RT Journal Article
T1 A phase I study of the SRC kinase inhibitor dasatinib with trastuzumab and paclitaxel as first line therapy for patients with HER2-overexpressing advanced breast cancer. GEICAM/2010-04 study.
A1 Ocana, Alberto
A1 Gil-Martin, Marta
A1 Martín, Miguel
A1 Rojo, Federico
A1 Antolín, Silvia
A1 Guerrero, Ángel
A1 Trigo, José Manuel
A1 Muñoz, Montse
A1 Pandiella, Atanasio
A1 Diego, Núria Gonzalo
A1 Bezares, Susana
A1 Caballero, Rosalía
A1 Carrasco, Eva
A1 Urruticoechea, Ander
K1 HER2 positive breast cancer
K1 SRC kinase
K1 dasatinib
K1 metastatic breast cancer
K1 trastuzumab resistance
AB The anti-HER2 antibody trastuzumab have shown clinical activity in combination with chemotherapy in different breast cancer settings. However, most of patients treated with this antibody progress after a period of treatment. Activation of the kinase SRC has been linked with resistance to trastuzumab in several preclinical studies. We designed a phase I clinical study to explore the activity of weekly trastuzumab (2 mg/kg) plus paclitaxel (80 mg/m2) in combination with the anti-SRC kinase inhibitor Dasatinib in the first line treatment of HER2 metastatic breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D); secondary objectives included efficacy, objective response rate (ORR), pharmacokinetics and pharmacodynamics. A "3+3" design guided dose escalation with two oral dose levels of dasatinib: 100mg (DL1) and 140 mg (DL2). 10 patients were included in the phase I part. Dasatinib 100 mg q.d. was established as the recommended RP2D. The median number of administered cycles was 12 (range, 1 to 18). Grade 3 treatment-related AEs at DL1 were diarrhea (n = 2), hyponatremia (n = 1), fatigue (n = 1), and AST/ALT elevation (n = 1). A significant reduction in p-SRC expression on epidermal keratinocytes on sequential skin biopsies was observed. In conclusion, we describe the feasibility of the combination of dasatinib, trastuzumab and paclitaxel, and its effect on proteins involved in trastuzumab resistance. The phase II part of this study is currently evaluating efficacy.
YR 2017
FD 2017-04-14
LK https://hdl.handle.net/10668/25132
UL https://hdl.handle.net/10668/25132
LA en
DS RISalud
RD Apr 4, 2025