Open unicenter phase I trial of a combination therapy of temsirolimus and irinotecan in patients withglioblastoma or brain metastases of solid tumors
- Conditions
- C71Malignant neoplasm of brain
- Registration Number
- DRKS00000689
- Lead Sponsor
- niversitätsklinikum Essen
- Brief Summary
The objective of the phase I TEMIR trial (EudraCT: 2010-021899-28) was to determine the maximum tolerable doses (MTD) by dose-limiting toxicities (DLT) of combined administration of temsirolimus, an mTOR inhibitor, and irinotecan, a gastrointestinal malignancy agent, in patients with glioblastoma or brain metastases from solid tumors. TEMIR was an open-label, unicenter, nonrandomized phase I dose-finding study. Visits were weekly. Treatment was started with irinotecan administration, with irinotecan applied every two weeks. Starting on day 8, temsirolimus was applied weekly. The dose of temsirolimus was increased according to the "3+3" design. 27 patients with gliablastomas were treated in 7 different groups. The most common adverse events were fatigue, thrombocytopenia, diarrhea, leukopenia, neutropenia, and headache. The most common cause of study discontinuation was tumor progression (59%, N = 16). A total of 479 adverse events occurred, of which 45 were serious. All patients (N = 27) were affected by adverse events, and 20 patients (74.1%) were affected by serious adverse events. In 33.0% (N = 158) of the adverse events, the cause was suspected to be either irinotecan or temsirolimus or both. Irinotecan was discontinued or dose reduced in 8 cases, and temsirolimus was discontinued or dose reduced in 4 cases. DLTs occurred in 15% (N = 4) of patients. Causes of DLTs included grade 3 nonhematologic toxicities lasting more than 3 days (in N = 3 patients) and grade 4 neutropenia lasting more than 5 days. 81.4% of patients received more than 50% of the planned total medication, 48.1% more than over 90%. One of the 19 patients evaluated showed a partial response (PR) within the study, 7 patients were stable (SD) and 11 patients showed progression. The average treatment duration was 9.5 weeks (median 8 weeks). No significant difference was found between dosing groups. Median progression-free survival after RECIST was determined by the Kaplan-Meier method and was 62 days (95% confidence interval [52, 97]). No significant difference was found between dosing groups. In the group of patients with CYP3A4 inducers, no further recruitment succeeded from dose level 2 onwards, because newer and no longer CYP3A4-inducing antiepileptic drugs became available and thus the prescription of CYP3A4-inducing drugs (in this case V.a. carbamazepine) no longer took place. Therefore, it is not possible to report an MTD for temsirolimus for this group. In the group without CYP3A4 inducers, the MTD determined was 50 mg temsirolimus. The dose-limiting toxicity was neutropenia, which occurred in the last of the planned temsirolimus dose groups at 75 mg. In the combination of irinotecan and temsirolimus, the known compound-typical adverse events were observed in the dose escalation with the expected frequencies and manifestations. In concordance with numerous clinical trials for the treatment of relapsed high-grade malignant gliomas, low objective response rates (one PR each during the study phase up to day 50 and one thereafter) or short-term disease stabilizations (7 SD at the end of the study on day 50) were observed. Clinically meaningful disease control of more than three months (104, 106, 163, and 211 days) was achieved in four (15%) patients stable at the end of the study at day 50.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete
- Sex
- All
- Target Recruitment
- 27
Recurrence or progression of a histologically confirmed malignant glioblastoma WHO-grade IV or anaplastic astrocytoma WHO-grade III without pathological safeguard fulfilling magnetic resonance imaging criteria of a glioblastoma
- Progressive singular cerebral metastasis of a solid tumor without the option of surgery or irradiation or multiple progressive cerebral metastases after standard irradiation therapy
- Remission of reversible adverse reactions of previous systemic therapy
- No administration or steady dose of glucocorticoids within at least the last week before the first cerebral MRI
- One line of therapy of the recurrent or progressive disease at most, which has to be completed at least 4 weeks, in case of first line administration of nitrosourea 6 weeks, before inclusion
- Patient consents to stay in hospital for the first combined administration of Temsirolimus and Irinotecan
- Age = 18 years
- ECOG Performance Status 0-2
- Estimated life expectancy of at least 3 months
- At least one measurable lesion on MRI according to RECIST
- Patient must avoid drinking of grapefruit juice during participation in the trial
- Signed informed consent
- A previous irradiation therapy must be terminated at least 12 weeks before inclusion
- A second malignoma requiring irradiation or chemotherapy
- Scheduled surgery within the timeframe of trial conduction
- Infratentorial localisation of the tumor
- Cardiac arrhythmia requiring anti-arrhythmic therapy
- Myocardial infarction < 6 months before start of therapy
- Symptomatic coronary disease
- Heart failure NYHA class III or IV or LVEF < 50% on echocardiogram or heart volume scintigram
- Angina pectoris
- Diarrhea at the start of therapy
- Neutrophil granulocytes < 1500/µl
- Haemoglobin < 10 g/dl
- Thrombocytes < 100 000/µl
- Serum creatinine > 1,5 times the laboratory´s upper limit value
- Bilirubin > 1.5 mg/dl
- Alkaline phosphatase > 2.5 times the laboratory´s upper limit value
- GOT / GPT > 2.5 times the laboratory´s upper limit value
- Hereditary fructose intolerance
- Inflammatory bowel disease
- Ileus
- Uncontrolled diabetes
- Hypersensitivity to Irinotecan or Temsirolimus
- Serious internistic or neurological disease with poor prognosis (e.g. HIV-infection)
- Diseases that are associated with repeated vomitting and thus interfere with the oral intake of medication
- Psychological, domestic, sociological or geographical circumstances which could interfere significantly with compliance in regard to attending follow-up visits
- Concurrent participation in other therapeutic trials
- Pregnancy / Breastfeeding
- patient did not practice safe contraception, only women of childbearing potential (intrauterine device plus condom, spermicide plus condom or intrauterine device plus spermicide)
- Men, whose female cohabitant of childbearing potential does not practice safe contraception (in this case hormonal contraception is regarded as safe)
- HIV-Infection
- Active drug abuse
- Chronic alcohol abuse
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Determining the maximum tolerable dose (MTD) of Irinotecan and Temsirolimus at combined administration by observing dose-limiting toxicities (DLT).
- Secondary Outcome Measures
Name Time Method - analysis of the pharmakokinetics and pharmakodynamics of temsirolimus and<br>irinotecan under combined administration on day 1, 8, 15, 22, 29, 36, 43 and 50<br>- time to progression on day 43<br>- Overall Survival (OS)<br>- ECOG at screening and on day 1, 8, 15, 22, 29, 36, 43 and 50<br>