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

Alberto Ocana, Marta Gil-Martin, Miguel Martín, Federico Rojo, Silvia Antolín, Ángel Guerrero, José Manuel Trigo, Montse Muñoz, Atanasio Pandiella, Núria Gonzalo Diego, Susana Bezares, Rosalía Caballero, Eva Carrasco, Ander Urruticoechea, Alberto Ocana, Marta Gil-Martin, Miguel Martín, Federico Rojo, Silvia Antolín, Ángel Guerrero, José Manuel Trigo, Montse Muñoz, Atanasio Pandiella, Núria Gonzalo Diego, Susana Bezares, Rosalía Caballero, Eva Carrasco, Ander Urruticoechea

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.

Keywords: HER2 positive breast cancer; SRC kinase; dasatinib; metastatic breast cancer; trastuzumab resistance.

Conflict of interest statement

CONFLICTS OF INTEREST Authors have no conflicts of interest with the content of this study.

Figures

Figure 1. Mean profiles of dasatinib plasma…
Figure 1. Mean profiles of dasatinib plasma concentration versus time sorted by dose and PK occasions in all treated patients
Figure 2. Immunohistochemical expression analysis of p-SRC,…
Figure 2. Immunohistochemical expression analysis of p-SRC, pAKT, p-ERK protein in sequential skin samples after treatment with dasatinib, the combination of dasatinib and trastuzumab (T) and in addition to paclitaxel (P)
A. p-SRC was detected in the membrane of keratinocytes. Partial suprabasal layers of epidermis (C1D1) and complete (C1D4 and C2D1) downregulation in p-SRC expression was achieved after dasatinib treatment. p-ERK and p-AKT were evaluated in nucleus of epidermal cells, showing a similar pattern of inhibition. B. Bar graphs show differential expression from baseline of p-SRC, p-AKT, p-ERK along dasatinib treatment in combination with trastuzumab and paclitaxel.

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