A randomized phase II multicenter study with a safety run-in to assess the tolerability and efficacy of the addition of oral tosedostat to standard induction therapy in AML and RAEB ≥ 66 years and very poor risk AML ≥ 18 years.

Randomized phase II study.



Primary objectives:

Part A of the study:

1. To assess the safety and tolerability of tosedostat added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) and select the feasible dose level for part B of the study;

2. To assess in a randomized comparison the effect of tosedostat on the CR rate.

Part B of the study:

1. To assess the safety and tolerability of tosedostat added to standard induction chemotherapy for AML (frequency and severity of toxicities and the durations of neutropenia and thrombocytopenia) as regards the selected dose level of tosedostat;

2. To assess in a randomized comparison the effect of the in Part A selected dose of tosedostat on the CR rate.



Secondary objectives:

Part B of the study:

1. To determine the efficacy profile (event free survival (EFS), disease free survival (DFS) and overall survival (OS)) associated with the two therapy regimens;

2. To measure MRD by immunophenotyping in relation to clinical response parameters;

3. To identify potential biomarkers predictive of response, EFS, DFS and OS by exploratory genomic analysis (microarray, gene mutations).



Patient population:

Patients with AML (except FAB M3) or RAEB with IPSS ≥ 1.5, previously untreated, age ≥ 66 yrs and very poor risk AML, age ≥ 18 yrs.



Study design:

This is a prospective, open label, multicenter study that is conducted in the frame of a masterprotocol with multiple parallel randomized phase II studies. The scheme of this design consists of one arm with the standard treatment for AML as compared to various arms with experimental treatments.

Patients in this study are treated with standard induction chemotherapy with or without tosedostat. During part A of the study the feasibility of combining lenalidomide with DNR/Cytarabine will be evaluated and the dose of tosedostat will be selected. Decisions regarding dose escalation, continuation with starting dose level or stopping, are based on the incidence of DLT (dose limiting toxicity: death within 31 days of start cycle I and before start cycle II).

During part B of the study that will be conducted with the selected dose of tosedostat, the CR rate (primary endpoint) and secondary endpoints (EFS, DFS, OS, as well as MRD and genomic profiling) will be assessed.



Duration of treatment:

Expected duration of 2 cycles of induction chemotherapy with or without tosedostat including evaluation is about 3 months.

To assess the tolerability and efficacy of the addition of oral tosedostat to standard induction therapy.

Clinical and laboratory evaluations:

1. At entry;

2. After each induction cycle;

3. During Follow Up, every 6 months.

1. Arm A: Cycle I: Dauno/Cytarabine, cycle II: Cytarabine;

2. Arm C: Cycle I: Dauno/Cytarabine/Tosedostat, cycle II: Cytarabine/Tosedostat.