Cavenagh J, Oakervee H, Baetiong-Caguioa P, Davies F, Gharibo M, Rabin N, Kurman M, Novak B, Shiraishi N, Nakashima D, Akinaga S, Yong K
Department of Haematology, St Bartholomew's Hospital, West Smithfield, London SE24 9LG, UK.
Benavides Cancer Institute, University of Santo Tomas Hospital, Manila and St Luke's Medical Center, Quezon City, The Philippines.
Br J Cancer. 2017 Oct 24;117(9):1295-1302. doi: 10.1038/bjc.2017.302. Epub 2017 Sep 5.
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).
Phase I dose escalation determined the recommended phase II dose (RP2D) of KW-2478 plus BTZ, which was then used during phase II.
The maximum tolerated dose was not reached during phase I and the RP2D was KW-2478 175 mg m plus BTZ 1.3 mg m 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%).
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.
KW-2478是一种新型非安莎霉素类Hsp90抑制剂，在复发/难治性骨髓瘤中具有适度的单药活性，但在临床前研究中显示与硼替佐米（BTZ）具有协同抗骨髓瘤活性。本研究确定了Hsp90抑制剂KW-2478联合BTZ用于复发/难治性多发性骨髓瘤（MM）患者的安全性、初步临床活性和药代动力学。
I期剂量递增确定了KW-2478加BTZ的推荐II期剂量（RP2D），随后在II期使用。
I期未达到最大耐受剂量，RP2D为每3周第1、4、8和11天给予KW-2478 175mg/m²加BTZ 1.3mg/m²。在按RP2D治疗的可评估疗效的I/II期人群（n = 79）中，客观缓解率为39.2%（95%置信区间：28.4 - 50.9%），临床获益率为51.9%（40.4 - 63.3%），中位无进展生存期为6.7（5.9 - 未达到（NR））个月，中位缓解持续时间为5.5（4.9 - NR）个月。在I/II期安全性人群（n = 95）中，最常观察到的3/4级治疗相关不良事件为腹泻、疲劳和中性粒细胞减少（各占患者的7.4%），以及恶心和血小板减少（各占5.3%）。
KW-2478加BTZ耐受性良好，在复发/难治性MM患者中无明显重叠毒性。本试验中KW-2478联合BTZ的抗骨髓瘤活性似乎相对适度；然而，该联合方案的良好耐受性将支持进一步探索替代给药方案和联合用药。
