title: A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer.
abstract: Heat shock protein 90 (Hsp90) facilitates maturation and stability of HER2. Combining an Hsp90 inhibitor and trastuzumab has demonstrated anti-tumor effects in patients with HER2+ breast cancer. Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m(2) retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks. A Simon's two-stage design determined trial expansion by dose-limiting toxicity (DLT) and response rates. Pharmacokinetics and electrocardiograms were evaluated. Twenty-six patients with median age 52.5 years (range 33-72) enrolled with a median of six prior chemotherapeutic regimens (range 2-20). On study, patients received a median of three treatment cycles (range 1-12). No DLTs were observed. Most adverse events (AEs) were grade 1 or 2; common treatment-related AEs included fatigue (46 %), nausea (31 %), and diarrhea (23 %). One patient had treatment-related serious AEs of grade 1 diarrhea and grade 3 hypokalemia. grade 3 transaminase elevation occurred in one patient (4 %) who also had metastatic liver disease. Sixteen patients (62 %) had stable disease, with a median on-study duration of 2.4 months (range 1.1-8.2). No confirmed responses were observed. Retaspimycin HCl at 300 mg/m² weekly in combination with trastuzumab was well tolerated and without significant toxicities. Modest clinical activity was observed, but did not meet criteria for trial expansion. The safety profile for patients on study raises the possibility of retaspimycin HCl underdosing that limited efficacy. Studies employing higher doses are ongoing.
authors.affiliation: Memorial Sloan-Kettering Cancer Center/Weill Cornell Medical College, 300 East 66th Street, New York, NY 10065, USA. modis@mskcc.org
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
authors.forename: Cristina
authors.initials: C
authors.lastname: Saura
authors.forename: Charles
authors.initials: C
authors.lastname: Henderson
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.forename: Reshma
authors.initials: R
authors.lastname: Mahtani
authors.forename: Jill
authors.initials: J
authors.lastname: Goddard
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rodenas
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C112765:tanespimycin