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

Study Overview
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Brief Summary
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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.

Official Title
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Phase II Study of Temozolomide in Previously Untreated Acute Myeloid Leukemia (AML)/Myelodysplastic Syndrome (MDS) Subjects Unsuitable for Standard Induction Therapy Exhibiting Low MGMT Expression

Conditions
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Leukemia, Acute Myeloid, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: temozolomide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temozolomide<br>Temozolomide capsules orally, once daily: 1 induction cycle (200 mg/m^2/day for 7 days in 1 28 day cycle), 1 consolidation cycle (200 mg/m^2/day for 7 days in 1 28 day cycle), then 200 mg/m^2/day for 7 days each 28-day cycle or for 5 days each 28-day cycle (12 cycle maximum). Alternatively participants could have received 100 mg/m^2/day for 21 days of each 28-day cycle (12 cycle maximum). | Drug: temozolomide<br> <br> * Other names: MK-7365;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | at the end of each cycle (approximately 4 weeks post start of cycle), up to a maximum 63 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | Start of treatment until death or end of study [up to 1 year after treatment ends (up to 115 weeks)] | 
| Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression | Low MGMT expression was defined as MGMT/β-actin ratio < 0.2. MGMT & β-actin are cancer biomarkers. | Baseline | 
| MGMT Expression in Leukemic Blasts at the Time of Relapse | Low MGMT expression was defined as MGMT/β-actin ratio of <0.2. MGMT & β-actin are cancer biomarkers. | Up to 1 year after treatment ends (up to 115 weeks) | 
| Number of Participants With CR, PR, or MLFS Who Received Modified Low Dose Maintenance Therapy (100 mg/m^2/Day x21 Days of Each 28 Day Cycle) and Experienced Toxicity | Toxicity was defined as any adverse event experienced by a participant regardless of causal relationship with study treatment. An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product, biologic (at any dose), or medical device, which did not necessarily have a causal relationship with the treatment. Adverse events may have included the onset of new illness and/or the exacerbation of preexisting conditions. | From first dose to 30 days after last dose of study drug (up to 67 weeks) | 
| Progression-free Survival for Participants Achieving PR, MLSF, or MR | Progression-free survival was defined as time to disease progression. 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. | Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)] | 
| Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-30 | The EORTC QLQ-C30 was a 30-item questionnaire developed to assess the QoL of cancer patients. Scores ranged from 0 -100. For functional and global QoL scales, higher scores meant a better level of function. For symptom-oriented scales, a higher score meant more severe symptoms and a decrease in QoL. | Baseline and post-study visit (63 weeks) | 
| Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by EORTC QLQ-LC13 | The EORTC QLQ-LC13 was a 13-item questionnaire developed to supplement the EORTC QLQ-C30 in lung cancer patients. It had a score range 0-100 with higher scores representing an increase in symptoms. | Baseline and post-study visit (63 weeks) | 
| Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by Functional Assessment of Cancer Therapy (FACT)-G | The FACT-G was a 27-item questionnaire developed to assess the QoL in patients with chronic illnesses. Scores ranged from 0 to 28. For physical well being, lower scores indicated a better outcome. For functional well being, higher scores indicated a better outcome. For social & emotional well being, whether a high score or a lower one indicated a better outcome depended on the question. | Baseline and post-study visit (63 weeks) |