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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.


- candidate number8361
- NTR NumberNTR2477
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR23-aug-2010
- Secondary IDsHO103TOS Hovon
- Public TitleA 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.
- Scientific TitleA 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
- ACRONYMHOVON 103 AML Tosedostat
- hypothesisTo assess the tolerability and efficacy of the addition of oral tosedostat to standard induction therapy.
- Healt Condition(s) or Problem(s) studiedAcute Myeloid Leukemia (AML), RAEB
- Inclusion criteria1. Patients eligible for standard chemotherapy;
2. Patients ≥ 66 years with a cytopathologically confirmed diagnosis according WHO classification of:
A. AML (not APL) (see appendix A1), or;
B. Refractory anemia with excess of blasts (RAEB) with an IPSS score ≥ 1.5.
OR
3. Patients of any age ≥ 18 years with a cytopathologically confirmed diagnosis according WHO classification of very poor risk AML;
4. Subjects with secondary AML progressing from antecedent (at least 4 months duration) myelodysplasia are also eligible;
5. SGOT (AST) and SGPT (ALT) ≤ 1.5 x the upper limit of the normal range (ULN) at the laboratory where the analyses were performed;
6. Total serum bilirubin level ≤ 1.5 x the ULN at the laboratory where the analysis was performed;
7. Serum creatinine concentration ≤ 1.5 x ULN at the laboratory where the analysis was performed;
8. WHO performance status ≤ 2;
9. Written informed consent;
10. Female patients of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to enrollment;
11. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.
- Exclusion criteria1. Acute promyelocytic leukemia;
2. Patients previously treated for AML (any antileukemic therapy including investigational agents), a short treatment period (< 2 weeks) with Hydroxyurea is allowed;
3. Past or current history (within the last 2 years prior to randomization) of malignancies except for the indication under this study and curatively treated:
A. Basal and squamous cell carcinoma of the skin;
B. In situ carcinoma of the cervix.
4. Blast crisis of chronic myeloid leukemia;
5. Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents (≤ 6 months prior to randomization), myocardial infarction (≤ 6 months prior to randomization), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure;
6. Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance;
7. Patients with any serious concomitant medical condition which could, in the opinion of the investigator, compromise participation in the study;
8. Patients who have senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent;
9. Pregnant or lactating patients;
10. Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 16-aug-2010
- planned closingdate15-sep-2012
- Target number of participants200
- Interventions1. Arm A: Cycle I: Dauno/Cytarabine, cycle II: Cytarabine;
2. Arm C: Cycle I: Dauno/Cytarabine/Tosedostat, cycle II: Cytarabine/Tosedostat.
- Primary outcomePart 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 outcomeFor part B:
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).
- TimepointsClinical and laboratory evaluations:
1. At entry;
2. After each induction cycle;
3. During Follow Up, every 6 months.
- Trial web sitewww.hovon.nl
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESProf. Dr. G.J. Ossenkoppele
- CONTACT for SCIENTIFIC QUERIESProf. Dr. G.J. Ossenkoppele
- Sponsor/Initiator HOVON Data Center
- Funding
(Source(s) of Monetary or Material Support)
Koningin Wilhelmina Fonds (KWF), HOVON, Chroma therapeutics
- PublicationsN/A
- Brief summaryRandomized 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.
- Main changes (audit trail)
- RECORD23-aug-2010 - 18-mrt-2011


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