E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly diagnosed Acute Myeloid Leukemia and Intermediate-2, or high-risk Myelodysplastic Syndrome |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000880 |
E.1.2 | Term | Acute myeloid leukaemia |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the objective response rate (ORR), defined as the percentage of subjects with a complete remission (CR) or partial remission (PR) to treatment with single-agent azacitidine (Arm A), single-agent MGCD0103 (Arm B), or azacitidine plus MGCD0103 combination therapy (Arm C) in elderly subjects with newly diagnosed acute myelogenous leukemia (AML), or newly diagnosed intermediate 2 (Int 2) or high risk myelodysplastic syndrome (MDS) classified by MDS International Prognostic Scoring System (IPSS) criteria as modified by the International Working Group (IWG). |
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E.2.2 | Secondary objectives of the trial |
To determine for each of the 3 treatment arms: •Duration of objective response (CR + PR); •Time to progression; •Progression-free survival; •Overall survival; •Red blood cell (RBC) transfusion independence; •Hematologic improvement (according to International Working Group [IWG] criteria); •Quality of life (QOL); •Safety profile; and •Pharmacokinetics of azacitidine and MGCD0103 when administered as single agents and in combination.
Exploratory Correlative Biology Objectives •To assess the prognostic significance of baseline levels of biomarkers isolated from plasma, peripheral blood cells, and/or bone marrow; and •To assess the pharmacodynamic effects of treatment on biomarkers isolated from plasma, peripheral blood cells, and/or bone marrow and correlate these effects with plasma study drug levels and/or treatment outcome.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
•Written informed consent, willingness, and ability to comply with all study procedures; •Pathologic confirmation of newly diagnosed (de novo or untreated secondary) AML or newly diagnosed Int-2 or high-risk MDS (IPSS classification) per WHO criteria; •Age ≥ 60 years; •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; •Total bilirubin = 1.5 x upper limit of normal (ULN) (unless increased due to Gilbert’s disease or hemolysis); •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 x ULN; •Serum creatinine = 2.0 x ULN; and •Use of adequate contraception when appropriate.
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E.4 | Principal exclusion criteria |
•Subjects considered fit for intensive chemotherapy who opt to be treated with intensive chemotherapy; •Prior transplantation or any prior anticancer therapy (standard or investigational, including chemotherapy, treatment with HDAC inhibitors, or combination HDAC and azacitidine) administered to treat AML or MDS. Prior treatments with agents such as hydroxyurea or corticosteroids used for peripheral count control will be allowed; •Known or suspected hypersensitivity to any components of MGCD0103 capsules or azacitidine formulation components (eg, mannitol); •Clinical evidence of central nervous system (CNS) involvement by leukemia; •In blast transformation of chronic myeloid leukemia (CML); •A diagnosis of promyelocytic leukemia; •Presence of advanced malignant hepatic tumors; •Any condition that will put the subject at undue risk or discomfort as a result of adherence to study procedures (eg , requirement to take MGCD0103 with low pH beverage); •Previous or concurrent malignancy except the following: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix; or other solid tumor treated curatively and without evidence of recurrence for at least 3 years prior to study entry; •Active and uncontrolled clinically significant infection; •History of gastrointestinal hemorrhage within the last 3 months; •Known positive serology for hepatitis B surface antigen, hepatitis C antibody; or human immunodeficiency virus; or •Less than 4 weeks elapsed since any major surgery.
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate, as defined by complete or partial remission. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The study will be closed when all randomized and treated subjects can be classified in one of the following groups: •CR, PR, or SD on or before Day 28 of Cycle 6 on randomized treatment arm. (For MDS, duration of CR or PR must be 4 weeks; duration of SD must be > 8 weeks); •Discontinuation prior to completion of Cycle 6 due to progressive disease, toxicity, or death on randomized treatment arm; or •Lost to follow-up.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |