Fennell, D.A., Danson, S. orcid.org/0000-0002-3593-2890, Woll, P.J. orcid.org/0000-0002-1118-0831 et al. (9 more authors) (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. ISSN 1078-0432
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 chemotherapy-naïve MPM patients.
Experimental Design: MESO-02 (ClinicalTrials.gov: NCT01590160) was a non-randomized, multicentre, 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 MPM patients. 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 enroled (cisplatin, n=16; carboplatin, n=11), 3 experienced dose-limiting toxicities: grade 3 nausea (cisplatin, n=1; carboplatin, n=1); grade 2 infusion-related reaction (carboplatin, n=1). Ganetespib's MTD was 200 mg/m2. Partial response was observed in 14/27 patients (52%; 61% in 23 response-evaluable patients) and 13/21 (62%) with epithelioid histology. At the MTD, 10/18 patients (56%) had partial response, 15/18 (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 (Hazard Ratio 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 American Association for Cancer Research. This is an author-produced version of a paper subsequently published in Clinical Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | phase Ib; mesothelioma; heatshock protein; ganetespib; platinum therapy |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 30 Jul 2020 06:34 |
Last Modified: | 21 Jan 2022 11:27 |
Status: | Published |
Publisher: | American Association for Cancer Research (AACR) |
Refereed: | Yes |
Identification Number: | 10.1158/1078-0432.ccr-20-1306 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:163845 |