Leukemia, Myeloid
Conditions
Brief summary
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
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).
Interventions
DRUGTemozolomide
Priming, Group 2 only, 100 mg/m2/day temozolomide. Induction (both arms) 200 mg/m2/day temozolomide
Sponsors
Schering-Plough
Bruno C. Medeiros
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate (CR + CRi + LFS) | up to 2 months | 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. |
Secondary
| Measure | Time frame |
|---|---|
| Toxicity Profile: Total Number of Drug-related Serious Adverse Events | 12 months |
| Toxicity Profile: Individual Subjects With Drug-related SAEs | 12 months |
Countries
United States
Participant flow
Recruitment details
42 subjects consented to screening for this study.
Pre-assignment details
6 of 42 subjects did not meet eligibility criteria and did not receive induction therapy. Of these, 1 subject had no evidence of AML; 1 had acute lymphoblastic leukemia, and 4 had disease progression and death before induction. None of the 6 were stratified to a treatment group, and were not treated on study.
Participants by arm
| Arm | Count |
|---|---|
| Methylated AGAT Promoter (Group 1) Induction: 200 mg/m2/day oral Temozolomide x 7 days | 5 |
| Un-Methylated AGAT Promoter (Group 2) Priming: 100 mg/m2/day oral Temozolomide x 14 days, followed by Induction: 200 mg/m2/day oral Temozolomide x 7 days | 31 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 5 |
| Overall Study | Lack of Efficacy | 1 | 16 |
Baseline characteristics
| Characteristic | Methylated AGAT Promoter (Group 1) | Un-Methylated AGAT Promoter (Group 2) | Total |
|---|---|---|---|
| Age, Continuous | 77 years | 75 years | 75 years |
| Sex: Female, Male Female | 2 Participants | 11 Participants | 13 Participants |
| Sex: Female, Male Male | 3 Participants | 20 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 5 | 23 / 31 |
| serious Total, serious adverse events | 4 / 5 | 28 / 31 |
Outcome results
Primary
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.
Time frame: up to 2 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylated AGAT Promoter (Group 1) | Response Rate (CR + CRi + LFS) | 3 participants |
| Un-Methylated AGAT Promoter (Group 2) | Response Rate (CR + CRi + LFS) | 10 participants |
Secondary
Toxicity Profile: Individual Subjects With Drug-related SAEs
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylated AGAT Promoter (Group 1) | Toxicity Profile: Individual Subjects With Drug-related SAEs | 4 participants |
| Un-Methylated AGAT Promoter (Group 2) | Toxicity Profile: Individual Subjects With Drug-related SAEs | 13 participants |
Secondary
Toxicity Profile: Total Number of Drug-related Serious Adverse Events
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Methylated AGAT Promoter (Group 1) | Toxicity Profile: Total Number of Drug-related Serious Adverse Events | 4 events |
| Un-Methylated AGAT Promoter (Group 2) | Toxicity Profile: Total Number of Drug-related Serious Adverse Events | 27 events |