Elsevier

Urology

Volume 78, Issue 3, September 2011, Pages 626-630
Urology

Medical Oncology
Multicenter Phase II Trial of the Heat Shock Protein 90 Inhibitor, Retaspimycin Hydrochloride (IPI-504), in Patients With Castration-resistant Prostate Cancer

https://doi.org/10.1016/j.urology.2011.04.041Get rights and content

Objective

To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC).

Methods

A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ≥1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout.

Results

A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively.

Conclusion

Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.

Section snippets

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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