Study With Temsirolimus Added to Standard Chemotherapy for Patients Over 60 Years With Acute Myeloblastic Leukemia

Study Overview
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Brief Summary
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Standard chemotherapy is capable of eliminating most leukemic blasts in acute myeloblastic leukemia (AML), while leukemia-initiating cells are not sufficiently eradicated. As a consequence, refractory disease and relapse frequently occur in AML, especially in elderly patients. The investigators propose that the addition of temsirolimus may improve standard AML chemotherapy. Furthermore, temsirolimus may specifically target the leukemia-initiating cells in AML, thereby reducing the risk of leukemia relapse. The study's main part is preceded by a open label run-in part, in which optimal temsirolimus dose and schedule for the main part o the study will be determined.

Official Title
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A Double-blind, Placebo-controlled, Randomized, Multicenter Phase II Trial to Assess the Efficacy of Temsirolimus Added to Standard Primary Therapy in Elderly Patients With Newly Diagnosed AML

Conditions
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Acute Myeloblastic Leukemia

Intervention / Treatment
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* Drug: sodium chloride solution 0.9%
* Drug: temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed AML (except APL) according to the FAB classification, including AML evolving from MDS or other hematological diseases and AML after previous cytotoxic therapy or radiation (secondary AML) Bone marrow aspirate or biopsy contains ≥ 20% blasts of all nucleated cells or differential blood count must contain ≥ 20% blasts. In AML FAB M6 ≥ 30% of non-erythroid cells in the bone marrow must be leukemic blasts. In AML defined by cytogenetic aberrations the proportion of blasts may be < 20%. Age ≥ 61 years Informed consent, personally signed and dated to participate in the study Willingness of male patients whose sexual partners are women of child-bearing potential (WOCBP), to use an effective form of contraception (pearl index < 1%) during the study and at least 6 months thereafter. Exclusion Criteria: Patients who are not eligible for standard chemotherapy Previous treatment for AML, except leukapheresis for patients with hyperleukocytosis (leukocytes > 100,000/µl and / or leukostatic syndrome) or hydroxyurea Known central nervous system manifestation of AML Cardiac Disease: Heart failure NYHA III° or IV°; active coronary artery disease (MI more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias, defined as: ventricular extrasystoles grade LOWN IV, sustained or non-sustained ventricular tachycardias, and history of ventricular fibrillation / ventricular flutter, unless patient is protected by an internal cardioverter / defibrillator or ventricular arrhythmia was attributable to a myocardial ischemia > 6 months before study entry. Chronically impaired renal function (creatinine clearance < 30 ml / min) Chronic pulmonary disease with relevant hypoxia Inadequate liver function (ALT and AST ≥ 2.5 x ULN) if not caused by leukemic infiltration Total bilirubin ≥ 1.2 mg/dL if not caused by leukemic infiltration Uncontrolled active infection Concurrent malignancies other than AML with an estimated life expectancy of less than two years and requiring therapy Known HIV and/or hepatitis C infection Evidence or history of CNS disease, including primary or metastatic brain tumors, seizure disorders History of organ allograft Concomitant treatment with kinase inhibitors, angiogenesis inhibitors, calcineurin inhibitors and Mylotarg Serious, non-healing wound, ulcer or bone fracture Allergy to study medication or excipients in study medication Investigational drug therapy outside of this trial during or within 4 weeks of study entry Any severe concomitant condition which makes it undesirable for the patient to participate in the study or which could jeopardise compliance with the protocol

Ages Eligible for Study
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Minimum Age: 61 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: sodium chloride solution 0.9%<br> | Drug: sodium chloride solution 0.9%<br>* intravenous application added to standard chemotherapy on up to 8 predefined days during the course of study treatment<br>|
| Experimental: temsirolimus<br> | Drug: temsirolimus<br>* intravenous application added to standard chemotherapy on up to 16 predefined days during the course of study treatment<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| median Event Free Survival (EFS) | Event Free Survival defined as time interval from day 1 of study treatment until treatment failure, relapse from complete remission (CR) or incomplete remission (CRi), or death from any cause, whichever occurs first. | participants will be followed for one year after start of study treatment | 
| event free survival probability | Event Free Survival defined as time interval from day 1 of study treatment until treatment failure, relapse from complete remission (CR) or incomplete remission (CRi), or death from any cause, whichever occurs first. | participants will be followed for one year after start of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| median Event Free Survival (EFS) of AML patients with different cytogenetic and molecular risk groups |  | participants will be followed for one year after start of study treatment | 
| rate of early response after the first induction cycle in the temsirolimus and the control group |  | participants will be followed for one year after start of study treatment | 
| rate of early response of AML patients with different cytogenetic and molecular risk groups |  | participants will be followed for one year after start of study treatment | 
| Complete Remission (CR) rate in the temsirolimus and the control group |  | participants will be followed for one year after start of study treatment | 
| CR rate of AML patients with different cytogenetic and molecular risk groups |  | participants will be followed for one year after start of study treatment | 
| Relapse Free Survival (RFS) of AML patients in the temsirolimus and the control group |  | participants will be followed for one year after start of study treatment | 
| Relapse Free Survival (RFS) of AML patients with different cytogenetic and molecular risk groups |  | participants will be followed for one year after start of study treatment | 
| Overall Survival (OS) of all AML patients in the temsirolimus and the control group |  | participants will be followed for one year after start of study treatment | 
| Overall Survival (OS) of AML patients with different cytogenetic and molecular risk groups |  | participants will be followed for one year after start of study treatment | 
| rate of molecular remissions in the temsirolimus and the control group |  | participants will be followed for one year after start of study treatment | 
| Number of adverse events in the temsirolimus and the control group |  | participants will be followed for one year after start of study treatment | 
| rate of molecular relapse after molecular remission of all AML patients in the temsirolimus and the control group after induction therapy and in the course of the first remission |  | participants will be followed for one year after start of study treatment |