A Phase I Dose-escalation trial of Trastuzumab and Alvespimycin Hydrochloride (KOS-1022; 17 DMAG) In the Treatment of Advanced Solid tumors
Menée sur 25 patientes atteintes d'un cancer du sein et 3 patientes atteintes d'un cancer de l'ovaire, cet essai de phase I évalue un traitement combinant un inhibiteur de Hsp90, l'alvespimycine, et le trastuzumab
Purpose:We conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK) and pharmacodynamics of alvespimycin (17-DMAG), an Hsp90 inhibitor, plus trastuzumab. Experimental Design:Patients were treated with trastuzumab followed by intravenous alvespimycin on a weekly schedule. Hsp90 client proteins were measured at baseline and serially in peripheral blood lymphocytes (PBLs) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible. Results:Twenty-eight patients (25, breast; 3, ovarian) were enrolled onto 3 dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m2 (n = 6). Dose-limiting toxicities were: grade 3 left ventricular systolic dysfunction/congestive heart failure in 1 patient (100mg/m2), and reversible grade 3 keratitis in 2 patients (80mg/m2). Drug-related grade 3 toxicity included 1 episode each of fatigue, diarrhea, myalgia and back pain. Common mild to moderate toxicities included diarrhea, fatigue, myalgia, arthralgia, nausea, blurry vision, headache, back pain and dry eyes. There was 1 partial response and 7 cases of stable disease (range, 4-10 months), all in HER2+ MBC. Additionally, an ovarian cancer patient had complete resolution of ascites and pleural effusion that lasted 24.8 months. There was no change in PK upon weekly dosing. Hsp70 effect continued to increase across 4 weeks and was most pronounced at 80 and 100 mg/m2. Conclusions:The combination of alvespimycin and trastuzumab is safe and tolerable at MTD. Antitumor activity was seen in patients with refractory HER2+ MBC and ovarian cancer. The recommended dose of alvespimycin in this combination is 80mg/m2 weekly.