1. Safety, efficacy, and pharmacokinetics of navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study.
- Author
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Tolcher AW, LoRusso P, Arzt J, Busman TA, Lian G, Rudersdorf NS, Vanderwal CA, Waring JF, Yang J, Holen KD, and Rosen LS
- Subjects
- Adenocarcinoma drug therapy, Adult, Aged, Aniline Compounds administration & dosage, Aniline Compounds adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Camptothecin administration & dosage, Camptothecin adverse effects, Camptothecin pharmacokinetics, Colonic Neoplasms drug therapy, Colonic Neoplasms pathology, Diarrhea chemically induced, Disease Progression, Dose-Response Relationship, Drug, Febrile Neutropenia chemically induced, Female, Hematologic Diseases chemically induced, Humans, Irinotecan, Male, Middle Aged, Neoplasms pathology, Salvage Therapy, Sulfonamides administration & dosage, Sulfonamides adverse effects, Treatment Outcome, Aniline Compounds pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Camptothecin analogs & derivatives, Neoplasm Proteins antagonists & inhibitors, Neoplasms drug therapy, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sulfonamides pharmacokinetics
- Abstract
Purpose: The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan., Methods: In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached., Results: All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response., Conclusion: The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients.
- Published
- 2015
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