title: Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity.
abstract: BACKGROUND
  Proteins of the BCL-2 family regulate clonal selection and survival of lymphocytes, and are frequently overexpressed in lymphomas. Navitoclax is a targeted high-affinity small molecule that inhibits the anti-apoptotic activity of BCL-2 and BCL-XL. We aimed to assess the safety and antitumour activity of navitoclax in patients with lymphoid tumours, and establish the drug's pharmacokinetic and pharmacodynamic profiles.
  
  
  METHODS
  In this phase 1 dose-escalation study, patients (aged ≥18 years) with relapsed or refractory lymphoid malignancies were enrolled and treated at seven sites in the USA between November, 2006, and November, 2009. A modified Fibonacci 3+3 design was used to assign patients to receive oral navitoclax once daily by one of two dosing schedules: intermittently for the first 14 days of a 21-day cycle (14/21) at doses of 10, 20, 40, 80, 110, 160, 225, 315, or 440 mg/day; or continuously for 21 days of a 21-day cycle (21/21) at doses of 200, 275, 325, or 425 mg/day. Study endpoints were safety, maximum tolerated dose, pharmacokinetic profile, pharmacodynamic effects on platelets and T cells, and antitumour activity. This trial is registered with ClinicalTrials.gov, number NCT00406809.
  
  
  RESULTS
  55 patients were enrolled (median age 59 years, IQR 51-67), 38 to receive the 14/21 dosing schedule, and 17 to receive the 21/21 dosing schedule. Common toxic effects included grade 1 or 2 anaemia (41 patients), infection (39), diarrhoea (31), nausea (29), and fatigue (21); and grade 3 or 4 thrombocytopenia (29), lymphocytopenia (18), and neutropenia (18). On the intermittent 14/21 schedule, dose-limiting toxic effects were hospital admissions for bronchitis (one) and pleural effusion (one), grade 3 increase in aminotransferases (one), grade 4 thrombocytopenia (one), and grade 3 cardiac arrhythmia (one). To reduce platelet nadir associated with intermittent 14/21 dosing, we assessed a 150 mg/day lead-in dose followed by a continuous 21/21 dosing schedule. On the 21/21 dosing schedule, two patients did not complete the first cycle and were excluded from assessment of dose-limiting toxic effects; dose-limiting toxic effects were grade 4 thrombocytopenia (one), grade 3 increase in aminotransferases (one), and grade 3 gastrointestinal bleeding (one). Navitoclax showed a pharmacodynamic effect on circulating platelets and T cells. Clinical responses occurred across the range of doses and in several tumour types. Ten of 46 patients with assessable disease had a partial response, and these responders had median progression-free survival of 455 days (IQR 40-218).
  
  
  CONCLUSIONS
  Navitoclax has a novel mechanism of peripheral thrombocytopenia and T-cell lymphopenia, attributable to high-affinity inhibition of BCL-XL and BCL-2, respectively. On the basis of these findings, a 150 mg 7-day lead-in dose followed by a 325 mg dose administered on a continuous 21/21 dosing schedule was selected for phase 2 study.
  
  
  BACKGROUND
  Abbott Laboratories, Genentech, and National Cancer Institute, National Institutes of Health.
authors.affiliation: National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. wilsonw@mail.nih.gov
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
authors.forename: Myron S
authors.initials: MS
authors.lastname: Czuczman
authors.forename: Ann S
authors.initials: AS
authors.lastname: LaCasce
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Anil
authors.initials: A
authors.lastname: Tulpule
authors.forename: Kieron
authors.initials: K
authors.lastname: Dunleavy
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Chiu
authors.forename: Yue
authors.initials: Y
authors.lastname: Cui
authors.forename: Todd
authors.initials: T
authors.lastname: Busman
authors.forename: Steven W
authors.initials: SW
authors.lastname: Elmore
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Krivoshik
authors.forename: Sari H
authors.initials: SH
authors.lastname: Enschede
authors.forename: Rod A
authors.initials: RA
authors.lastname: Humerickhouse
mesh_terms: D000368:Aged; D000814:Aniline Compounds / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000187:drug effects; D004304:Dosage Forms; D016503:Drug Delivery Systems; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004304:Dosage Forms; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax