Pre-operative Zoledronate in Triple Negative Breast Cancer
Status:
Terminated
Trial end date:
2018-06-08
Target enrollment:
Participant gender:
Summary
Recent evidences suggest that zoledronate (zol), one of the most used bisphosphonates (BPs)
in the clinical setting for the prevention and treatment of bone metastasis in cancer
patients, may have antitumor activity in early breast cancer in terms of improved disease
free survival, overall survival and better response in BPs treated patients. BPs are
mevalonate pathway inhibitors and one of the most intriguing hypothesis supporting their
anticancer activity relies on the modulation of the mevalonate downstream metabolism.
Biologically active mevalonate metabolites are involved in tumour cell proliferation and
invasion and selected cancer subtypes may present a more pronounced mevalonate activity, able
of maintaining an aggressive phenotype. The mevalonate pathway has deep impact on the
function of YAP/TAZ, transcriptional regulators of tumour growth, and preclinical evidences
suggest that BPs are able to interfere with YAP/TAZ expression, via mevalonate pathway. This
study addresses the clinical role of BPs in triple negative breast cancer (TNBC) patients
selected by the level of mevalonate pathway regulation, namely the p53 expression. This study
is a multicenter single-arm, phase II study primarily aimed at assessing the anti-tumor
activity of pre-operative zol measured through its effect on the Ki67 proliferative
biomarker, in TNBC patients classified according to the p53 expression (high vs low p53
expression). Patients with newly diagnosed, untreated, operable TNBC, intended to definitive
breast surgery and suitable for pre-operative therapy with zoledronate will receive a
pre-operative, single administration of zol (4mg i.v.), 7 days before definitive breast
surgery. Ki67 levels will be assessed in tumor samples collected at the time of diagnosis and
after zoledronate treatment at the time of definitive surgery. The secondary objective of the
study is to investigate the effect of zoledronate on critical genes/proteins related to p53
and mevalonate pathways, p53/PIN1 and YAP/TAZ, analyzed in the tumor tissue collected at the
time of diagnosis and at definitive surgery. Zol safety profile will be evaluated by the
NCI-CTCAE scale, version 4.0, and by the occurrence of serious adverse reactions. The total
number of patients required is forty. The overall duration of the project is 32 months (30
months for accrual, followed by 2 months of follow-up after the recruitment of the last
patient).
Phase:
Phase 2
Details
Lead Sponsor:
Mario Negri Institute for Pharmacological Research