E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
advanced or therapy refractory breast cancer, endometrial cancer, or ovarian cancer. |
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MedDRA Classification |
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 |
The primary objective of this Phase 1b study is to identify the maximum tolerated dose (MTD) and recommended phase II dose of the combination of temsirolimus and Caelyx® in patients with advanced or therapy refractory breast cancer, endometrial cancer, or ovarian cancer. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety and toxicity profile. To assess the pharmacokinetic profile of the combination of temsirolimus and PLD. To assess the anti tumour activity of the combination of temsirolimus and PLD. To assess the early effect on tumor metabolism by FDG-PET (baseline, after 2 and 6 weeks) To assess the effects on regulatory T cells, the IGF pathway and on circulating tumour cells (CTCs) and circulating endothelial cells (CECs).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Patients with proven advanced breast cancer, endometrial cancer or ovarian cancer, who are refractory to standard therapies or for whom no standard therapy exists. •Age ≥ 18 years •Patients who have an ECOG status of 0 or 1 •Patients who have a life expectancy of at least 12 weeks •Negative pregnancy test for female patients of childbearing potential •Signed informed consent
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E.4 | Principal exclusion criteria |
•Adequate bone marrow: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L and haemoglobin ≥ 5.0 mmol/l •Adequate renal function: GFR ≥ 60 ml/min •Adequate liver function: ALT and AST < 2.5 x ULN, total bilirubin ≤ 1x ULN •Fasting level of total cholesterol of no more than 350 mg/dL (9.1 mmol/L) and triglyceride level of no more than 400 mg/L (4.5 mmol/L) •Left ventricular ejection fraction (LVEF) < 50% •History of serious cardiac disease •Active clinically serious bacterial, viral or fungal infections (> grade 2). •Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C •Clinically symptomatic brain or meningeal metastasis. Patients with seizure disorders requiring medication (such as steroids or antiepileptics). Concomitant treatment with strong CYP3A4 inductors (such as rifampicin, St. John´s Wort) or CYP3A4 inhibitors (such as ketoconazole, voriconazole, itraconazole, diltiazem, verapamil, erythromycin) within 2 weeks prior to start. •Moderate or weak CYP3A4 modifiers should be used concomitantly only after careful assessment of risk-benefit ratio. Concomitant use of carbamazepine, phenobarbital, phenytoin or chronic use of dexamethasone is not allowed. (Table 1) •Other concomitant anti-cancer therapy (except steroids) •Concomitant use of streptozocin, mercaptopurine. •Previous treatment with one of the study drugs. •Previous treatment with other mTOR inhibitors •Prior investigational therapy/agents within 4 weeks of start, in case of bevacizumab at least 60 days between bevacizumab discontinuation and first dosing of temsirolimus. •Surgical treatment or radiation therapy in the past 4 weeks. Palliative radiotherapy at focal sites on the extremities is allowed, also within 4 weeks before start •Unresolved toxicity CTC ≥ grade 2 from previous anti-cancer therapy except alopecia. •Known or suspected allergy to any investigational agent or any agent given in association with this trial. •Substance abuse, medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results •Any condition that is unstable or which could jeopardize the safety of patient and his compliance in the study. •Antracyclines: > 450 mg/m2 doxorubicin or and > 600 mg/m2 epirubicin •Medications known to have dysrhythmic potential is not permitted (ie, terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide) •Usage of coumarin-derivate anticoagulants. Low molecular weight heparin is permitted and advised.
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E.5 End points |
E.5.1 | Primary end point(s) |
Maxiumum tolerated dose for the combination of temsirolimus and PLD. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
first combination of temsirolimus and PLD in humans |
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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 | No |
E.8.1.1 | Randomised | No |
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) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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
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Provided in the protocol. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 15 |