Abstract B101: Safety, tolerability, and pharmacokinetics of IPI-493, an oral Hsp90 inhibitor, in patients with advanced cancers.
Authors: Senzer Neil N. , Mendelson David , Weekes Colin , Rosen Lee , LoRusso Pat , Just Richard , Smith Doug , Ritchie Ellen , DeLucia Dianne , Quigley Travis , Dunbar Joi , Schmalbach Tess , Cortes Jorge 
Published: June 2012

Background: Inhibition of the Hsp90 chaperone protein is associated with clinical activity in selected patients (pts). IPI-493, an oral Hsp90 inhibitor, was assessed in advanced solid and hematologic malignancies in two phase 1 studies. Study objectives included determination of the following: maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended phase 2 dose, safety/tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and clinical activity.

Methods: Pts with advanced cancers received oral IPI-493 for 21-day cycles in a routine 3+3, sequential dose escalation design with three unique schedules: three times weekly for 2 weeks + 1 week rest (TIW), twice weekly for 2 weeks + 1 week rest (BIW), and once weekly continuously (QW). PK and PD samples were obtained in Cycle 1 during Weeks 1 and 3. CT scans were performed at baseline and every 2 cycles thereafter.

Results: IPI-493 (TIW n=14, BIW n=21 and QW n=22) at doses from 50 to 250 mg was administered to 57 pts (53 with solid tumors, 4 with hematologic malignancies) with a median age of 58 years (range 21–86), ECOG score 0–1, and a median of 5 previous chemotherapy agents (range 1–16). The most common tumor types were colorectal cancer (10 pts) and gastrointestinal stromal tumor (6 pts). The median time on study was 65 days (range 15–544). Fourteen total DLTs were observed in 4 pts on the TIW (200 mg and 150 mg) schedule and 1 pt on the BIW (125 mg) schedule, which were primarily elevations in aspartate aminotransferase (AST), alanine aminotransferase, and alkaline phosphatase (ALP). No DLTs were observed on the QW schedule. DLTs of metabolic acidosis and acute renal failure were fatal in a single pt; all other DLTs were reversible. A maximum tolerated dose was not determined. The most common treatment-related adverse events were fatigue (35%), diarrhea (30%), elevated AST (28%), elevated ALP (25%), and nausea (21%). Maximal plasma concentrations occurred approximately 2–3 hours following single and repeat oral administration. Across all doses and schedules, the mean terminal elimination half life was approximately 14 hours, with no drug accumulation observed upon repeat dosing. Systemic exposure increased with dose across the 50–150 mg dose levels and demonstrated a plateau at 150 mg with no further increases in mean exposure at doses up to 250 mg.

Conclusions: IPI-493 tolerability was schedule dependent, with increasing toxicity identified on the TIW schedule. Development of IPI-493 is no longer being pursued due to the lack of increased exposure with increasing doses.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B101.