Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan-CDK inhibitor, in patients with advance
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ORIGINAL ARTICLE
Phase 1 study of the HSP90 inhibitor onalespib in combination with AT7519, a pan‑CDK inhibitor, in patients with advanced solid tumors Khanh T. Do1,10 · Geraldine O’Sullivan Coyne2 · John L. Hays3 · Jeffrey G. Supko4 · Stephen V. Liu5 · Kristin Beebe6 · Len Neckers6 · Jane B. Trepel7 · Min‑Jung Lee7 · Tomoko Smyth8 · Courtney Gannon1 · Jennifer Hedglin1 · Alona Muzikansky9 · Susana Campos1 · John Lyons8 · Percy Ivy2 · James H. Doroshow2 · Alice P. Chen2 · Geoffrey I. Shapiro1 Received: 12 August 2020 / Accepted: 9 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose We conducted a phase 1 trial of the HSP90 inhibitor onalespib in combination with the CDK inhibitor AT7519, in patients with advanced solid tumors to determine the safety profile and maximally tolerated dose, pharmacokinetics, preliminary antitumor activity, and to assess the pharmacodynamic (PD) effects on HSP70 expression in patient-derived PBMCs and plasma. Methods This study followed a 3 + 3 trial design with 1 week of intravenous (IV) onalespib alone, followed by onalespib/ AT7519 (IV) on days 1, 4, 8, and 11 of a 21-days cycle. PK and PD samples were collected at baseline, after onalespib alone, and following combination therapy. Results Twenty-eight patients were treated with the demonstration of downstream target engagement of HSP70 expression in plasma and PBMCs. The maximally tolerated dose was onalespib 80 mg/m2 IV + AT7519 21 mg/m2 IV. Most common drug-related adverse events included Grade 1/2 diarrhea (79%), fatigue (54%), mucositis (57%), nausea (46%), and vomiting (50%). Partial responses were seen in a palate adenocarcinoma and Sertoli–Leydig tumor; a colorectal and an endometrial cancer patient both remained on study for ten cycles with stable disease as the best response. There were no clinically relevant PK interactions for either drug. Conclusions Combined onalespib and AT7519 is tolerable, though below monotherapy RP2D. Promising preliminary clinical activity was seen. Further benefit may be seen with the incorporation of molecular signature pre-selection. Further biomarker development will require the assessment of the on-target impact on relevant client proteins in tumor tissue. Keywords Heat-shock chaperone · HSP90 · HSP70 · AKT
Introduction
Khanh T. Do and Geraldine O’Sullivan Coyne contributed equally to this manuscript. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04176-z) contains supplementary material, which is available to authorized users. * Khanh T. Do [email protected] Extended author information available on the last page of the article
The 90 kDa heat-shock protein (HSP90) is a member of a class of evolutionarily conserved molecular chaperones that have an integral role in the maintenance of protein homeostasis within cells. These chaperones assist in the folding, stabilization, activation, and proteolytic turnover of newly synthesized “client” proteins [1–3]. Among these client
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