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

Myelodysplastic Syndrome Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00687323
• Other study ID #: P05052
• Secondary ID: MK-7365-240
• Status: Completed
• Phase: Phase 2
• First received: May 27, 2008
• Last updated: February 12, 2015
• Start date: July 2007
• Est. completion date: December 2012

Study information

• Verified date: February 2015
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Health Canada
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 47
• Est. completion date: December 2012
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Acute Myeloid
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• temozolomide

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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)	No
Secondary	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)]	No
Secondary	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)]	No
Secondary	Number of Previously Untreated Participants With Low O6-Methylguanine Methyltransferase (MGMT) Expression	Low MGMT expression was defined as MGMT/ß-actin ratio < 0.2. MGMT & ß-actin are cancer biomarkers.	Baseline	No
Secondary	MGMT Expression in Leukemic Blasts at the Time of Relapse	Low MGMT expression was defined as MGMT/ß-actin ratio of <0.2.; MGMT & ß-actin are cancer biomarkers.	Up to 1 year after treatment ends (up to 115 weeks)	No
Secondary	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)	Yes
Secondary	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)]	No
Secondary	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)	No
Secondary	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)	No
Secondary	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)	No