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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Recurrent Adult Acute Myeloid Leukemia; Acute Myeloid Leukemia, in Relapse	Drug: MEN1112	Phase 1

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	50 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	First in Man Study With MEN1112, a CD157 Targeted Monoclonal Antibody, in Relapsed or Refractory Acute Myeloid Leukemia.
Actual Study Start Date :	December 2014
Estimated Primary Completion Date :	June 2019
Estimated Study Completion Date :	May 2020

Arms and Interventions

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Arm

Intervention/treatment

Experimental: MEN1112; Dose escalation will occur using a standard 3+3 dose escalation approach, beginning in dose level I with dose cohorts and rules for escalation

Drug: MEN1112; Intravenous infusion of MEN1112 pro/Kg body weight dose on days 1, 8, 15 of a 21-day cycle. Two induction cycles followed by a 3 week End of induction period. Post-induction/Maintenance Visits every 4 weeks with or without maintenance treatment administration, whilst clinical benefit is maintained as per Investigator's judgement. 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).

Outcome Measures

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Primary Outcome Measures :

1. 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
2. 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).

Secondary Outcome Measures :

1. Treatment Emergent Signs and Symptoms (TESSs) [ Time Frame: 6 months ]
   Incidence, severity, seriousness and treatment-causality of Treatment Emergent Signs and Symptoms (TESSs)
2. 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.
3. MEN1112 PK parameter Cmax [ Time Frame: Estimated maximum time frame: 4 weeks ]
   Cmax is the maximum serum drug concentration
4. MEN1112 PK parameter t1/2 [ Time Frame: Estimated maximum time frame: 4 weeks ]
   t1/2 is the drug elimination half-life
5. 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
6. 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%].
7. Overall survival [ Time Frame: 6 months ]
   number of days between the first study drug administration and death from any cause

Other Outcome Measures:

1. Immunogenicity of MEN1112 [ Time Frame: 64 days ]
   Incidence of anti-MEN1112 auto-antibodies

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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 Visit 1 (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).

Contacts and Locations

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Contacts

Contact: Angela Capriati, MD, Corporate Director	+39 055 5680 ext 9990	acapriati@menarini-ricerche.it
Contact: Simone Baldini, Clinical Research Physician	+39 055 5680 ext 9740	sbaldini@menarini-ricerche.it

Locations

Belgium
ZNA Stuivenberg	Active, not recruiting
Antwerp, Belgium, 2060
	Active, not recruiting
Bruxelles, Belgium, 1200
	Active, not recruiting
Liège, Belgium, 4000
	Active, not recruiting
Yvoir, Belgium, 5530
France
	Active, not recruiting
Lille, France, 59037
	Active, not recruiting
Marseille, France, 13273
	Active, not recruiting
Nantes, France, 44093
	Active, not recruiting
Toulouse, France, 31059
	Active, not recruiting
Villejuif, France, 94805
Germany
	Recruiting
Dresden, Germany
	Recruiting
Essen, Germany, 45147
	Recruiting
Frankfurt, Germany, 60590
	Recruiting
Munich, Germany, 81377
Italy
	Active, not recruiting
Bologna, Italy, 40126
	Active, not recruiting
Brescia, Italy, 25123
	Active, not recruiting
Milano, Italy, 20132
	Active, not recruiting
Rome, Italy, 00133
	Active, not recruiting
Torino, Italy, 10126
Spain
	Active, not recruiting
Badalona, Spain, 08916
	Active, not recruiting
Barcelona, Spain, 08035
	Active, not recruiting
Valencia, Spain, 46026

Sponsors and Collaborators

Menarini Group

Investigators

Study Chair:	Adriano Venditti, Professor, MD	Hematology Department, "Tor Vergata" University Viale Oxford, 81 00133 Rome, Italy

More Information

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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Menarini Group
ClinicalTrials.gov Identifier:	NCT02353143 History of Changes
Other Study ID Numbers:	ARMY-1; 2014-002433-59 ( EudraCT Number )
First Posted:	February 2, 2015
Last Update Posted:	October 11, 2018
Last Verified:	October 2018

Keywords provided by Menarini Group:

Acute Myeloid Leukemia; AML; Relapsed	Refractory; MEN1112; Monoclonal antibody

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type	Neoplasms; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs