Study of Temozolomide in Previously Untreated Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression (P05052)

Merck Sharp & Dohme LLC47 enrolled

Overview

The primary objective of this study is to evaluate the safety, tolerability, and efficacy of temozolomide in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) participants who are not candidates for standard induction therapy and exhibit low MGMT expression.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Leukemia, Acute Myeloid Myelodysplastic Syndrome

Interventions

temozolomideDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Confirmed diagnosis of acute myeloid leukemia (AML), any subtype except acute promyelocytic leukemia (APL), by the World Health Organization (WHO) criteria, or high risk MDS with blasts between 10 and 20% in the bone marrow. * No prior AML chemotherapy except hydroxyurea. * Leukemic blast count \<30x10\^9/L at the start of therapy. Prior cytoreduction with hydroxyurea (maximum 14 days) is permitted. * Participant is not a candidate for aggressive induction based on at least one of the following: adverse-risk cytogenetics (complete or partial deletion of 5 or 7, complex \[\>3\] cytogenetic abnormalities, inv3, 11q23 abnormalities); secondary AML (antecedent hematologic disorder or therapy-related AML); comorbid medical illnesses precluding standard induction therapy; participant's refusal of standard induction therapy. * Confirmed low MGMT expression (MGMT: beta-actin ≤0.2), as evaluated by Western blot, or weak MGMT expression defined as \> 0.2 and ≤2.5 if promoter is methylated, upon Sponsor approval. * Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. * Use of medically approved contraception in fertile males and females. * Negative urine or serum pregnancy test for women of childbearing potential (72 hours prior to Baseline). Exclusion Criteria: * Serum bilirubin \>2 times the upper limit of normal (ULN), or serum aspartate aminotransferase/ alanine aminotransferase \>5 times ULN. * Serum creatinine \>200 umol/L. * History of other malignancies within 1 year prior to study entry, with the exception of localized nonmelanomatous skin cancer or cervical cancer in situ. * Presence of active uncontrolled infection. * Known human immunodeficiency virus (HIV) infection. * Any medical condition that may interfere with protocol evaluation or oral medication intake. * Prior chemotherapy other than hydroxyurea.

Outcomes

Primary Outcomes

Clinical Response at the End of Temozolomide Induction

Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent. Morphologic leukemia-free state (MLFS): complete clearance of blasts from marrow and blood, but criteria for CR or CRp not met. Partial response (PR): decrease ≥ 50% BM blasts. Minimal Response (MR): decrease ≥ 25% but \<50% BM blasts.

Time frame: at the end of each cycle (approximately 4 weeks post start of cycle), up to a maximum 63 weeks

Secondary Outcomes

Duration of Response in Participants Achieving Complete Response (CR) and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide

Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease.

Time frame: Up to 1 year after treatment ends (up to 115 weeks)

Relapse-free Survival in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide

Relapse-free survival was defined as time to disease progression. Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent.

Time frame: Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)]

Overall Survival (OS) in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide

OS was defined as the time from start of treatment until death or end of study. Complete Response (CR): \< 5% blasts in normocellular bone marrow (BM); Absolute Neutrophil Count (ANC) \> 1.0 x 10\^9/L, platelets \> 100 x 10\^9/L, and no extramedullary disease. CR with incomplete platelet recovery (CRp): All the criteria of CR but with platelets \< 100 x 10\^9/L but ≥ 50 x 10\^9/L and platelet transfusion independent.

Data from ClinicalTrials.gov

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