Study With Temsirolimus Added to Standard Chemotherapy for Patients Over 60 Years With Acute Myeloblastic Leukemia (TOR-AML)

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Myeloblastic Leukemia
• Intervention / Treatment: Drug: sodium chloride solution 0.9%; Drug: temsirolimus

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 10117
    • Charité University Hospital Berlin, Campus Benjamin Franklin
  • Dresden, Germany, 01307
    • University Hospital Dresden
  • Erlangen, Germany, 91054
    • University Hospital Erlangen
  • Frankfurt am Main, Germany, 60590
    • University Hospital Frankfurt
  • Münster, Germany, 48149
    • University Hospital Münster

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 59 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Goethe University
• Investigators: Study Director: Christian Brandts, MD, Goethe University

Publications and helpful links

General Publications

• Posting of Results in EUDRACT Database: https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-002365-37/results

Helpful Links

• University Cancer Center Frankfurt
• German Competency Network for Leukemia

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): April 26, 2017
• Study Completion (Actual): April 26, 2017

Study Registration Dates

• First Submitted: May 25, 2012
• First Submitted That Met QC Criteria: May 31, 2012
• First Posted (Estimate): June 4, 2012

Study Record Updates

• Last Update Posted (Actual): May 24, 2023
• Last Update Submitted That Met QC Criteria: May 23, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus; Temsirolimus; MTOR Inhibitors
• Other Study ID Numbers: 3066K1-1165

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No