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Clinical Trial
. 2016 Mar 15;18(1):34.
doi: 10.1186/s13058-016-0691-7.

Phase 1b/2a Study of Trastuzumab Emtansine (T-DM1), Paclitaxel, and Pertuzumab in HER2-positive Metastatic Breast Cancer

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Free PMC article
Clinical Trial

Phase 1b/2a Study of Trastuzumab Emtansine (T-DM1), Paclitaxel, and Pertuzumab in HER2-positive Metastatic Breast Cancer

Ian E Krop et al. Breast Cancer Res. .
Free PMC article

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Trial registration: ClinicalTrials.gov NCT00951665 . Registered August 3, 2009.

Figures

Fig. 1
Fig. 1
Design of (a) phase 1b and (b) phase 2a. aMTD is the highest dose at which 0/3 patients or 1/6 patients experienced a dose-limiting toxicity. bBrain metastases that have required any type of therapy to control symptoms in the 60 days prior to first study treatment. ECOG Eastern Cooperative Oncology Group, HER2 human epidermal growth factor receptor 2, LABC locally advance breast cancer, LD loading dose, MBC metastatic breast cancer, MTD maximum tolerated dose, qw weekly, q3w every three weeks, T-DM1 trastuzumab emtansine
Fig. 2
Fig. 2
Feasibility of delivering weekly paclitaxel in combination with T-DM1 with or without pertuzumab. T-DM1 trastuzumab emtansine
Fig. 3
Fig. 3
Investigator-assessed progression-free survival among phase 2a patients. CI confidence interval, NE not estimable. + censored due to withdrawal or enrollment in the extension study

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