A Phase I Study of G3139 (NSC 683428) in Combination With Salvage Chemotherapy for Treatment of Refractory and Relapsed Acute Myeloid Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL)
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.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Guido Marcucci, MD
Ohio State University Comprehensive Cancer Center
United States: Food and Drug Administration
|Arthur G. James Cancer Hospital - Ohio State University||Columbus, Ohio 43210|