Abstract P3-14-10: A Dose-Escalation Study of Trastuzumab-DM1 (T-DM1), Paclitaxel (T), and Pertuzumab (P) in Patients with HER2-Positive, Locally Advanced or Metastatic Breast Cancer (MBC) Previously Treated with a Trastuzumab-Containing Regimen
Authors: Krop IE , Modi S , Elias A , LoRusso P , Choi YJ , Lu M. 
Published: April 2011

Abstract
Background
T-DM1 is an antibody-drug conjugate that combines the biological activity of trastuzumab with targeted delivery of an anti-microtubule agent to HER2-expressing cancer cells. T-DM1 monotherapy is effective and well tolerated in pts with pretreated HER2-positive MBC. Nonclinical data suggest synergy for the combination of T-DM1 with taxanes as well as with P. Methods
This 3+3 design phase Ib study (T-DM1 4652g) investigates tolerability and dose-limiting toxicities (DLTs) for the combination of T-DM1 (q3w and q1w), T (q1w) and P (q3w). Part 1 consisted of q3w T-DM1 and q1w T dose cohorts. In Part 2, P is added to the MTD of Part 1. In Part 3, q1w T-DM1 will be evaluated. Each cycle is comprised of T-DM1 on day 1, and T on days 1 (day -1 for cycle 1 only), 8, and 15. P (840 mg load followed by 420 mg q3w) is given on day 1 when applicable. Pts were monitored for DLTs for 23 days before determining the next cohort dose level. Results
Parts 1 and 2 have completed enrollment with 21 pts. Results reported here are from 14 pts in Part 1, who had finished the DLT observation period as of Mar 30, 2010. The median age was 56 yrs and the median number of prior systemic therapies excluding hormonal therapy was 10 (range 5-23). All pts had received prior therapy with trastuzumab, 13 pts had prior taxane and 11 pts had prior lapatinib therapy. Pts received a median of 4.5 and 11 doses of T-DM1 and T, respectively (range 1-10 and 1-29, respectively). Two pts experienced DLTs in Cohort 1, at T-DM1 2.4 mg/kg q3w and T 65 mg/m2 q1w (n=5); a gr 3 AST/ALT elevation, and a gr 3 dehydration secondary to nausea and vomiting. Therefore the next cohort (Cohort A) opened at a reduced T-DM1 dose, 2.0 mg/kg q3w with T 65 mg/m2 q1w (n=3), where no DLT was observed. In Cohort B (T-DM1 2.0 mg/kg q3w, T 80 mg/m2 q1w, n = 6), 1 pt experienced DLT; a gr 3 neutropenia. Six SAEs in 3 pts have been reported: gr 2 vomiting (considered related), gr 3 dehydration (considered related), gr 3 cellulitis, gr 3 muscular weakness, gr 3 interverterbral disc protrusion, and gr 3 hypersensitivity (considered related). One pt discontinued due to gr 2 thrombocytopenia. Six pts experienced AEs that led to discontinuation of T alone. The preliminary PK assessment suggests a low potential for PK-based T-DM1 T interaction with combination therapy.
Overall, 2 objective responses (confirmed) and 4 additional partial responses (unconfirmed) were observed from limited follow-up. Five of these 6 pts remain on study. Conclusions
The combination of T-DM1 and T are encouraging given the observed responses. In these extensively pretreated pts with a median of 10 prior therapies, the MTD has been established for q3w T-DM1 at 2.0 mg/kg in combination with T 80 mg/m2, at a dose of T-DM1 well below the single agent dose of 3.6 mg/kg. Maximizing the dose of T-DM1 will be further explored in combination with T and P.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-10.