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Ganetespib in combination with pemetrexed-platinum chemotherapy in patients with pleural Mesothelioma (MESO-02): A phase Ib trial

Fennell, D; Danson, S; Woll, P; Forster, M; Talbot, D; Child, J; Farrelly, L; ... Wheeler, G; + view all (2020) Ganetespib in combination with pemetrexed-platinum chemotherapy in patients with pleural Mesothelioma (MESO-02): A phase Ib trial. Clinical Cancer Research , 26 (18) pp. 4748-4755. 10.1158/1078-0432.CCR-20-1306. Green open access

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Abstract

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/m2, 150 mg/m2, 200 mg/m2; days 1 and 15) with pemetrexed (500 mg/m2; day 1) and cisplatin (75 mg/m2; 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/m2. 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.

Type: Article
Title: Ganetespib in combination with pemetrexed-platinum chemotherapy in patients with pleural Mesothelioma (MESO-02): A phase Ib trial
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/1078-0432.CCR-20-1306
Publisher version: https://doi.org/10.1158/1078-0432.CCR-20-1306
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10103047
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