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

Oncotarget
Alberto OcanaAnder 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/m(2)) 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 exp...Continue Reading

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Citations

Nov 4, 2017·International Journal of Molecular Sciences·Andrea NicoliniAngelo Carpi
Mar 23, 2019·The Journal of Pharmacology and Experimental Therapeutics·Tanaya R VaidyaSihem Ait-Oudhia
Oct 26, 2018·Breast Cancer Research : BCR·Brooke N McKnight, Nerissa T Viola-Villegas
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Feb 16, 2021·Frontiers in Pharmacology·Qinghui ZhengXuli Meng

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Methods Mentioned

BETA
biopsies
enzyme-linked immunosorbent assay

Clinical Trials Mentioned

NCT01306942

Software Mentioned

SPSS
SAS Enterprise Guide
GEICAM
WinNonlin
Phoenix

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