title: A phase I trial of pegylated liposomal doxorubicin (PLD), carboplatin, bevacizumab and veliparib in recurrent, platinum-sensitive ovarian, primary peritoneal, and fallopian tube cancer: An NRG Oncology/Gynecologic Oncology Group study.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of veliparib combined with PLD and carboplatin (CD) in patients with recurrent, platinum-sensitive epithelial ovarian cancer. To determine the tolerability at the MTD combined with bevacizumab.
  
  
  METHODS
  Patients received PLD (30mg/m(2), IV) and carboplatin (AUC 5, IV) on day 1 with veliparib on days 1-7 (intermittent) or days 1-28 (continuous). Standard 3+3 design was used in the dose escalation phase with DLTs based on the first cycle. Once the MTDs were determined, cohorts of 6 patients were enrolled to each regimen with bevacizumab (10mg/kg on days 1 and 15) to assess feasibility. DLTs were based on the first 4cycles of treatment in the bevacizumab cohorts.
  
  
  RESULTS
  In the dose-escalation phase, 27 patients were treated at 3 dose levels with DLTs noted in 6 patients including grade 4 thrombocytopenia (n=4), and prolonged neutropenia >7days (n=3). At the MTD of veliparib (80mg p.o. b.i.d. for both dosing arms), myelosuppression was the DLT. At MTD, 12 additional patients were treated with bevacizumab with 9 patients experiencing DLTs including grade 4 thrombocytopenia (n=4), prolonged neutropenia >7days (n=1), grade 3 hypertension (n=5), and grade 5 sepsis (n=1).
  
  
  CONCLUSIONS
  The MTD of veliparib combined with CD is 80mg p.o. b.i.d. in women with recurrent, platinum-sensitive ovarian cancer. With bevacizumab, DLTs were noted in 9 out of 12 patients. Lower doses of veliparib will need to be considered when given in combination with platinum-based therapies.
authors.affiliation: Department of OB/GYN, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States. Electronic address: lisa-landrum@ouhsc.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Landrum
authors.affiliation: NRG Oncology/Gynecologic Oncology Group Statistics & Data Center, Roswell Park Cancer Institute, Buffalo, NY, United States. Electronic address: wbrady@gogstats.org.
authors.forename: William E
authors.initials: WE
authors.lastname: Brady
authors.affiliation: Department of Gynecology & Obstetrics, Johns Hopkins Kimmel Cancer Center, Baltimore, MD, United States. Electronic address: armstde@jhmi.edu.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Armstrong
authors.affiliation: Department of OB/GYN, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States. Electronic address: Kathleen-Moore@ouhsc.edu.
authors.forename: Kathleen N
authors.initials: KN
authors.lastname: Moore
authors.affiliation: Department of Gynecologic Oncology, Women and Infant's Hospital, Providence, RI, United States. Electronic address: pdisilvestro@wihri.org.
authors.forename: Paul A
authors.initials: PA
authors.lastname: DiSilvestro
authors.affiliation: Department of Gynecologic Oncology, The Ohio State University, Columbus, OH, United States. Electronic address: omalley.46@osu.edu.
authors.forename: David M
authors.initials: DM
authors.lastname: O'Malley
authors.affiliation: Department of Gynecologic Oncology, University of Chicago, Chicago, IL, United States. Electronic address: mtenney@babies.bsd.uchicago.edu.
authors.forename: Meaghan E
authors.initials: ME
authors.lastname: Tenney
authors.affiliation: Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Cleveland Clinic, Cleveland, OH, United States. Electronic address: rosep@ccf.org.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Rose
authors.affiliation: Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, United States; Bristol-Myers Squibb Company, Princeton, NJ, United States. Electronic address: fracasso@virginia.edu.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Fracasso
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D001562:Benzimidazoles; C506643:liposomal doxorubicin; C521013:veliparib; D000068258:Bevacizumab; D011092:Polyethylene Glycols; D004317:Doxorubicin; D016190:Carboplatin
keywords: PARP inhibitors; Thrombocytopenia; VEGF inhibitors