| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| First-Line Treatment in Subjects with Advanced Renal Cell Carcinoma |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038409 |
| E.1.2 | Term | Renal cell carcinoma NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 or red blood cell growth factors 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)
PT and PTT ≤1.5 x ULN (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.) If site only reports INR and not PT, then INR must be < 1.5.
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
|
|
| 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 up to 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. Cardiovascular disease defined as congestive heart failure (NYHA Class II, III, or IV), angina pectoris requiring nitrate therapy, or myocardial infarction within the last 6 months prior to randomization;
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 history of pulmonary hypertension or non-infectious interstitial pneumonitis.
11. More than 1 episode of DVT/PE within the last 6 months prior to randomization..
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 > 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.) However if a subject is at risk for having undiagnosed HCV (due to history of injection drug use or due to geographic location for example), testing at screening should be considered.
18. Chronic treatment with corticosteroids (prednisone > 12.5 mg/day or dexamethasone > 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 during the treatment phase and for 6 months after the last dose of bevacizumab.
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 prior to randomization. Subjects with a history of cervical CIS or
breast DCIS or breast LCIS are considered eligible provided they have completed definitive therapy..
22. Any other significant medical illness, medical condition 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.5.1.1 | Timepoint(s) of evaluation of this end point |
| Independently assessed Progression Free Survival (PFS) - every 8 weeks (Primary analysis ~ 472 Ind PFS). |
|
| E.5.2 | Secondary end point(s) |
Investigator Assessed PFS:
Interval from the date of randomization until the earlier date of progression or death, censored at the last tumor evaluation date. For analysis of the secondary endpoint, PFS as assessed by the investigator will be used. For subjects progressing early due to symptomatic deterioration PFS will be declared at the date of symptomatic deterioration.
Objective Response Rate:
Objective response rate is the proportion of subjects who achieve tumor response assessed by independent
radiologist during the study per RECIST. The ORR assessed by investigators will be evaluated as a supportive analysis.
Overall Survival:
Overall survival is defined |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety - every 4 weeks;
Investigator assessed Progression Free Survival (PFS), objective response rate - every 8 weeks;
Survival - every 8 weeks; |
|
| 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 | 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 |
| Exploratory: Health outcomes: EQ-5D and FKSI-15 |
|
| 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 | 3 |
| 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 |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Croatia |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Hungary |
| India |
| Italy |
| Korea, Democratic People's Republic of |
| Malaysia |
| Mexico |
| Netherlands |
| Poland |
| Portugal |
| Russian Federation |
| Serbia |
| Singapore |
| Slovakia |
| Slovenia |
| South Africa |
| Spain |
| Taiwan |
| Ukraine |
| United Kingdom |
| United States |
|
| 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 |
Print
