Schéma : This trial is designed as an open label, non randomised, dose escalation and cohort expansion, first administration to human study to be conducted in approximately 20 European sites. The study is aiming to identify the Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD), to assess the pharmacokinetics and to determine the clinical activity and potential immunogenicity of MEN1112, administered as IV infusion given once every week in a 21 days cycle in patients with relapsed/refractory acute myeloid leukemia (AML).
Approximately 50 male and female ≥ 18 years-old patients, with a documented diagnosis of relapsed or refractory AML (not M3 FAB subtype), will be treated in the study, which consists of two steps.
Step 1 is the dose escalation phase according to a 3+3 patients cohort design.Incremental mg/Kg doses will be tested given at day 1, 8 and 15 of a 21-day cycle. Briefly, MEN1112 doses are to be administered to 3 patients; if no DLT is observed in a cohort of 3 DLT evaluable patients at a given dose level, the next cohort of 3 new patients will be treated with the next higher dose. In case of DLT occurrence by one of the three patients at any dose, the cohort will be expanded to 6 DLT evaluable patients at the same dose level. If two or more patients at a given dose level exhibit DLT, the dose escalation phase will be concluded as the MTD will be identified as one dose level below the one at which ≥ 2 DLT out of 6 treated patients occur.
Step 2 is the cohort expansion phase which will include patients treated at the MTD or the maximum dose level judged to be tolerable.
In each study Step, patients will be given two induction cycles of MEN1112 followed by a three weeks End of Induction period. Patients will then undergo to 4 post-induction/maintenance visits every 28 days (maintenance administration is allowed in patients who achieve a clinical benefit based on Investigator's judgement) and to an End of Study Visit. Along the study period, adverse events, changes in hematology/serum biochemistry parameters and bone marrow treatment response will represent the major clinical findings to be monitored on regular basis. The individual experimental clinical phase will last up to 6 months (except for female patients of childbearing potential that will undergo monthly pregnancy test until 6 months from the last study drug administration) encompassing 40 planned visits at site, including Screening, Induction, End of Induction, Post-induction/Maintenance and the End of Study visit.
Current primary outcome:
- Dose limiting toxicity (DLT) [ Time Frame: over 3 weeks after the first dose ]
DLT is defined as an adverse event occurring within the first induction cycle, judged to be related to MEN1112 and meeting any of the following criteria:
Grade 3 non- haematological toxicity lasting more than 7 days.
Grade ≥ 4 non- haematological toxicity
- Maximum tolerated dose (MTD) [ Time Frame: over 3 weeks after the first dose ]
MTD is defined as one dose level below the Maximum Administered Dose (i.e. one dose level below the one at which ≥ 2 DLTs out of 6 treated patients occur).
Current secondary outcomes:
- Treatment Emergent Signs and Symptoms (TESSs) [ Time Frame: 6 months ]
Incidence, severity, seriousness and treatment-causality of Treatment Emergent Signs and Symptoms (TESSs)
- MEN1112 Pharmacokinetic (PK) parameter AUC0-∞ [ Time Frame: Estimated maximum time frame: 4 weeks ]
AUC0-∞ is the area under the serum concentration-time curve from time zero extrapolated to infinite time.
- MEN1112 PK parameter Cmax [ Time Frame: Estimated maximum time frame: 4 weeks ]
Cmax is the maximum serum drug concentration
- MEN1112 PK parameter t1/2 [ Time Frame: Estimated maximum time frame: 4 weeks ]
t1/2 is the drug elimination half-life
- Complete remission (CR) rate [ Time Frame: 6 months ]
CR rate at any time point, where CR is defined as: bone marrow blasts <5%, absence of extramedullary disease, absolute neutrophil count >1 x 109/L and platelet count > 100 x 109/L
- Best response rate [ Time Frame: 6 months ]
best observed response at any time point between CR, CRi [where CRi is defined as: all criteria for CR except residual thrombocytopenia (platelets <100 x 109/L) and/or neutropenia (absolute neutrophil count <1 x 109/L)] and partial remission [(PR): all haematological criteria for CR with bone marrow blasts 5-25% and decrease of pre-treatment bone marrow blast percentage by at least 50%].
- Overall survival [ Time Frame: 6 months ]
number of days between the first study drug administration and death from any cause
- Immunogenicity of MEN1112 [ Time Frame: 64 days ]
Incidence of anti-MEN1112 auto-antibodies
Phase : I
Stade : NA
2, 3, 4, X