A multicenter trial evaluating retaspimycin HCL (IPI-504) plus trastuzumab in patients with advanced or metastatic HER2-positive breast cancer Journal Article
| Authors: | Modi, S.; Saura, C.; Henderson, C.; Lin, N. U.; Mahtani, R.; Goddard, J.; Rodenas, E.; Hudis, C.; O'Shaughnessy, J.; Baselga, J. |
| Article 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/m2 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/mÂsup2 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. © 2013 The Author(s). |
| Keywords: | adult; clinical article; treatment outcome; aged; disease-free survival; middle aged; constipation; drug tolerability; fatigue; advanced cancer; area under the curve; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; side effect; treatment duration; outcome assessment; prospective study; anorexia; progression free survival; multiple cycle treatment; phase 2 clinical trial; breast cancer; nausea; antineoplastic combined chemotherapy protocols; epidermal growth factor receptor 2; breast neoplasms; abdominal pain; alanine aminotransferase blood level; aminotransferase blood level; aspartate aminotransferase blood level; asthenia; chill; drug fever; dyspnea; gamma glutamyl transferase blood level; alanine aminotransferase; alkaline phosphatase; aspartate aminotransferase; chemotherapy induced emesis; drug induced headache; gastrointestinal toxicity; hypokalemia; liver metastasis; multicenter study; drug response; tanespimycin; drug clearance; receptor, erbb-2; alkaline phosphatase blood level; maximum plasma concentration; drug blood level; drug half life; aminotransferase; trastuzumab; amylase blood level; heart left ventricle ejection fraction; electrocardiogram; eye toxicity; amylase; benzoquinones; lactams, macrocyclic; phase 2; retaspimycin; urine color; antibodies, monoclonal, humanized; her2+ mbc; retaspimycin plus trastuzumab; drug rechallenge; first degree atrioventricular block |
| Journal Title: | Breast Cancer Research and Treatment |
| Volume: | 139 |
| Issue: | 1 |
| ISSN: | 0167-6806 |
| Publisher: | Springer |
| Date Published: | 2013-05-01 |
| Start Page: | 107 |
| End Page: | 113 |
| Language: | English |
| DOI: | 10.1007/s10549-013-2510-5 |
| PROVIDER: | scopus |
| PMCID: | PMC3646160 |
| PUBMED: | 23580070 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 June 2013" - "CODEN: BCTRD" - "Source: Scopus" |
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