Phase I trial to study the effectiveness of augmerosen plus fludarabine and cytarabine in
treating patients who have refractory or relapsed acute myeloid leukemia or acute
lymphoblastic leukemia. Drugs used in chemotherapy use different ways to stop cancer cells
from dividing so they stop growing or die. Gene therapy such as augmerosen may make cancer
cells more sensitive to chemotherapy drugs. Combining more than one drug with augmerosen may
kill more cancer cells.
I. Determine the maximum tolerated dose of fludarabine and cytarabine when combined with
augmerosen (G3139) in patients with refractory or relapsed acute myeloid leukemia or acute
lymphoblastic leukemia and recommend a starting dose for phase II studies.
II. Determine the qualitative and quantitative toxic effects of this regimen in these
patients with regard to organ specificity, time course, predictability, and reversibility.
III. Document the therapeutic response in patients treated with this regimen. IV. Measure
bcl-2 and related antiapoptotic and proapoptotic proteins in circulating and/or marrow
leukemia cells before, during, and after treatment with G3139.
V. Measure WT1 expression in leukemic blasts as a surrogate marker for minimal residual
disease and correlate it with bcl-2 and related antiapoptotic and proapoptotic gene
VI. Determine the time required for bcl-2 levels to recover after treatment with this
VII. Determine if TP53 mutations are present in leukemic blasts and how these mutations may
affect expression of BAX, level of treatment induced apoptosis, and clinical endpoints.
VIII. Assess apoptosis in leukemic cells before, during, and after treatment with this
IX. Determine the pharmacokinetics of fludarabine and cytarabine in patients treated with
X. Perform pharmacodynamic studies of fludarabine and cytarabine on the leukemic cells of
patients prior to treatment.
OUTLINE: This is a dose-escalation study of fludarabine and cytarabine.
Patients receive augmerosen IV continuously on days 1-10 and filgrastim (G-CSF)
subcutaneously beginning on day 5 and continuing until blood counts recover. Patients
receive fludarabine IV over 30 minutes followed 3.5 hours later by cytarabine IV over 4
hours on days 6-10. Patients who achieve complete response (CR) receive a second course
beginning 4 weeks after completion of the first course. Patients who achieve CR and have a
matched sibling or unrelated bone marrow donor may undergo allogeneic bone marrow
transplantation. Cohorts of 3-6 patients receive escalating doses of fludarabine and
cytarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the
dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.
- Histologically proven refractory or relapsed acute myeloid leukemia or acute
- Marrow cellularity must be at least 20%
- Must have diagnostic lumbar puncture and treatment with prophylactic intrathecal
methotrexate within 1 week prior to entering study
- No active CNS involvement
- CNS involvement allowed if no residual leukemic cells are detected in CSF following
- Age: 16 and over
- Performance status: ECOG 0-2
- Life expectancy: At least 4 weeks
- Bilirubin no greater than 2 times upper limit of normal(ULN)
- ALT and AST no greater than 2 times ULN
- Alkaline phosphatase no greater than 2 times ULN*
- Unless attributable to malignancy
- Creatinine no greater than 1.5 mg/dL unless attributable to malignancy
- No symptomatic congestive heart failure
- No unstable angina pectoris No or cardiac arrhythmia
- Resting cardiac ejection fraction no less than 45% unless attributable to malignancy
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception before and during study
- No history of allergy to study medications
- No uncontrolled concurrent illness
- No active infection
- No serious medical or psychiatric illness that would preclude informed consent or
limit survival to less than 4 weeks
PRIOR CONCURRENT THERAPY:
- At least 2 weeks since prior chemotherapy except hydroxyurea
- No concurrent corticosteroids except for grade 4 toxicity unresponsive to all other
- At least 4 weeks since prior radiotherapy
- No other concurrent investigational or standard agents or therapies for leukemia