Ganetespib in Combination with Pemetrexed-Platinum Chemotherapy in Patients with Pleural Mesothelioma (MESO-02): A Phase Ib Trial.

Autor:	Fennell DA; Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, United Kingdom. df132@leicester.ac.uk., Danson S; Sheffield ECMC, University of Sheffield, Weston Park Hospital, Sheffield, United Kingdom., Woll PJ; Sheffield ECMC, University of Sheffield, Weston Park Hospital, Sheffield, United Kingdom., Forster M; UCL Hospitals & CRUK Lung Cancer Centre of Excellence, London, United Kingdom., Talbot D; Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom., Child J; Cancer Research UK & University College London Cancer Trials Centre, London, United Kingdom., Farrelly L; Cancer Research UK & University College London Cancer Trials Centre, London, United Kingdom., Sharkey A; Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, United Kingdom., Busacca S; Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, University of Leicester & University Hospitals of Leicester NHS Trust, Leicester, United Kingdom., Ngai Y; Cancer Research UK & University College London Cancer Trials Centre, London, United Kingdom., Hackshaw A; Cancer Research UK & University College London Cancer Trials Centre, London, United Kingdom., Wheeler GM; Cancer Research UK & University College London Cancer Trials Centre, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Sep 15; Vol. 26 (18), pp. 4748-4755. Date of Electronic Publication: 2020 Jul 15.
DOI:	10.1158/1078-0432.CCR-20-1306
Abstrakt:	Purpose: Ganetespib, a highly potent, small-molecule Heatshock protein 90 inhibitor, has potential efficacy in malignant pleural mesothelioma (MPM) via activity on critical survival pathways and known synergies with antifolates and platinum chemotherapy. We conducted a dose-escalation study to identify the maximum tolerated dose (MTD) of ganetespib in patients with chemotherapy-naïve MPM. Patients and Methods: MESO-02 (ClinicalTrials.gov: NCT01590160) was a nonrandomized, multicenter, phase Ib trial of 3-weekly ganetespib (100 mg/m 2 , 150 mg/m 2 , 200 mg/m 2 ; days 1 and 15) with pemetrexed (500 mg/m 2 ; day 1) and cisplatin (75 mg/m 2 ; day 1) or carboplatin (area under concentration-time curve 5; day 1) in patients with MPM. Dose escalation was performed using the 3 + 3 design (cisplatin) and accelerated titration design (carboplatin). Secondary endpoints included best response, progression-free survival (PFS), and pharmacogenomic analyses. Results: Of 27 patients enrolled (cisplatin, n = 16; carboplatin, n = 11), 3 experienced dose-limiting toxicities: grade 3 nausea (cisplatin, n = 1; carboplatin, n = 1) and grade 2 infusion-related reaction (carboplatin, n = 1). Ganetespib's MTD was 200 mg/m 2 . Partial response was observed in 14 of 27 patients (52%; 61% in 23 response-evaluable patients) and 13 of 21 (62%) with epithelioid histology. At the MTD, 10 of 18 patients (56%) had partial response, 15 of 18 (83%) had disease control, and median PFS was 6.3 months (95% CI, 5.0-10.0). One responder exhibited disease control beyond 50 months. Global loss of heterozygosity was associated with shorter time to progression (HR 1.12; 95% CI, 1.02-1.24; P = 0.018). Conclusions: Ganetespib can be combined safely with pemetrexed and platinum chemotherapy to treat patients with MPM. This class of agent should be investigated in larger randomized studies. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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