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

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).

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed Acute Myeloid Leukemia, as defined by the WHO classification.

2. Patients must be considered unfit for conventional induction chemotherapy, unwilling to receive such treatment or have evidence of disease relapse or refractory disease.

3. 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).

4. Age > 60 years of age.

5. Life expectancy of greater than 3 months.

6. ECOG performance status greater than 2.

7. Patients must have normal organ and marrow function as defined below:

8. Adequate hepatic function: Total bilirubin 1.5mg/dL, AST(SGOT)/ALT(SGPT) 2.5 X institutional upper limit of normal.

9. 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.

10. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. 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.
2. Patients may not be receiving any other investigational agents.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or DTIC
4. History of gastrointestinal disease or significant bowel resection that could interfere with drug absorption.
5. 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.
6. Prior allogeneic stem cell transplantation.
7. Inability to swallow tablets
8. Prior radiation up to more than 25% of bone marrow.