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

First in Man Study With MEN1112, a CD157 Targeted Monoclonal Antibody, in Relapsed or Refractory Acute Myeloid Leukemia.

The Sponsor accepted the iDSMB recommendation to terminate the study due to evidence of unpredictable liver toxicity and meaningful target engagement not translating into any clinical objective response.

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.

Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation

Intravenous infusion of MEN1112 pro/Kg body weight dose will be administered for two 21-day cycles; MEN1112 dose is administered as' one shot infusion' (first group of patients) and as a dose to be infused in 3 days for the first two doses in Cycle 1 (second group of patients). Two treatment cycles will be followed by a 4-week End of Treatment Period and a Follow-up period. The individual treatment/observation period is six months (except for female patients of childbearing potential that will undergo monthly pregnancy test until 6 months from the last study drug administration).

Identification of DLT defined as an adverse event occurring during the first treatment 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.

Identification of MTD 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).

Incidence, severity, seriousness and treatment related causality of Treatment Emergent Signs and Symptoms (TESSs)

Under ramp-up schedule during Cycle 1, at the end of Day 1 and 2 infusions (when applicable) and at the end of Day 3 infusion; and under one-shot schedule during Cycle 2, at the end of the third infusion (Day 36). Each cycle lasts 21 days.

Under ramp-up schedule during Cycle 1, at the end of Day 1 and 2 infusions (when applicable) and at the end of Day 3 infusion; and under one-shot schedule during Cycle 2, at the end of the third infusion (Day 36). Each cycle lasts 21 days.

AUC (0-∞) is the area under the serum concentration-time curve from time 0 extrapolated to infinite time

Under ramp-up schedule during Cycle 1, at the end of Day 1 and 2 infusions (when applicable) and at the end of Day 3 infusion; and under one-shot schedule during Cycle 2, at the end of the third infusion (Day 36). Each cycle lasts 21 days.

Under ramp-up schedule during Cycle 1, at the end of Day 1 and 2 infusions (when applicable) and at the end of Day 3 infusion; and under one-shot schedule during Cycle 2, at the end of the third infusion (Day 36). Each cycle lasts 21 days.

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 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%].

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).