Medical OncologyMulticenter Phase II Trial of the Heat Shock Protein 90 Inhibitor, Retaspimycin Hydrochloride (IPI-504), in Patients With Castration-resistant Prostate Cancer
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Patient Population
Adults (>18 years old) with progressive CRPC, defined as either 2 serial increases in prostate-specific antigen (PSA) or progressive radiographic metastases in the setting of castrate levels of serum testosterone (testosterone <50 ng/mL), were eligible for enrollment. The patients were enrolled into 2 groups: those who were chemotherapy naive (group 1) and those with evidence of radiographic metastases, progression during, or intolerance to, docetaxel-based chemotherapy, and ≤3 previous
Patient Enrollment, Characteristics, Disposition, and Exposure
A total of 34 patients were screened for enrollment (6 in group 1 and 28 in group 2). A total of 19 patients met all of the inclusion criteria and were enrolled and treated with IPI-504. The baseline characteristics of groups 1 (n = 4) and 2 (n = 15) are listed in Table 1. Most patients in both groups had bone metastases and measurable disease. Also, most patients in both groups had previously been treated with multiple lines of hormonal therapy, and the patients in group 2 had received a
Comment
In the present study of IPI-504 for patients with both chemotherapy-naive and docetaxel-treated CRPC, negligible activity and 2 treatment-related deaths were observed (1 attributed to hepatic failure and 1 to ketoacidosis). Hepatotoxicity has been observed with several Hsp90 inhibitors, which has limited the clinical development of geldanamycin,14 and was a dose-limiting toxicity in several Phase I trials of 17-AAG.15, 16, 17 The causality and mechanism of hyperglycemia in the patient who died
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The heat shock response and small molecule regulators
2021, European Journal of Medicinal ChemistryCitation Excerpt :However, research on IPI-493 was halted in favor of the more active and clinically feasible candidate, IPI-504 [131,132]. IPI-504 demonstrated anti-proliferative activity against pancreatic cancer cells and also blocked the unfolded protein response in multiple myeloma [133]. Disappointingly, it has also demonstrated low impact and unacceptable toxicity in patients with castration resistant prostate cancer [134–139].