjects with Advanced Renal Cell Carcinoma |
|
| MedDRA Classification |
| 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 independently assessed progression free survival of subjects with clear cell type renal cell carcinoma (all risk groups) treated with bevacizumab + temsirolimus (experimental) versus bevacizumab + interferon-alfa (control) in subjects with advanced renal cell carcinoma. |
|
| E.2.2 | Secondary objectives of the trial |
Safety
Investigator assessed progression free survival
Objective response rate (CR + PR) per RECIST (independently assessed)
Overall survival
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects greater than or equal to 18 years.
2. Subject with histologically and/or cytologically confirmed, advanced (stage IV or recurrent) RCC, for whom a majority component of conventional clear-cell type is mandatory. (Subjects with predominantly papillary or sarcomatoid features, and subjects with chromophobe, oncocytoma, collecting duct tumors, Bellini tumors or transitional cell carcinoma are not allowed.)
3. At least 1 measurable lesion (per RECIST).
4. Karnofsky Performance Status greater than or equal to 70.
5. Screening laboratory values within the following parameters:
ANC: > or equal to 1.5 x 109/L (1500/mm3)
Platelet count: > or equal to 100 x 109/L (100,000/mm3)
Hemoglobin: > or equal to 8.0 g/dL (80g/L) without transfusion within 2 weeks of first dose of test article
Serum creatinine < or equal to 1.5 x upper limit of normal (ULN)
Total bilirubin < or equal to 1.5 x upper limit of normal (ULN)
AST and ALT < or equal to 2.5 x upper limit of normal (ULN) [< or equal to 5 x upper limit of normal (ULN) with liver metastases]
Fasting serum cholesterol < or equal to350 mg/dL (9.0 mmol/L)
Fasting serum triglycerides < or equal to 400 mg/dL (4.56 mmol/L)
HgbA1c < 10% (optimal therapy permitted)
INR and PTT < or equal to 1.5 (Anticoagulation is allowed if target INR <3 and INR is therapeutic on a stable dose of a coumarin type anticoagulation, or if the subject is on a stable dose of LMW heparin for >2 weeks at time of randomization.)
6. QTc interval < or equal to 450 msec for males and < or equal to 470 msec for females.
7. Life expectancy of at least 12 weeks.
8. Signed and dated institutional review board (IRB) or independent ethics committee (IEC) approved informed consent form before any protocol-specific screening procedures
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|
| E.4 | Principal exclusion criteria |
1. Prior systemic treatment for RCC in the neoadjuvant, adjuvant or metastatic setting. Prior treatment with bevacizumab, temsirolimus, sirolimus, IFN, sunitinib or sorafenib, for any indication.
2. Evidence of current or prior central nervous system (CNS) metastases or any imaging abnormality indicative of CNS metastases or spinal cord compression.
3. Major surgery (incl. open biopsy) or radiation therapy within 28 days prior to randomization. (Palliative radiotherapy to painful bone lesions is allowed within 14 days prior to randomization). Subject must have recovered from prior surgery and radiation.
4. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to randomization.
5. Significant cardiovascular disease defined as congestive heart failure (NYHA Class II, II, or IV), angina pectoris requiring nitrate therapy, or myocardial infarction within the last 6 months;
6. Inadequately controlled hypertension (defined as a blood pressure of > or equal to 150 mmHg systolic and/or > or equal to 100 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy.
7. History of stroke or transient ischemic attack within 6 months prior to randomization
8. Significant vascular disease (e.g., aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease
9. Known congenital long QT syndrome, history of torsades de pointes or ventricular tachycardia.
10. Known pulmonary hypertension or pneumonitis.
11. More than 1 episode of DVT/PE within the last 6 months.
12. Evidence or history of bleeding diathesis or coagulopathy.
13. Chronic daily aspirin >325 mg/day or clopidogrel (>75 mg/day)
14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization
15. Any of the following serious, non-healing conditions: wound, ulcer, or bone fracture
16. Proteinuria at screening as demonstrated by either:
- Urine dipstick > or equal to 2+ (subjects discovered to have a > or equal to 2+ proteinuria on dipstick urinalysis at baseline should undergo 24-hour urine collection and must demonstrate < or equal to 1g of protein in 24 hours to be eligible.
- 24-hour urine collection demonstrates > or equal to 1g of protein in 24 hours.
17. 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 [anti HCV] with confirmatory testing. Note: Testing is not mandatory to be eligible for the study.)
18. Chronic treatment with corticosteroids (prednisone > or equal to 12.5 mg/day or dexamethasone > or equal to 2 mg/day) excluding inhaled steroids.
19. Pregnant or nursing women, women of childbearing potential not using a medically acceptable contraceptive method, or men not using a medically acceptable contraceptive method with partners of childbearing potential. A woman of childbearing potential is defined as a woman who is biologically capable of becoming pregnant. Subjects (men and women) must agree to use medically accepted contraceptive methods for 12 weeks after the last dose of study drug.
20. Known hypersensitivity to any component of the test articles or excipients, or documented medical condition that would prohibit adequate pre-medication with antihistamine.
21. Current active second malignancy other than non-melanoma skin cancers and clinically localized prostate cancer. Subjects are not considered to have a currently active malignancy if they have completed anti-cancer therapy and are disease-free at least 5 years.
22. Any other significant medical illness, 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 subjects participation in the study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective of this study is a comparison of independently assessed progression free survival (PFS) of subjects with clear cell type renal cell carcinoma (all risk groups) treated with bevacizumab + temsirolimus (experimental arm) versus bevacizumab + IFN (control arm) in subjects with advanced renal cell carcinoma. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Information not present in EudraCT |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Exploratory: Health outcomes: EQ-5D and FKSI-15 |
|
| 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 | 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 | 19 |
| 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 | 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
|
| The end of the study is the death (or withdrawal of consent) of the last subject, or when the sponsor decides to terminate the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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