A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors. Academic Article uri icon

Overview

MeSH

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized
  • Benzoquinones
  • Female
  • Humans
  • Lactams, Macrocyclic
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Staging
  • Trastuzumab
  • Treatment Outcome

MeSH Major

  • Antineoplastic Combined Chemotherapy Protocols
  • Neoplasms

abstract

  • We conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics of alvespimycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, given in combination with trastuzumab. 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 (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible. Twenty-eight patients (25, breast; 3, ovarian) were enrolled onto three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m(2) (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m(2)), and reversible grade III keratitis in two patients (80 mg/m(2)). Drug-related grade III toxicity included one 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 one partial response and seven cases of stable disease (range, 4-10 months), all in HER2+ MBC. In addition, 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 four weeks and was most pronounced at 80 and 100 mg/m(2). 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 for further study in this combination is 80 mg/m(2) weekly. ©2012 AACR.

publication date

  • September 15, 2012

has subject area

  • Adult
  • Aged
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Combined Chemotherapy Protocols
  • Benzoquinones
  • Female
  • Humans
  • Lactams, Macrocyclic
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms
  • Trastuzumab
  • Treatment Outcome

Research

keywords

  • Clinical Trial, Phase I
  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-11-3200

PubMed ID

  • 22781552

Additional Document Info

start page

  • 5090

end page

  • 5098

volume

  • 18

number

  • 18