Phase I trial of KOS-953, a heat shock protein 90 inhibitor, and trastuzumab (T)

Abstract

501 Background: KOS-953 (17-AAG in Cremophor) is a potent Hsp90 inhibitor that in vivo induces rapid degradation of Her2, loss of pAKT and tumor growth inhibition in a Her2+ breast cancer xenograft. Objectives: Define the phase 2 dose of KOS-953 + T. Define toxicity and PK of KOS-953, its active metabolite and T. Assess changes in intracellular signaling proteins (such as Hsp70) in leucocytes. Describe antitumor activity. Methods: Eligible pts with advanced solid tumors (Her2 + was not required) received standard weekly doses of T followed by IV KOS-953 in escalating doses over 2 hrs. Results: 25 pts enrolled in 4 cohorts (225, 300, 375 and 450 mg/m 2 ; 4, 3, 8 and 10 patients per cohort), receiving a total of 94 cycles (median 3, range <1 - 12+). Demographics: 21 female (17 with Her2+ metastatic breast cancer ‘MBC‘, 1 Her2 status unknown); median age/KPS 66 yrs/90; # prior T-containing regimens for MBC pts (n=18) equaled 2 (range 0–5). DLT was observed at the 3 rd and 4 th cohort (1 pt each): 2-week dose delay for recovery from Grade 4 fatigue/Grade 2 nausea & anorexia at 375 mg/m 2 ; delayed recovery of platelets at 450 mg/m 2 . Drug-related Grade 3 toxicity: emesis, increased ALT and hypersensitivity (n=2); Grade 4 drug-induced thrombocytopenia in a pt with Hashimoto’s disease after 7 cycles. In general the drug was well tolerated. Grade 1 or 2 toxicities included fatigue, nausea, diarrhea, emesis, headache, rash/pruritus, increased AST/ALT and anorexia. Most toxicities (except headache) were not dose dependent. PK of parent (n=21): t½ 3.0 ± 2.1 h; clearance 31.8 ± 12.8 L/h; Vz 164 ± 101 L. Metabolite: Tmax 30–60 min after end-of-infusion with similar AUC and longer t½ of 6.1 ± 1.7 h. PK of T showed no changes compared to previous reports. Among 17 pts with Her2 + MBC s/p multiple regimens of T: PR= 1, MR = 3, 5 pts with SD (5, 7+, 9 and 12+ months). Pts with PR and MRs had confirmed progression of disease prior to study on T-containing regimen. Pharmacodynamic testing showed reactive induction of Hsp70/72 in leucocytes at all dose levels. Conclusions: KOS-953 added to T is active in refractory Her2 + MBC with no change in PK compared to single-agent therapy. The phase 2 dose of KOS-953 is 450 mg/m 2 ; enrollment to the phase 2 trial of this combination in Her2+ MBC is on-going. [Table: see text]