P1-12-19: Phase I Study of Single Agent Trastuzumab Emtansine in Japanese Patients with Human Epidermal Growth Factor Receptor2 (HER2)-Positive Metastatic Breast Cancer (JO22591).
Authors: Aogi K , Ando M , Iwata H , Hara F , Matsubara M , Fujiwara Y 
Published: June 2012

Abstract
Background Trastuzumab emtansine (T-DM1), first-in-class anti-HER2 antibody-drug conjugate (ADC) is under development for the treatment of HER2−postive recurrent locally advanced or metastatic breast cancer (MBC). T-DM1 is composed of: trastuzumab; DM1, an inhibitor of tubulin polymerization derived from maytansine; and the stable MCC linker that conjugates DM1 and trastuzumab. T-DM1 has been evaluated at multiple dose levels in a phase I trial (TDM3569g): every 3 weeks (q3w) (0.3−1.8 mg/kg) and weekly (1.2−2.9 mg/kg), and in two subsequent phase II trials (TDM4258g and TDM4374g) for patients with heavily pretreated HER2−positive MBC. T-DM1 monotherapy (3.6 mg/kg q3w) has demonstrated robust clinical efficacy in these two phase II clinical studies. Dose escalation data from the TDM3569g provided the basis for this phase I study (JO22591) study, to investigate the maximal tolerated dose (MTD) in Japanese patients.
Methods This Japanese Phase I study was a single-arm, dose-escalation study in patients with HER2−positive MBC who had received prior therapies that included trastuzumab. The objective of the study was to determine the MTD of T-DM1 during Cycle 1, using the continual reassessment method, among three dose cohorts when administered as a single agent and to investigate safety, tolerability and pharmacokinetics of T-DM1 in patients with HER2−positive MBC. Eligibility criteria were standard for this type of study. T-DM1 was administered every 3 weeks at a dose level of 1.8 mg/kg, 2.4 mg/kg or 3.6 mg/kg. Outcomes were assessed by standard solid-tumor phase I methods. Adverse events were reported using CTCAE version 3.0, and tumor response was assessed according to RECIST version 1.0.
Results Ten patients were recruited: (1.8 mg/kg [n=1], 2.4 mg/kg [n=4], or 3.6 mg/kg [n=5]. One patient in the 2.4 mg/kg group experienced DLTs (Grade 3 AST increase and ALT increase). No other adverse events corresponding to a DLT were observed in any other patients during the DLT observation period. As a result, the MTD in Japanese MBC patients was determined to be 3.6 mg/kg q3w.
The most frequently reported adverse events, regardless of whether they were related to the study drug, were nausea, fatigue, arthralgia and pyrexia. The main changes in laboratory test values recorded were platelet count decrease, AST increase and ALT increase. Efficacy was preliminarily assessed with tumor responses, a partial response was observed in two patients. Most of the AEs were mild and manageable. There were no marked differences in any pharmacokinetic parameters for T-DM1, DM1 or total trastuzumab following administration of T-DM1 between the JO22591 study and the two Western studies (TDM3569g and TDM4258g), and no data obtained suggested any ethnic differences.
Conclusions T-DM1 monotherapy (3.6 mg/kg every 3 weeks) was well-tolerated in Japanese patients. PK and safety in Japanese patients were comparable to PK and safety in the Western population. These results support further clinical studies with T-DM1 in Japanese patients.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-19.