A Phase I Study of PF-04929113 (SNX-5422), an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Patients with Refractory Solid Tumor Malignancies and Lymphomas

Abstract

Purpose To determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic-pharmacodynamic profile of the heat shock protein 90 (Hsp90) inhibitor PF-04929113 (SNX-5422) in patients with advanced solid tumors and lymphomas. Methods This was a single institution, phase I, dose-escalation study of PF-04929113 dosed twice-weekly. Endpoints included determination of dose-limiting toxicities (DLT), MTD, the safety profile of PF-04929113, pharmacodynamic assessment of PF-04929113 on Hsp70 induction, pharmacokinetic (PK) analysis of PF 04928473 (SNX-2112) and its prodrug PF-04929113 and assessment of response. Results Thirty three patients with advanced malignancies were treated. Dose escalation was continued up to 177 mg/m2 administered orally twice a week. One DLT (non-septic arthritis) was noted. No grade 4 adverse events (AEs) were seen; grade 3 AEs included diarrhea (9%), non-septic arthritis (3%), AST elevation (3%) and thrombocytopenia (3%). No objective responses were seen in 32 evaluable patients. Fifteen patients (47%) had stable disease; 17 patients (53%) had progressive disease. PK data revealed rapid absorption, hepatic and extra-hepatic clearance, extensive tissue binding and almost linear pharmacokinetics of the active drug PF 04928473. PD studies confirmed inhibition of Hsp90 and a linear correlation between PK parameters and Hsp70 induction. Conclusions PF-04929113 administered orally twice weekly is well tolerated and inhibits its intended target Hsp90. No objective responses were seen but long lasting stabilizations were obtained. Although no clinically significant drug-related ocular toxicity was seen in this study the development of PF-04929113 has been discontinued due to ocular toxicity seen in animal models and in a separate phase I study.

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

“…Visual disturbances also occurred; these events were typically transient and low grade. Ophthalmologic toxicity may be an inherent property of potent water-soluble HSP90 inhibitors, as these findings have been reported with other agents, including 17-DMAG and AUY922 (8,25,26). Other commonly occurring AT13387 treatmentrelated AEs ($30%) included nausea and injection site events and systemic infusion reactions, all of which were grade 1 or 2 and managed prophylactically or treated symptomatically.…”

First-in-Human Phase I Dose-Escalation Study of the HSP90 Inhibitor AUY922 in Patients with Advanced Solid Tumors

“…Visual AEs were reported, which were most frequent at the higher (40-70 mg/m 2 ) dose levels, although typically grade 1 to 2, and were reversible following interruption or discontinuation of study treatment. Visual disturbances have been reported with other geldanamycin and non-geldanamycin HSP90 inhibitors (32)(33)(34). These effects may be attributable to HSP90 inhibitor-induced photoreceptor degeneration and possibly related to tissue distribution of water-soluble agents facilitating a high retina/plasma concentration ratio, as well as the retinal elimination profile (35).…”

TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

“…TAS-116 addresses the issues that have hampered the clinical development of HSP90 inhibitors because it shows a favorable tissue distribution profile. One of the most notable HSP90-related adverse events universally observed but to differing degrees in the clinic is visual disturbance (18)(19)(20)(21)(45)(46)(47)(48). The observed symptoms include night blindness, photopsia, blurred vision, and visual impairment, which are likely associated with retinal dysfunction (20,21).…”

“…For example, neurological toxicities such as syncope and dizziness were seen in a phase I trial of the purine analogue BIIB021 (17), although there is no evidence to support this to be target or purine-scaffold related. In clinical trials of other HSP90 inhibitors, the most commonly observed HSP90-related adverse events have been visual disorders such as night blindness, photopsia, blurred vision, and visual impairment, though the frequency and degree varied among the compounds (18)(19)(20)(21). For example, 43% of patients suffered visual disturbances in a phase I trial of NVP-AUY922 (21).…”