OT3-01-02: Imatinib Mesylate in Combination with Vinorelbine for Patients with Metastatic Breast Cancer – An Ongoing Phase I/II Clinical Trial.

Abstract

Abstract Background Imatinib mesylate is a tyrosine kinase inhibitor which originally had been developed to block pathognomonic bcr-abl oncoprotein in chronic myeloic leukemia. It is also an inhibitor of the receptor tyrosine kinases of platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and ab1. Therefore it also inhibits PDGF- and SCF-mediated cellular events, as tumor cell proliferation in solid tumors. Additionally, inhibition of PDGF- b-receptor relieves tumor hypertension in solid tumors and thereby helps to deliver higher concentrations of cytotoxic drugs into the tumor cell. Vinorelbine is a semisynthetic vincaalcaloid with antitumor activity. As a single agent and as a combination partner of other cytotoxic drugs, it has proven good tolerability and high effectiveness in treatment of patients with metastatic breast cancer (MBC). This study was designed to evaluate the feasability of the combination of imatinib mesylate and the cytotoxic drug of vinorelbine in different concentrations in patients with advanced and MBC. Study design: This is a prospective open-label, single arm phase I/II study combining 400 mg Imatinib Mesylate p.o. daily (amended from 600 mg) with an escalating dose of vinorelbine i.v. weekly for patients with locally advanced or metastatic breast cancer. Patients must have tumors expressing PDGF-receptor-α and/or -β and/or c-kit and have received pretreatment with an anthracyclin containing regimen. Main study endpoints are feasibility and tolerability of this novel combination. In addition to the total toxicity and the incidences of hematological and non-hematological toxicity of grade 3 and 4, the clinical activity together with the clinical response rate and the time to disease progression will be evaluated.The quality of life is examined during the whole course of treatment. Recruitment started for level one with 10 mg/m2 vinorelbine and proceeds to the next higher levels 15, 20 and 25 mg/m2. Each dose level will be filled with at least five patients. Patients of one dose level will be followed for a minimum of 28 days during therapy, before enrolment of patients for the next dose level can start. For translational research multiple skin biopsies will be taken (skin wounding assays). When feasible tumor-biopsies are taken before and during therapy. Expression of tyrosine kinase receptors (c-kit and PDGF-receptor) will be correlated with treatment response. Present accrual and target accrual: 33 patients have been enrolled into the study. Dose levels I-III have been fully recruited. In dose level IV two patients with visceral metastasis are ongoing on study medication. Safety and clinical data will be available after the last patient discontinues study treatment. Information on the study protocol, the translational subprotocol and details on c-kit and PDGF-receptor expression analysis will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT3-01-02.