Journal of Clinical Oncology, 2008 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 26, No 15S (May 20 Supplement), 2008: 1029
© 2008 American Society of Clinical Oncology

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Abstract

A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients (pts) with advanced HER2+ breast cancer (BC)

Genentech, Inc., South San Francisco, CA; Institute for Drug Development, San Antonio, TX; Dana-Farber Cancer Institute, Boston, MA; Sarah Cannon Research Institute, Nashville, TN; Memorial Sloan-Kettering Cancer Center, New York, NY

1029

Background: T-DM1 is a first-in-class HER2 antibody-drug conjugate (ADC) in development for HER2-positive BC, and is designed to combine the biological activity of trastuzumab (T) with the targeted delivery of a highly potent antimicrotubule agent (DM1) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20–100 times more potently than vincristine. T-DM1 binds to HER2 without inducing downregulation with affinity similar to T. T-DM1 has activity in T-sensitive and T-insensitive HER2+ BC xenografts; principal preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. In a phase I study of T-DM1 given every 3 weeks, the MTD was 3.6 mg/kg, with DLT of gr 4 thrombocytopenia (TCP); tumor responses were seen at doses at or below MTD. The effect of more frequent dosing of T-DM1 on its exposure and safety profile is unknown. Methods: This ongoing phase I study is evaluating the safety and pharmacokinetics (PK) of T-DM1 given IV once weekly to pts with advanced HER2+BC who have progressed on a T- containing regimen. Dose levels for successive cohorts are escalated if DLT is observed in <1/3 of pts within 21 days of first study treatment according to a 3+3 evaluation scheme. Results: Seven pts (median age 53 (range 44–63); all PS 0–1); median number prior metastatic chemo regimens 2 (range 1–4) have received 72 doses of T-DM1 at 3 dose levels (1.2 mg/kg, 3 pts; 1.6 mg/kg, 3 pts; 2.0 mg/kg, 1 pt) on a weekly schedule. Related mild-moderate AEs include fatigue (grade [gr] 1, 3 pts; gr 2, 1 pt), TA elevations gr 2, 1 pt), and headache (gr 2; 1 pt). Related gr >2 AEs have been limited to rapidly reversible TCP (gr 3, 1 pt). No cardiac-specific toxicity has been observed. No DLTs have been observed. Concentration-time profiles appear consistent with predictions based on allometric scaling. Four pts have had partial responses (none confirmed as of the data cutoff date). Conclusions: Related gr 2 AEs have been infrequent and manageable, and objective tumor responses observed, on a weekly schedule of T-DM1. Dose escalation will continue until an MTD is identified. A phase II trial of T-DM1 on a q3-week schedule in advanced HER2+ BC is ongoing.

Author Disclosure

Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GenentechTM BioOncology Genentech, Inc. GenentechTM BioOncology Genentech, Inc. Genentech, Inc.

Abstract presentation from the 2008 ASCO Annual Meeting