title: A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).
abstract: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy.
  
  
  
  Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response.
  
  
  
  Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53).
  
  
  
  Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible.
  
  
  
  NCT01281852.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Siteman Cancer Center, Washington University School of Medicine, St. Louis.
authors.forename: P H
authors.initials: PH
authors.lastname: Thaker
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University School of Medicine, Columbus, USA.
authors.forename: R
authors.initials: R
authors.lastname: Salani
authors.affiliation: NRG/Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, USA.
authors.forename: W E
authors.initials: WE
authors.lastname: Brady
authors.affiliation: NRG/Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Lankes
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University School of Medicine, Columbus, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Cohn
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Siteman Cancer Center, Washington University School of Medicine, St. Louis.
authors.forename: D G
authors.initials: DG
authors.lastname: Mutch
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Oklahoma, Oklahoma City, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Mannel
authors.affiliation: Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Bell-McGuinn
authors.affiliation: Department of Obstetrics and Gynecology, Women & Infants Hospital, Providence, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Di Silvestro
authors.affiliation: Division of Medical Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, USA.
authors.forename: D
authors.initials: D
authors.lastname: Jelovac
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Carter
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University College of Medicine, Columbus, USA.
authors.forename: W
authors.initials: W
authors.lastname: Duan
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Case Western Reserve University School of Medicine, Cleveland, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Resnick
authors.affiliation: Division of Medical Gynecologic Oncology, Massachusetts General Hospital Cancer Center, Boston, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Dizon
authors.affiliation: Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: C
authors.initials: C
authors.lastname: Aghajanian
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of Virginia, Charlottesville, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Fracasso
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000008:administration & dosage*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000187:drug effects / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D001562:Benzimidazoles; C521013:veliparib; C499320:PARP1 protein, human; C483041:PARP2 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017239:Paclitaxel; D002945:Cisplatin
keywords: PARP inhibitors; cervical cancer; novel therapeutics