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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT00687323
First received: May 27, 2008
Last updated: June 16, 2014
Last verified: June 2014

May 27, 2008
June 16, 2014
July 2007
May 2011   (final data collection date for primary outcome measure)
Clinical Response at the End of Temozolomide Induction [ Time Frame: at the end of each cycle (approximately 4 weeks post start of cycle), up to a maximum 63 weeks ] [ Designated as safety issue: No ]

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.

Clinical response at the end of temozolomide induction. [ Time Frame: End of the temozolomide induction phase. ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00687323 on ClinicalTrials.gov Archive Site
  • Duration of Response in Participants Achieving Complete Response (CR) and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide [ Time Frame: Up to 1 year after treatment ends (up to 115 weeks) ] [ Designated as safety issue: No ]
    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.
  • Relapse-free Survival in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide [ Time Frame: Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)] ] [ Designated as safety issue: No ]
    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.
  • Overall Survival (OS) in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide [ Time Frame: Start of treatment until death or end of study [up to 1 year after treatment ends (up to 115 weeks)] ] [ Designated as safety issue: No ]

    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.

  • Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Low MGMT expression was defined as MGMT/β-actin ratio < 0.2. MGMT & β-actin are cancer biomarkers.
  • MGMT Expression in Leukemic Blasts at the Time of Relapse [ Time Frame: Up to 1 year after treatment ends (up to 115 weeks) ] [ Designated as safety issue: No ]

    Low MGMT expression was defined as MGMT/β-actin ratio of <0.2.

    MGMT & β-actin are cancer biomarkers.

  • 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 [ Time Frame: From first dose to 30 days after last dose of study drug (up to 67 weeks) ] [ Designated as safety issue: Yes ]
    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.
  • Progression-free Survival for Participants Achieving PR, MLSF, or MR [ Time Frame: Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)] ] [ Designated as safety issue: No ]
    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.
  • 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 [ Time Frame: Baseline and post-study visit (63 weeks) ] [ Designated as safety issue: No ]
    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.
  • Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by EORTC QLQ-LC13 [ Time Frame: Baseline and post-study visit (63 weeks) ] [ Designated as safety issue: No ]
    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.
  • Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by Functional Assessment of Cancer Therapy (FACT)-G [ Time Frame: Baseline and post-study visit (63 weeks) ] [ Designated as safety issue: No ]
    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.
  • Duration of response in patients achieving complete response and proceeding to reduced dose-intensity maintenance therapy with temozolomide (200 mg/m^2/day for 5 days every 28 days). [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
  • Relapse-free survival and overall survival in patients achieving complete response who are maintained on a reduced dose-intensity regimen of temozolomide (200 mg/m^2/day for 5 days every 28 days). [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
  • Frequency of low MGMT expression in previously untreated AML patients. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
  • MGMT expression in leukemic blasts at the time of relapse. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
  • Safety and tolerability of a reduced dose-intensity maintenance regimen of temozolomide in patients achieving complete response. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: Yes ]
  • Safety and tolerability of a modified low-dose temozolomide maintenance regimen (100 mg/m^2/day for 21 days every 28 days) in patients who achieve partial response. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: Yes ]
  • Progression-free survival for a modified low-dose temozolomide maintenance regimen (100 mg/m^2/day for 21 days every 28 days) in patients who achieve partial response. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
  • Quality of life of patients receiving a long-term temozolomide maintenance regimen. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
  • Correlation between MGMT expression by Western blot and by direct immunohistochemistry. This will evaluate whether the latter assay could potentially serve as a useful screening tool for MGMT expression in AML. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
  • Correlation between responses to temozolomide and expression of the mismatched repair gene MLH1. This will evaluate whether this gene may be a mediator of drug resistance to temozolomide in low MGMT-expressing AML. [ Time Frame: End of Study (December 2011) ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Study of Temozolomide in Previously Untreated Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression (P05052)
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

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.

Not Provided
Interventional
Phase 2
Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Leukemia, Acute Myeloid
  • Myelodysplastic Syndrome
Drug: temozolomide
Other Names:
  • Temodol
  • SCH 052365
  • MK-7365
Experimental: Temozolomide
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).
Intervention: Drug: temozolomide
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. Epub 2007 Jan 25.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
47
December 2012
May 2011   (final data collection date for primary outcome measure)

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.
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
Not Provided
 
NCT00687323
P05052, MK-7365-240
Yes
Merck Sharp & Dohme Corp.
Merck Sharp & Dohme Corp.
Not Provided
Not Provided
Merck Sharp & Dohme Corp.
June 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP