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

Abstract

Abstract Abstract #3136 Background: T-DM1, a novel HER2 antibody-drug conjugate (ADC) in development for HER2+ breast cancer (BC), combines activity of trastuzumab (T) with the targeted delivery of maytansinoid DM1 (potent antimicrotubule agent) to HER2-expressing cells. DM1 binds tubulin competitively with vinca alkaloids, 20-100x more potently than vincristine. It is bound to T by MCC, a linker that is stable with protease activity and under many pH or redox conditions. T-DM1 is the first ADC with an MCC linker to enter clinical trials. Main preclinical AEs were reversible transaminase (TA) elevations, reversible platelet decreases, and neuropathy. A phase I study of T-DM1 every 3 wks (q3w) in patients (pts) with advanced HER2+ BC who progressed on T-containing chemotherapy regimen, the maximum tolerated dose (MTD) was 3.6 mg/kg, with DLT of grade (Gr) 4 thrombocytopenia (TCP); tumor responses were seen in 5 of 9 pts (4 confirmed, 44%) with measurable disease treated at MTD. We undertook this dose escalation study of T-DM1 given once/wk (q1w) to explore pharmacokinetics (PK), safety, and tolerability of more frequent dosing.
 Methods: Pts with advanced HER2+ BC who had progressed on a T-containing chemotherapy regimen received T-DM1 IV q1w continuously. Dose levels were escalated in successive 3+3 cohorts if DLT was seen in <1/3 of pts within 21 days of Cycle 1 Day 1.
 Results: As of 19 May 2008, enrollment is complete with 27 pts (15 at the MTD). Data is available for 19 pts [median age 54.0 (range 41-71); all PS 0-1; median number prior metastatic chemo agents 5.0 (range 2-8); median wks of prior trastuzumab 122 (range 29-325)] who have received 246 doses of T-DM1 at 1.2, 1.6, 2.0, 2.4, and 2.9 mg/kg. Common related AEs include fatigue (Gr1, 3 pts; Gr2, 4 pts; Gr3, 1 pt), thrombocytopenia (Gr 1, 4 pts; Gr2, 3 pts; Gr3, 2 pts), nausea (Gr1, 7 pts; Gr 2, 1 pt), TA elevations (Gr1, 1 pt; Gr2, 4 pts; Gr3, 1 pt), vomiting (Gr1, 3 pts; Gr2, 1 pt) and headache (Gr1, 2 pts; Gr2, 1 pt). Dose-limiting toxicity was seen in 2 pts at 2.9 mg/kg (toxicity preventing retreatment on Cycle 1 Day 8, from Gr2-3 thrombocytopenia). No Gr4 AEs or cardiac toxicity were seen. Preliminary PK analyses suggest that steady-state T-DM1 exposure at 2.4 mg/kg q1w will be ∼2x that associated with 3.6 mg/kg q3w. Of 15 pts evaluable for response, 9 had partial responses (8 confirmed, 53%).
 Conclusions: The MTD of T-DM1 on a weekly schedule is 2.4 mg/kg. Related Gr ≥2 AEs were reversible and manageable. The activity and safety results observed on q1w dosing were consistent with q3w dosing, supporting further study. Three Phase II trials of q3w T-DM1 in advanced HER2+ BC will enroll pts in 2008; preliminary results from the first trial will be reported in 2008. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3136.