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)
| Autor: | Hiroshi Nokihara, Tomohide Tamura, Hao Xiong, Vincent L. Giranda, Hideyuki Hashiba, Stacie Peacock Shepherd, Jane Qian, Shigehiro Yagishita, Shintaro Kanda, Satoru Kitazono, Yutaka Fujiwara, Hidehito Horinouchi, Hidenori Mizugaki, Noboru Yamamoto |
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| Jazyk: | angličtina |
| Předmět: |
Male
Oncology Cancer Research Lung Neoplasms non-small cell lung cancer (NSCLC) Pharmacology NSCLC Toxicology Carboplatin chemistry.chemical_compound Japan Carcinoma Non-Small-Cell Lung Antineoplastic Combined Chemotherapy Protocols Pharmacology (medical) Leukopenia Drug Synergism Middle Aged Combined Modality Therapy Tumor Burden Tolerability Paclitaxel Area Under Curve Female Original Article Drug Eruptions medicine.symptom Adult medicine.medical_specialty Veliparib Poly(ADP-ribose) Polymerase Inhibitors Neutropenia PARP Pharmacokinetics Internal medicine medicine Humans Aged Salvage Therapy Dose-Response Relationship Drug business.industry medicine.disease Hematologic Diseases Radiography chemistry Benzimidazoles business Veliparib (ABT-888) |
| Zdroj: | Cancer Chemotherapy and Pharmacology |
| ISSN: | 0344-5704 |
| DOI: | 10.1007/s00280-015-2876-7 |
| Popis: | Abstact Introduction 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/m2) 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 Cmax 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. |
| Databáze: | OpenAIRE |
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