Abstract

In pre-clinical studies, the anti-tumor activity of T-DM1 was enhanced when combined with taxanes or pertuzumab. This phase 1b/2a study evaluated the safety/tolerability of T-DM1?+?paclitaxel?±?pertuzumab in HER2-positive advanced breast cancer.In phase 1b (n?=?60), a 3?+?3 dose-escalation approach was used to determine the maximum tolerated dose (MTD) of T-DM1?+?paclitaxel?±?pertuzumab. The primary objective of phase 2a was feasibility, with 44 patients randomized to T-DM1?+?paclitaxel?±?pertuzumab at the MTD identified in phase 1b.The MTD was T-DM1 3.6 mg/kg every three weeks (q3w) or 2.4 mg/kg weekly?+?paclitaxel 80 mg/m(2) weekly?±?pertuzumab 840 mg loading dose followed by 420 mg q3w. Phase 2a patients had received a median of 5.0 (range: 0-10) prior therapies for advanced cancer. In phase 2a, 51.2 % received =12 paclitaxel doses within 15 weeks, and 14.0 % received 12 paclitaxel doses by week 12. Common all-grade adverse events (AEs) were peripheral neuropathy (90.9 %) and fatigue (79.5 %). A total of 77.3 % experienced grade =3 AEs, most commonly neutropenia (25.0 %) and peripheral neuropathy (18.2 %). Among the 42 phase 2a patients with measurable disease, the objective response rate (ORR) was 50.0 % (95 % confidence interval (CI) 34.6-65.4); the clinical benefit rate (CBR) was 56.8 % (95 % CI 41.6-71.0). No pharmacokinetic interactions were observed between T-DM1 and paclitaxel.This regimen showed clinical activity. Although there is potential for paclitaxel to be added to T-DM1?±?pertuzumab, peripheral neuropathy was common in this heavily pretreated population.ClinicalTrials.gov NCT00951665 . Registered August 3, 2009.

View details for DOI 10.1186/s13058-016-0691-7

View details for PubMedID 26979312

View details for PubMedCentralID PMC4791863