Back to resultsStudy of Temozolomide in Previously Untreated Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression (P05052) (TALL)
Primary Purpose
Leukemia, Acute Myeloid, Myelodysplastic Syndrome
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
temozolomide
Sponsored by
About this trial
This is an interventional treatment trial for Leukemia, Acute Myeloid
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.
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Temozolomide
Arm Description
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).
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00687323
Brief Title
Study of Temozolomide in Previously Untreated Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression (P05052)
Acronym
TALL
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
2. Study Status
Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
July 30, 2007 (Actual)
Primary Completion Date
May 9, 2011 (Actual)
Study Completion Date
December 23, 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Acute Myeloid, Myelodysplastic Syndrome
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
47 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Temozolomide
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
temozolomide
Other Intervention Name(s)
Temodol, SCH 052365, MK-7365
Primary Outcome Measure Information:
Title
Clinical Response at the End of Temozolomide Induction
Description
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 Outcome Measure Information:
Title
Duration of Response in Participants Achieving Complete Response (CR) and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
Description
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)
Title
Relapse-free Survival in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
Description
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)]
Title
Overall Survival (OS) in Participants Achieving CR or CRp and Proceeding to Reduced Dose-intensity Maintenance Therapy With Temozolomide
Description
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.
Time Frame
Start of treatment until death or end of study [up to 1 year after treatment ends (up to 115 weeks)]
Title
Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression
Description
Low MGMT expression was defined as MGMT/β-actin ratio < 0.2. MGMT & β-actin are cancer biomarkers.
Time Frame
Baseline
Title
MGMT Expression in Leukemic Blasts at the Time of Relapse
Description
Low MGMT expression was defined as MGMT/β-actin ratio of <0.2.
MGMT & β-actin are cancer biomarkers.
Time Frame
Up to 1 year after treatment ends (up to 115 weeks)
Title
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
Description
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.
Time Frame
From first dose to 30 days after last dose of study drug (up to 67 weeks)
Title
Progression-free Survival for Participants Achieving PR, MLSF, or MR
Description
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.
Time Frame
Start of treatment until disease progression [up to 1 year after treatment ends (up to 115 weeks)]
Title
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
Description
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.
Time Frame
Baseline and post-study visit (63 weeks)
Title
Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by EORTC QLQ-LC13
Description
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.
Time Frame
Baseline and post-study visit (63 weeks)
Title
Quality of Life (QoL) in Participants Receiving Long Term Temozolomide Therapy Assessed by Functional Assessment of Cancer Therapy (FACT)-G
Description
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.
Time Frame
Baseline and post-study visit (63 weeks)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
17252015
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.
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Study of Temozolomide in Previously Untreated Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression (P05052)
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