title: Safety and pharmacokinetics of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer: final results of a phase I study.
abstract: The purpose of this study was to investigate the safety, pharmacokinetics and preliminary efficacy of bivatuzumab mertansine in patients with CD44v6-positive metastatic breast cancer. Anthracycline and taxane-pretreated patients with metastatic breast cancer that expressed CD44v6 received one single infusion of bivatuzumab mertansine and were observed for 21 days within one treatment course. Starting dose was 25 mg/m, while dose was escalated by increments of 25 mg/m. Patients who experienced a disease stabilization were eligible for further courses with bivatuzumab mertansine. Blood serum samples were taken throughout the treatment period for pharmacokinetic analysis. Twenty-four patients were treated at eight different dose levels (25-200 mg/m), seven of these patients received more than one course of bivatuzumab mertansine. Two dose-limiting toxicities occurred: one patient treated with 125 mg/m developed transient National Cancer Institute Common Toxicity Criteria grade 4 elevation of liver enzymes; another patient treated at 175 mg/m experienced National Cancer Institute Common Toxicity Criteria grade 3 vomiting. She died from renal failure, which might have been caused by deterioration of pre-existing renal insufficiency. The most common toxicities were transient and mild skin disorders in 75% of patients. As a consequence of one fatal toxic epidermal necrolysis that occurred in a study running in parallel, the clinical trials programme of bivatuzumab mertansine was discontinued. None of the patients developed antibodies against bivatuzumab mertansine. No objective responses were observed. Disease stabilization was achieved in 50% of patients independently of dose level. In conclusion, bivatuzumab mertansine targets CD44v6 and appears to stabilize heavily pretreated metastatic breast cancer that expresses CD44v6. The maximum tolerated dose could not be determined in this trial as the sponsor discontinued the clinical development of bivatuzumab mertansine.
authors.affiliation: Department of Gynecology and Obstetrics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Rupp
authors.forename: Eva
authors.initials: E
authors.lastname: Schoendorf-Holland
authors.forename: Michael
authors.initials: M
authors.lastname: Eichbaum
authors.forename: Florian
authors.initials: F
authors.lastname: Schuetz
authors.forename: Ilka
authors.initials: I
authors.lastname: Lauschner
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidt
authors.forename: Alexander
authors.initials: A
authors.lastname: Staab
authors.forename: Gertraud
authors.initials: G
authors.lastname: Hanft
authors.forename: Jens
authors.initials: J
authors.lastname: Huober
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Sinn
authors.forename: Christof
authors.initials: C
authors.lastname: Sohn
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006023:Glycoproteins / Q000032:analysis*; D006207:Half-Life; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis*; D007150:Immunohistochemistry; D007676:Kidney Failure, Chronic / Q000150:complications; D008111:Liver Function Tests; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000473:pathology; D013262:Stevens-Johnson Syndrome / Q000473:pathology; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C112697:CD44v6 antigen; D006023:Glycoproteins; D018960:Hyaluronan Receptors; C479239:monoclonal antibody BIWA 4