Study of MEN1112 Intravenous Infusion in Relapsed or Refractory Acute Myeloid Leukemia

The purpose of this study is to assess the safety of MEN1112, given as intravenous infusion, in patients with relapsed or refractory AML. Pharmacokinetics, clinical activity and potential immunogenicity of MEN1112 will be evaluated as well.

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 for two 21-day cycles.

Approximately 100 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. 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 four-week End of Treatment period and a Follow-up period. In Step 1 and Step 2, DLT and MTD will be assessed when MEN1112 is given as a 'one shot' infusion (first group of patients) for all doses as well as a 'ramp up' administration to be infused in 3 days for the first two doses in Cycle 1 (second group of patients).

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 approx. 40 planned visits at site, including Screening,Treatment, End of Treatment, Follow-up period and the End of Study visit.

Eligibility Criteria:
Inclusion Criteria:

* Male or female patients aged ≥ 18 years.
* Documented definitive diagnosis of AML (according to WHO criteria, 2008) that is relapsed/refractory to standard treatment, for which no standard therapy is available or the patient refuses standard therapy.
* WBC count ≤ 10 x 109/L at Visit 1/Day 1; hydroxyurea is allowed to lower WBC count.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at Visit1/Day 1.
* Life expectancy of at least 2 months.
* Adequate renal and hepatic laboratory assessments: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic organ involvement, Total Bilirubin ≤2.0 × ULN, Serum creatinine ≤2.0 × ULN.
* Able to give written informed consent before any study related procedure

Exclusion Criteria:

* Acute promyelocytic leukaemia (French-American-British M3 classification).
* Active central nervous system involvement.
* Haematopoietic stem cell transplantation (HSCT) performed within 3 months prior to Screening Visit.
* Active infection requiring intravenous antibiotics.
* Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety or interfere with the patient's ability to comply with the study activities.
* Anti-tumour therapy within 14 days of study Visit 1/Day 1, excluding hydroxyurea.
* Prior participation in an investigational study (procedure or device) within 21 days of study Visit 1/Day 1.
* Radiotherapy within 28 days prior to study Visit 1/Day 1 or scheduled along the study conduct.
* Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).
* Other active malignancies. History of malignancy in the last 12 months (except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast or non-melanoma skin cancer).