| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic non-clear cell renal carcinoma |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050076 |
| E.1.2 | Term | Metastatic renal carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
| Primary objective of the study is to demonstrate a statistical significant difference between the two arms in progression free survival (PFS) measured from randomisation until progression or death, whichever occurs first. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are the characterization of objective response, Tolerability/Safety, One Year Rate of Progression Free Survival (1YPFSR) and overall survival (OS) on both treatment arms and the comparsion of the two arms. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Identification of predictive biomarkers in patients with metastatic disease receiving Torisel therapy
The aim of the biomarker program is the identification of molecular markers which allow the prediction of therapy response as well as an early detection of therapy resistance in patients with non-clear cell renal cell carcinoma (RCC). For that, different studies on tumor tissues and blood samples are planed.
(a) Identification of predictive markers in tumor tissue
A tissue microarray (TMA) will be constructed from paraffin blocks from primary tumors for analysis of components of the mTOR-pathway.
Furthermore, protein profiling on fresh tumor tissue will be performed in cases were fresh tissue is available.
(b) Identification of predictive markers in serum
Protein profiling by using SELDI-TOF-MS will be performed on serum samples in order to identify specific protein patterns which are associated with clinical response and resistance. From these protein signatures most significant proteins have to be identified and to test for routine diagnostics. For this part, it is necessary to collect blood samples before therapy and at time points of clinical visit for restaging (every 3 month).
|
|
| E.3 | Principal inclusion criteria |
1.Adult males and females: ≥ 18 years of age.
2.Locally advanced or metastatic, histological confirmed, non-clear cell RCC of all subtypes. Patients must have advanced non-clear cell of one of the following subtypes: papillary, chromophobe, collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), or unclassified.
3.Patients with measurable disease (at least one uni-dimensionally measurable target lesion by CT-scan or MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) If prior palliative radiotherapy to metastatic lesions: ≥ 1 measurable lesion that has not been irradiated.
4.PS 0-2 ECOG
5.Signed written informed consent.
6.White blood cell count (WBC) ≥ 4x10*9/L with neutrophils ≥1.5 x 10*9/L, platelet count ≥100x10*9/L, hemoglobin ≥9 g/dL.
7. Total bilirubin < 2 x upper limit of normal.
8. AST and ALT <2.5 x upper limit of normal, or <5 x upper limit of normal in case of liver metastases.
9.Serum creatinine <2.0 x upper limit of normal.
10.Normal ECG without QT prolongation (QTc < 450 msec ).
11.Adequate cardiac function (left ventricular ejection fraction > 40% as assessed by ECHO.
|
|
| E.4 | Principal exclusion criteria |
1.Predominant clear-cell RCC
2.Resectability or other curative options
3.Any investigational drug within the 30 days before inclusion.
4.Prior systemic treatment for their RCC.
5.Known or suspected allergy or hypersensitivity reaction to any of the components of study treatments.
6.Radiotherapy within the last 4 weeks.
7.Pregnancy (absence to be confirmed by beta-hCG test) or lactation period.
8.Men or women of child-bearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial.
9.Clinically symptomatic brain or meningeal metastasis. (known or suspected)
10.Cardiac arrhythmias requiring anti-arhythmics (excluding beta blockers or digoxin).
11.History of any of the following cardiac events within the past 6 months:
• myocardial infarction (including severe/unstable angina),
• coronary/peripheral artery bypass graft,
• congestive heart failure (CHF),
• cerebrovascular accident,
• transient ischemic attack,
• pulmonary embolism.
12.hemorrhage ≥ grade 3 within the past 4 weeks
13.Uncontrolled severe hypertension (failure of diastolic blood pressure to fall below 90 mm Hg despite the use of ≥3 anti-hypertensive drugs
14.History of relevant pulmonary hypertension or interstitial lung disease.
15.Acute or sub-acute intestinal occlusion or history of inflammatory bowel disease or chronic diarrhea
16.Previous malignancy (other than renal cancer cancer) in the last 5 years except basal cell cancer of the skin, pre-invasive cancer of the cervix or superficial bladder tumor [Ta, Tis and T1].
17.History of organ allograft
18.Significant disease which, in the investigator`s opinion would exclude the patient from the study
19.Patients with seizure and epileptic disorder or other conditions requiring medication (such as phenytoin, carbamazepin, phenobarbital)
20.Patients under strong inducers or inhibitors to CYP Isoenzymes
21.Patients with hypersensitivity to the antihistamine or patients who cannot receive the antihistamine for other medical reasons
22.Patients requiring long-term cortisone therapy (replacement doses of corticosteroids and topical/inhaled corticosteroids are allowed)
23.Patients requiring oral anticoagulation treatment, such as marcoumar. (Anticoagulation treatment with heparin or low molecular weight heparin [LMWH] is allowed provided that close monitoring is performed).
24.Surgery within 2 weeks prior to randomization
25.HIV seropositivity.
26.Abnormal pulmonary function (DLCO < 50%).[Pulmonary function tests need only to be performed if abnormal pulmonary function present in medical history].
27.Poorly controlled diabetes mellitus.
28.Liver cirrhosis, chronic hepatitis
29.Legal incapacity or limited legal capacity
30.Known alcohol or drug abuse.
31.Medical or psychological conditions that would not permit the patient to complete the study or sign informed consent.
32. Current fistula formation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS: progression free survival (PFS) measured from randomization until progression or death, whichever occurs first. PFS is censored at the last time point of tumor assessment where the patient was SD or better if that patient dropped out between two scheduled assessment time points. |
|
| 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) | 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 | 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | No |
| 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
| |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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