Oral Debio1143 (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 Journal Article
| Authors: | DiPersio, J. F.; Erba, H. P.; Larson, R. A.; Luger, S. M.; Tallman, M. S.; Brill, J. M.; Vuagniaux, G.; Rouits, E.; Sorensen, J. M.; Zanna, C. |
| Article Title: | Oral Debio1143 (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 |
| Abstract: | 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-α 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. © 2015 Elsevier Inc. All rights reserved. |
| Keywords: | adult; clinical article; treatment response; unclassified drug; drug tolerability; fatigue; neutropenia; area under the curve; cancer risk; diarrhea; drug efficacy; side effect; cytarabine; anorexia; protein blood level; cd34 antigen; stem cell factor receptor; bone marrow; heart disease; mucosa inflammation; nausea; stomatitis; thrombocytopenia; vomiting; qt prolongation; interleukin 8; cohort analysis; alanine aminotransferase blood level; aspartate aminotransferase blood level; drug dose escalation; febrile neutropenia; fever; alanine aminotransferase; aspartate aminotransferase; bilirubin; hypokalemia; tnf; tumor necrosis factor alpha; drug accumulation; blood sampling; multicenter study; daunorubicin; acute myeloblastic leukemia; open study; skin disease; maximum plasma concentration; time to maximum plasma concentration; eye disease; phase 1 clinical trial; drug half life; leukemia relapse; convalescence; neurologic disease; bilirubin blood level; monocyte chemotactic protein 1; peripheral blood mononuclear cell; drug exposure; pharmacokinetics; respiratory tract disease; hypocalcemia; leukemia remission; decreased appetite; hypertransaminasemia; treatment resistance; interleukin; antileukemic agent; human; male; female; article; ciap1; debio 1143 |
| Journal Title: | Clinical Lymphoma, Myeloma and Leukemia |
| Volume: | 15 |
| Issue: | 7 |
| ISSN: | 2152-2650 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2015-07-01 |
| Start Page: | 443 |
| End Page: | 449 |
| Language: | English |
| DOI: | 10.1016/j.clml.2015.02.020 |
| PROVIDER: | scopus |
| PUBMED: | 25842225 |
| PMCID: | PMC5028895 |
| DOI/URL: | |
| Notes: | Export Date: 2 September 2015 -- Source: Scopus |
