title: A phase 1 study evaluating the pharmacokinetics and preliminary efficacy of veliparib (ABT-888) in combination with carboplatin/paclitaxel in Japanese subjects with non-small cell lung cancer (NSCLC).
abstract: BACKGROUND
  Veliparib is a potent, orally bioavailable PARP inhibitor that enhances efficacy of DNA-damaging chemotherapeutic agents. The study objectives were to determine the recommended phase 2 dose (RPTD) of veliparib plus carboplatin and paclitaxel, and assess pharmacokinetics (PK), tolerability, and preliminary efficacy in Japanese patients with solid tumors.
  
  
  METHODS
  Carboplatin (AUC 6 mg/mL min) and paclitaxel (200 mg/m(2)) were administered on day 3 of a 21-day cycle. Oral veliparib (40, 80, or 120 mg BID) was administered on days 1-7. Patients received ≤6 cycles. Adverse events (AEs) were reported using NCI-CTCAE version 4.03, PK parameters were analyzed using noncompartmental methods, and responses were measured by RECIST version 1.1.
  
  
  RESULTS
  Twelve patients with non-small cell lung cancer (NSCLC) were treated. Common treatment-emergent AEs, consistent with toxicities associated with carboplatin and paclitaxel, included leukopenia (100 %), neutropenia (100 %), anemia (83 %), thrombocytopenia (75 %), increased alanine aminotransferase (67 %), and increased aspartate aminotransferase (67 %). Grade 3/4 AEs (in ≥2 patients) included neutropenia (100 %), leukopenia (33 %), anemia (25 %), and hyponatremia (17 %). No AEs led to veliparib, carboplatin, or paclitaxel interruption; no DLTs were observed. The RPTD was determined to be 120 mg BID. Veliparib C max and AUC were approximately dose proportional. Six partial responses were observed.
  
  
  CONCLUSIONS
  Veliparib PK was not impacted by carboplatin and paclitaxel. The safety profile was manageable. The 120 mg BID RPTD confirmed in Japanese patients is the dose being evaluated in global studies of veliparib. Preliminary efficacy suggests veliparib may enhance carboplatin and paclitaxel activity, providing benefit to patients with NSCLC.
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mizugaki
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan. nbryamam@ncc.go.jp.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Horinouchi
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kanda
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Kitazono
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Yagishita
authors.affiliation: AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Qian
authors.affiliation: AbbVie, GK, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hashiba
authors.affiliation: AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Stacie P
authors.initials: SP
authors.lastname: Shepherd
authors.affiliation: AbbVie, Inc., North Chicago, IL, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Giranda
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D001562:Benzimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D003875:Drug Eruptions / Q000209:etiology; D004357:Drug Synergism; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011859:Radiography; D016879:Salvage Therapy; D047368:Tumor Burden
chemical_list: D001562:Benzimidazoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C521013:veliparib; D016190:Carboplatin; D017239:Paclitaxel
keywords: Carboplatin; NSCLC; PARP; Paclitaxel; Veliparib (ABT-888)