Clinical Research Papers:
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
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Abstract
Alberto Ocana1, Marta Gil-Martin2, Miguel Martín3, Federico Rojo4, Silvia Antolín5, Ángel Guerrero6, José Manuel Trigo7, Montse Muñoz8, Atanasio Pandiella9, Núria Gonzalo Diego10, Susana Bezares11, Rosalía Caballero12, Eva Carrasco11 and Ander Urruticoechea13
1 Department of Medical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
2 Department of Medical Oncology, Institut Català d’Oncologia-IDIBELL, L’Hospitalet, Barcelona, Spain
3 Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain
4 Fundación Jiménez Díaz, Madrid, Spain
5 Department of Medical Oncology, Complejo Hospitalario Universitario A Coruña, La Coruña, Spain
6 Department of Medical Oncology, Instituto Valenciano de Oncología, València, Spain
7 Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, Málaga, Spain
8 Department of Medical Oncology, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain
9 Centro de Investigación del Cáncer and CIBERONC, CSIC-Universidad de Salamanca, Salamanca, Spain
10 Pharmacokinetics Laboratory, Farmacia ICO Metropolitana, IDIBELL, Instituto Catalán de Oncología, Hospital Duran i Reynals, Barcelona, Spain
11 Scientific Department, GEICAM Spanish Breast Cancer Group, Spain
12 Translational Department, GEICAM Spanish Breast Cancer Group, Spain
13 Department of Medical Oncology, Fundación Onkologikoa, Donostia, Gipuzkoa, Spain
Correspondence to:
Alberto Ocaña, email:
Keywords: HER2 positive breast cancer, dasatinib, SRC kinase, trastuzumab resistance, metastatic breast cancer
Received: March 04, 2017 Accepted: April 04, 2017 Published: April 14, 2017
Abstract
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.
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