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).
  
  
  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.
  
  
  CONCLUSIONS
  Debio1143 ≤ 400 mg/d showed good tolerability in combination with daunorubicin and cytarabine. Additional studies in subsets of patients with AML are warranted.
authors.affiliation: Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO. Electronic address: jdipersi@dom.wustl.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
authors.affiliation: University of Michigan, Ann Arbor, MI.
authors.forename: Harry P
authors.initials: HP
authors.lastname: Erba
authors.affiliation: University of Chicago Medicine, Chicago, IL.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
authors.forename: Selina M
authors.initials: SM
authors.lastname: Luger
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Martin S
authors.initials: MS
authors.lastname: Tallman
authors.affiliation: Ascenta Therapeutics Inc, Malvern, PA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brill
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Vuagniaux
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rouits
authors.affiliation: Ascenta Therapeutics Inc, Malvern, PA.
authors.forename: J Mel
authors.initials: JM
authors.lastname: Sorensen
authors.affiliation: Debiopharm International S.A., Lausanne, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zanna
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001392:Azocines / Q000008:administration & dosage*; D001559:Benzhydryl Compounds / Q000008:administration & dosage*; D003561:Cytarabine / Q000008:administration & dosage; D016207:Cytokines / Q000097:blood; D003630:Daunorubicin / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged
chemical_list: D001392:Azocines; D001559:Benzhydryl Compounds; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; C559144:N-benzhydryl-5-(2-(methylamino)propanamido)-3-(3-methylbutanoyl)-6-oxodecahydropyrrolo(1,2-a)(1,5)diazocine-8-carboxamide; D003561:Cytarabine; D003630:Daunorubicin
keywords: Interleukin; Pharmacokinetics; TNF; Treatment resistance; cIAP1
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