Journal
BRITISH JOURNAL OF CANCER
Volume 117, Issue 9, Pages 1295-1302Publisher
SPRINGERNATURE
DOI: 10.1038/bjc.2017.302
Keywords
KW-2478; multiple myeloma; bortezomib; Hsp90 inhibitor
Categories
Funding
- Kyowa Kirin Pharmaceutical Development, Inc. (Princeton, NJ, USA) (KKD)
- KKD
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Background: KW-2478 is a novel non-ansamycin Hsp90 inhibitor with modest single-agent activity in relapsed/refractory myeloma but which shows synergistic antimyeloma activity with bortezomib (BTZ) in preclinical studies. This study determined the safety, preliminary clinical activity, and pharmacokinetics of KW-2478, an Hsp90 inhibitor, in combination with BTZ in patients with relapsed/refractory multiple myeloma (MM). Methods: Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II. Results: The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m(-2) plus BTZ 1.3 mg m(-2) on days 1, 4, 8, and 11 every 3 weeks. In the efficacy evaluable phase I/II population treated at the RP2D (n = 79), the objective response rate was 39.2% (95% confidence interval: 28.4-50.9%), clinical benefit rate 51.9% (40.4-63.3%), median progression-free survival 6.7 (5.9-not reached (NR)) months, and median duration of response 5.5 (4.9-NR) months. In the phase I/II safety population (n = 95), the most frequently observed treatment-related grade 3/4 adverse events were diarrhoea, fatigue, and neutropenia (each in 7.4% of patients), and nausea and thrombocytopenia (each in 5.3%). Conclusions: KW-2478 plus BTZ was well tolerated with no apparent overlapping toxicity in patients with relapsed/refractory MM. The antimyeloma activity of KW-2478 in combination with BTZ as scheduled in this trial appeared relatively modest; however, the good tolerability of the combination would support further exploration of alternate dosing schedules and combinations.
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