Oral Debio 1143 (AT406), an Antagonist of Inhibitor of Apoptosis Proteins, Combined With Daunorubicin and Cytarabine in Patients With Poor-Risk Acute Myeloid Leukemia-Results of a Phase I Dose-Escalation Study

Poor-risk patients with acute myeloid leukemia (AML) were treated with Debio1143 at an oral dose of 5 400 mg every 5 weeks, along with daunorubicin and cytarabine. The tolerability was acceptable, and on-target activity was demonstrated by cellular inhibitor of apoptosis protein 1 suppression and plasma increases in cytokines. With the 100-mg dose, the tumor response was slightly greater than for the 7 plus 3 combinations in patients with more favorable cytogenetic factors. Background: Treatment of acute myeloid leukemia (AML) remains difficult owing to the development of treatment resistance, which might be overcome through antagonists of inhibitors of apoptosis proteins (IAPs). Patients and Methods: The present multicenter, open-label, dose-escalation study aimed to evaluate the tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of Debio1143 (formerly AT-406), a new IAP antagonist, when given along with a standard 7 plus 3 regimen of daunorubicin and cytarabine to poor-risk patients with AML during the induction cycle. Consecutive patient cohorts received once-daily 100, 200, 300, or 400 mg of oral Debio1143 on treatment days 1 to 5. Blood samples were collected regularly until hematologic recovery or response was documented. Bone marrow samples were collected on days 0, 14, and 29 and PK and PD samples on days 1, 3, 5, 8, and 10 and 1, 2, and 8, respectively. Results: Of the 29 enrolled patients, 23 completed the study. The most common adverse events of any grade deemed related to treatment were nausea (31% of patients), diarrhea (14%), and febrile neutropenia (14%). Exposure exceeded dose proportionality, without accumulation over 5 days. Inhibition of cellular IAP1 was detectable in the CD34/CD117(+) cells and blasts. A total of 11 patients (38%) achieved complete remission, most in the 100-mg dose cohort. Of these, 6 (56%) developed a relapse within the study period. The patients with a response more frequently showed plasma increases of tumor necrosis factor-a and interleukin-8 after the first dose of Debio1143. Conclusion: Debio1143 <= 400 mg/d showed good tolerability in combination with daunorubicin and cytarabine. Additional studies in subsets of patients with AML are warranted. (C) 2015 Elsevier Inc. All rights reserved.