Phase 1 experience with BIIB021, an oral, synthetic, non-ansamycin Hsp90 inhibitor
Daniel D. Von Hoff, Murali Beeram, S. O' Brien, Nicole Lammanna, Januario E. Castro, Mitesh J. Borad, Francis J. Burrows, Denise Trone, James R. Woodworth, Shabnam Tangri, Rachelle Perea, Chris M. Storgard, M. W. Saif · Molecular Cancer Therapeutics · 2007
A123 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.