First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors

Abstract

Purpose: AT13387 is a potent second-generation, fragmentderived HSP90 inhibitor. This phase I study investigated the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and safety, pharmacokinetic, and pharmacodynamic profiles of two AT13387 regimens in a refractory solid tumor population.Experimental Design: Standard 3þ3 dose escalation was used. MTD and RP2D determinations were based on the occurrence of dose-limiting toxicities (DLT) and overall toxicity, respectively. Pharmacokinetic parameters were measured after single and multiple doses. AT13387-mediated induction of HSP70 was evaluated in plasma, peripheral blood mononuclear cells, and paired tumor biopsies.Results: Sixty-two patients were treated with doses ranging from 10 to 120 mg/m 2 twice weekly and 150 to 310 mg/m 2 once weekly (both for 3 weeks every 28 days). One DLT of visual disturbance occurred at 120 mg/m 2 , which was considered the MTD and RP2D for the twice-weekly regimen. No formal DLTs occurred in the once-weekly regimen, but multiple moderately severe toxicities, including diarrhea, nausea, vomiting, fatigue, and systemic infusion reactions, led to selection of 260 mg/m 2 as the RP2D. Exposures of AT13387 increased proportionally with dose. Target engagement as measured by HSP70 induction occurred in plasma and tumor biopsy samples. One patient with gastrointestinal stromal tumor (GIST) who had progressive disease on imatinib had a partial response and remained on treatment for 10 months. Twenty-one patients (34%) had stable disease, which lasted >120 days in 7 patients.Conclusion: AT13387 administered once or twice weekly has an acceptable safety profile and demonstrated evidence of target engagement and preliminary antitumor activity.

HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling

“…The feasibility of the clinical use of HSP90 inhibitors has already been demonstrated in several clinical trials. 23,32 The potential synergism between inhibitors targeting HSP90 and specific BCR-dependent kinases should be explored in future studies. Because HSP90 inhibitors target several important BCR signaling effectors at once, they might also become a valuable tool in the context of kinase inhibitor resistance, which is driven by mutations in the target kinase itself or bypass mechanisms through other cell survival promoting kinases.…”

“…[20][21][22][23] To study the effects of HSP90 inhibition at the molecular level, we analyzed the consequences of HSP90 inhibitors on the proteome-and tyrosine-enriched phosphoproteome (pYome) of BL cells using SILAC-based MS (see supplemental Figure 1C for details). We found that both AT13387 and STA-9090 induced highly correlated changes in the pYome of DG75 (r 5 0.825) and Daudi cells (r 5 0.831) after 24 and 16 hours of HSP90 inhibition, respectively (Figure 2A-B).…”

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

“…The study also showed that AT13387 depletes KIT, AKT and their phosphorylated forms in GIST cell lines regardless of the KIT mutation status. A phase I, open-label trial evaluated AT13387 in 62 patients with refractory solid tumors (7 of who had GIST) [121]. The drug was given through an i.v.…”

Efficacy of Onalespib, a Long-Acting Second-Generation HSP90 Inhibitor, as a Single Agent and in Combination with Temozolomide against Malignant Gliomas

“…This suggests that targeting HSP90 could potentially overcome these resistance mechanisms and improve sensitivity to therapies (15, 16). Currently, several HSP90 inhibitors are being evaluated in trials against solid tumors and are in different stages of clinical development (17–19). They bind to the N-terminal ATPase-pocket, affecting the chaperone activity and leading to the depletion of HSP90 substrates by subsequent proteosomal degradation (11–13).…”