Phase 1 experience with BIIB021, an oral, synthetic, non-ansamycin Hsp90 inhibitor

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Hsp90 inhibitors hold great promise as anti-tumor therapies because Hsp90 is a critical chaperone of key proteins involved in tumor growth and survival. A series of fully synthetic non-ansamycin, small molecule Hsp90 inhibitors have been developed for oral administration (po) to overcome the toxicity and development challenges observed with geldanamycin-based agents (i.e. 17-AAG). Pre-clinical data reveals that the lead clinical investigational compound, BIIB021, binds to Hsp90, induces client protein degradation and Hsp70 induction, and shows potent anti-tumor activity comparable to that of 17-AAG in a variety of xenograft models including breast and prostate cancer. Multiple Phase 1 studies have been initiated to assess safety, MTD, tolerability, and pharmacokinetics (PK) of BIIB021 in patients (pts) with advanced solid tumors (ST) or chronic lymphocytic leukemia (CLL). Methods: Three to 6 pts were enrolled into sequential dose cohorts of BIIB021 po daily for 3 weeks followed by 1 week off (CLL) or po twice weekly for 3 weeks followed by 1 week off (ST). Pts remained on study until tumor progression or unacceptable toxicities occurred. Results: As of July 27, 2007, data is available for 23 pts administered BIIB021 (5 in CLL; 18 in ST). 14 were men (3 in CLL and 11 in ST); median (range) age was 66 (45, 79) years in CLL and 59.5 (35, 81) in ST. Safety: The MTD has not been reached. No DLTs or treatment-related (TR) serious AEs were reported. 18 pts reported TR AEs. Grade 3 or 4 TR AEs in ST were fatigue, hyponatremia and hypoglycemia; in CLL 1 pt experienced grade 3 abnormal LFT. TR AEs in CLL in >1 pts were: abdominal pain and diarrhea (n=2 each). TR AEs in ST in >2 pts were: fatigue (n=6); nausea, vomiting, hot flush (n=5 each), dry mouth (n=4), flushing (n=3). No evidence of drug-related hepatotoxicity has been observed up to the current 700 mg twice weekly dosing. PK/PD: PK data was available through 50 mg in CLL, and through 600 mg in ST; BIIB021 demonstrated dose-linear kinetics with a T_1/2 of ~1 h and no evidence of accumulation with multiple dosing. PD assessments indicate significant induction of Hsp70 and inhibition of the biomarker Her 2/neu extracellular domain (ECD) in the ST trial. Efficacy: One pts with CLL receiving 25 mg was noted to have a reduction in peripheral lymph nodes within one week of treatment per investigator report. Response assessment in this pts 4 months after dosing demonstrated an overall 39% reduction in lymph node size. Conclusions: BIIB 021 administered up to 600 mg twice weekly and 50 mg daily 3w on/1w off appears to be well tolerated in these pts with no evidence of hepatotoxicity. Biologic activity has been confirmed with elevations of serum and intracellular Hsp70 and a dose-related decrease in serum Her-2 ECD. Further studies evaluating BIIB021 without a drug holiday and BIIB021 in combination with chemotherapy and targeted agents are warranted.