Phase I Study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors
Mené sur 41 patients atteints d'une tumeur solide de stade avancé, cet essai de phase I évalue la toxicité et l'activité antitumorale d'un composé appelé BIIB028, un promédicament conçu pour inhiber l'activité de la protéine de choc thermique Hsp90
Purpose:Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity. Experimental Design: Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a week in 21-day cycles (3+3 design). Response was evaluated after 2 cycles. Results: Forty-one patients received doses of 6 to 192 mg/m2. The maximum tolerated dose was 144 mg/m2. Dose-limiting toxicities were syncope (n=1) and fatigue (n=1). Common toxicities at least possibly related to drug were grade 1-2, including fatigue (46%), diarrhea (44%), nausea (44%), vomiting (29%), hot flushes (29%) and abnormal dreams (17%). The concentration-time curves for Day 1 and Day 18 for both prodrug and active metabolite (CF2772) showed a negligible difference. There was a dose-dependent increase in plasma exposure for BIIB028 (CF3647) and CF2772 with plasma half-life of 0.5 and 2.1 hours, respectively. Pharmacodynamic analyses demonstrated significant increases in Hsp70 in peripheral blood mononuclear cells and significantly decreased circulating human epidermal growth factor receptor 2- extracellular domain in all patients who received BIIB028 at dose levels ≥48mg/m2. Stable disease for at least 8 cycles (24 weeks) was achieved in 5 (12%) patients (6, 6, 8, 12.5 and 19 months). Conclusions: BIIB028 is a well-tolerated molecule that demonstrated target impact and was associated with prolonged stable disease in 2 patients.