Clinical trial NCT00687323: Study of Temozolomide in Previously Untreated Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression (P05052)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia, Acute Myeloid
Myelodysplastic Syndrome
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2008-05-30
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Clinical Response at the End of Temozolomide Induction
timeFrame: at the end of each cycle (approximately 4 weeks post start of cycle), up to a maximum 63 weeks
Secondary outcomes:
measure: Duration of Response in Participants Achieving Complete Response (CR) and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
timeFrame: Up to 1 year after treatment ends (up to 115 weeks)
measure: Relapse-free Survival in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
timeFrame: Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)]
measure: Overall Survival (OS) in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
timeFrame: Start of treatment until death or end of study [up to 1 year after treatment ends (up to 115 weeks)]
measure: Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression
timeFrame: Baseline
measure: MGMT Expression in Leukemic Blasts at the Time of Relapse
timeFrame: Up to 1 year after treatment ends (up to 115 weeks)
measure: 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
timeFrame: From first dose to 30 days after last dose of study drug (up to 67 weeks)
measure: Progression-free Survival for Participants Achieving PR, MLSF, or MR
timeFrame: Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)]
measure: 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
timeFrame: Baseline and post-study visit (63 weeks)
measure: Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by EORTC QLQ-LC13
timeFrame: Baseline and post-study visit (63 weeks)
measure: Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by Functional Assessment of Cancer Therapy (FACT)-G
timeFrame: Baseline and post-study visit (63 weeks)
Other outcomes:
Locations:
Study officials:
References:
citation: Brandwein JM, Yang L, Schimmer AD, Schuh AC, Gupta V, Wells RA, Alibhai SM, Xu W, Minden MD. A phase II study of temozolomide therapy for poor-risk patients aged >or=60 years with acute myeloid leukemia: low levels of MGMT predict for response. Leukemia. 2007 Apr;21(4):821-4. doi: 10.1038/sj.leu.2404545. Epub 2007 Jan 25. No abstract available.