Phase 2 Study of Temozolomide to Treat Poor Risk / Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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Open-label, non-randomized, parallel assignment, phase 2 trial assessing the safety and efficacy of distinct temozolomide treatment regimens for patients with AML and poor prognosis

Detailed Description
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This is a single institution phase 2 clinical trial evaluating the efficacy, safety, and tolerability of tailored temozolomide therapy for patients with acute myeloid leukemia (AML) and poor risk features. Patients will be assigned to 1 of 2 parallel treatment groups based on their AGAT promoter region methylation status, as determined by PCR. Patients achieving a complete remission after 1 to 2 cycles of chemotherapy will be eligible to receive up to an additional 5 cycles of temozolomide of 5 or 19 days, depending on the methylation status of the AGAT promoter (consolidation phase).

Official Title
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Phase II Study of Two Distinct Tailored Temozolomide Regimens for Patients With Acute Myeloid Leukemia Age > 60 Years and Poor Risk/Refractory Disease

Conditions
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Leukemia, Myeloid

Intervention / Treatment
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* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed Acute Myeloid Leukemia, as defined by the WHO classification. Patients must be considered unfit for conventional induction chemotherapy, unwilling to receive such treatment or have evidence of disease relapse or refractory disease. For patients who have received no prior conventional chemotherapy, one of the following must be present: Poor risk cytogenetics (complex abnormalities, deletions of chromosome 7 or 5, 11q23 abnormalities, inv[3]) Secondary leukemia (prior hematologic disorder or therapy-related leukemia). Age > 60 years of age. Life expectancy of greater than 3 months. ECOG performance status greater than 2. Patients must have normal organ and marrow function as defined below: Adequate hepatic function: Total bilirubin 1.5mg/dL, AST(SGOT)/ALT(SGPT) 2.5 X institutional upper limit of normal. Adequate renal function: serum creatinine within normal institutional limits or Calculated creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Patients may not be receiving any other investigational agents. History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or DTIC History of gastrointestinal disease or significant bowel resection that could interfere with drug absorption. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Prior allogeneic stem cell transplantation. Inability to swallow tablets Prior radiation up to more than 25% of bone marrow.

Ages Eligible for Study
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Minimum Age: 60 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylated AGAT Promoter (Group 1)<br>Induction: 200 mg/m2/day oral Temozolomide x 7 days | Drug: Temozolomide<br>* Priming, Group 2 only, 100 mg/m2/day temozolomide. Induction (both arms) 200 mg/m2/day temozolomide<br>* Other names: Temodar, Temodal;|
| Experimental: Un-Methylated AGAT Promoter (Group 2)<br>Priming: 100 mg/m2/day oral Temozolomide x 14 days, followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days | Drug: Temozolomide<br>* Priming, Group 2 only, 100 mg/m2/day temozolomide. Induction (both arms) 200 mg/m2/day temozolomide<br>* Other names: Temodar, Temodal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (CR + CRi + LFS) | Response determined per European LeukemiaNet response criteria: CR = bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count > 1.0 x 10e9/L; platelet count > 100 x 10e9/L; and independence of red cell transfusions. CRi = all CR criteria except for residual neutropenia (< 1.0 x 10e9/L) or thrombocytopenia (< 100 x 10e9/L)]. Morphologic leukemia-free state (LFS) = bone marrow blasts <5%; absence of blasts with Auer rods; absence of extramedullary disease; with no hematologic recovery required. Relapse = bone marrow blasts >5%; reappearance of blasts in the blood; or development of extramedullary disease. | up to 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity Profile: Total Number of Drug-related Serious Adverse Events |  | 12 months | 
| Toxicity Profile: Individual Subjects With Drug-related SAEs |  | 12 months |