title: Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study.
abstract: OBJECTIVE
  The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan.
  
  
  METHODS
  In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached.
  
  
  RESULTS
  All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response.
  
  
  CONCLUSIONS
  The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients.
authors.affiliation: South Texas Accelerated Research Therapeutics (START), 4383 Medical Dr., San Antonio, TX, 78229, USA. atolcher@start.stoh.com.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.affiliation: Yale Cancer Center, Yale University, New Haven, CT, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Arzt
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Busman
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Guinan
authors.initials: G
authors.lastname: Lian
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Niki S
authors.initials: NS
authors.lastname: Rudersdorf
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Vanderwal
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: Waring
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Jianning
authors.initials: J
authors.lastname: Yang
authors.affiliation: AbbVie Inc., North Chicago, IL, USA.
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.affiliation: UCLA Division of Hematology-Oncology, Santa Monica, CA, USA.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000814:Aniline Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D064147:Febrile Neutropenia / Q000139:chemically induced; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D016879:Salvage Therapy; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome
chemical_list: D000814:Aniline Compounds; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D000077146:Irinotecan; C528561:navitoclax; D002166:Camptothecin
keywords: Bcl-2 inhibitor; Irinotecan; Navitoclax; Pharmacokinetic parameters; Safety