title: Phase 1b/2a study of trastuzumab emtansine (T-DM1), paclitaxel, and pertuzumab in HER2-positive metastatic breast cancer.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00951665 . Registered August 3, 2009.
authors.affiliation: Breast Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA. Ian_Krop@dfci.harvard.edu.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Krop
authors.affiliation: Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.|Weill Cornell Medical College, 445 E 69th St, New York, NY, 10021, USA.
authors.forename: Shanu
authors.initials: S
authors.lastname: Modi
authors.affiliation: Yale University, 800 Howard Ave, New Haven, CT, 06519, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Stanford Cancer Institute, Stanford University School of Medicine, 900 Blake Wilbur, Stanford, CA, 94305, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pegram
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Ellie
authors.initials: E
authors.lastname: Guardino
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Betsy
authors.initials: B
authors.lastname: Althaus
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Lu
authors.affiliation: F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel, ch-4070, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strasak
authors.affiliation: University of Colorado Cancer Center, 1665 Aurora Ct, Aurora, CO, 80045, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Elias
mesh_terms: D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008453:Maytansine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008453:Maytansine; C485206:pertuzumab; D000068878:Trastuzumab; D017239:Paclitaxel; D000080044:Ado-Trastuzumab Emtansine