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

Komal Jhaveri, Kathy Miller, Lee Rosen, Bryan Schneider, Linnea Chap, Alison Hannah, Ziyang Zhong, Weining Ma, Clifford Hudis, Shanu Modi

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. 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 (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible. Results: Twenty-eight patients (25, breast; 3, ovarian) were enrolled on to three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m2 (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m2), and reversible grade III keratitis in two patients (80 mg/m2). 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 inHER2+ 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/m2. Conclusion: 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/m2 weekly.

Original languageEnglish (US)
Pages (from-to)5090-5098
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number18
DOIs
StatePublished - Sep 15 2012

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17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
Neoplasms
HSP90 Heat-Shock Proteins
Maximum Tolerated Dose
Myalgia
Back Pain
Ovarian Neoplasms
Therapeutics
Fatigue
Diarrhea
Pharmacokinetics
Keratitis
Arthralgia
Left Ventricular Dysfunction
Pleural Effusion
Trastuzumab
Ascites
Nausea
Headache
Appointments and Schedules

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors. / Jhaveri, Komal; Miller, Kathy; Rosen, Lee; Schneider, Bryan; Chap, Linnea; Hannah, Alison; Zhong, Ziyang; Ma, Weining; Hudis, Clifford; Modi, Shanu.

In: Clinical Cancer Research, Vol. 18, No. 18, 15.09.2012, p. 5090-5098.

Research output: Contribution to journalArticle

Jhaveri, Komal ; Miller, Kathy ; Rosen, Lee ; Schneider, Bryan ; Chap, Linnea ; Hannah, Alison ; Zhong, Ziyang ; Ma, Weining ; Hudis, Clifford ; Modi, Shanu. / A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 18. pp. 5090-5098.
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T1 - A phase I dose-escalation trial of trastuzumab and alvespimycin hydrochloride (KOS-1022; 17 DMAG) in the treatment of advanced solid tumors

AU - Jhaveri, Komal

AU - Miller, Kathy

AU - Rosen, Lee

AU - Schneider, Bryan

AU - Chap, Linnea

AU - Hannah, Alison

AU - Zhong, Ziyang

AU - Ma, Weining

AU - Hudis, Clifford

AU - Modi, Shanu

PY - 2012/9/15

Y1 - 2012/9/15

N2 - Purpose: 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. 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 (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible. Results: Twenty-eight patients (25, breast; 3, ovarian) were enrolled on to three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m2 (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m2), and reversible grade III keratitis in two patients (80 mg/m2). 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 inHER2+ 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/m2. Conclusion: 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/m2 weekly.

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