Clinical trial NCT00525759: Investigating the Biological Effects of the Addition of Zoledronic Acid to Pre-operative Chemotherapy in Breast Cancer
Official title: A Randomised Phase II Feasibility Study Investigating the Biological Effects of the Addition of Zoledronic Acid to Neoadjuvant Combination Chemotherapy on Invasive Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: Breast cancer
Zoledronic acid
Neoadjuvant chemotherapy
Synergy
Apoptosis
Lead sponsor: Sheffield Teaching Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Sheffield
First posted: 2007-09-06
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: There is clear preclinical in vitro and in vivo evidence of sequence dependent synergy between chemotherapy agents and zoledronic acid. The aim of the study is to investigate if the synergistic increase in tumour cell apoptosis observed in preclinical studies occurs in patients. The hypothesis for this study is that there may be anti-tumour benefits of the sequential application of chemotherapy agents followed by zoledronic acid in patients with invasive breast cancer.


Eligibility criteria: Inclusion Criteria:

* Women with histological diagnosis of invasive breast cancer requiring neoadjuvant chemotherapy
* T2 tumour or above
* WHO Performance status of 0,1 or 2
* Must consent to or have undergone a core biopsy for diagnosis of breast cancer AND consent to undergo an additional core biopsy prior to the second cycle of chemotherapy (Day 5 +/- Day 21)
* Written informed consent

Exclusion Criteria:

* Previous chemotherapy or radiotherapy to treated breast
* Evidence of metastatic disease or recurrent breast cancer or previous malignancy (some exceptions)
* Calculated creatinine clearance \< 40mls/min
* Prior treatment with bisphosphonates in last year or known contraindications to bisphosphonate therapy
* Concurrent tamoxifen or aromatase inhibitor medication
* Pregnant or lactating women
* Cardiac dysfunction that precludes use of anthracycline chemotherapy
* Unwilling to have extra interim biopsy

Primary outcomes:
measure: Increase in apoptotic index between diagnostic core biopsy and repeat core biopsy taken on day 5
timeFrame: Repeat biopsy on day 5 (+/- day 21)
Secondary outcomes:
measure: Reduction in Ki67 immunostaining between preoperative core biopsy, repeat core biopsy on day 5, +/- day 21, and operative specimen
timeFrame: Day 5, +/- Day 21, surgical specimen
measure: Changes in serum angiogenesis markers between pre-treatment and operative time points
timeFrame: Pre-treatment, Day 5, day 21, pre-surgery
measure: Changes in bone biochemical markers between pre-treatment, treatment and operative timepoints
timeFrame: Pre-treatment, Day 5, day 21, pre-surgery
measure: Detection of, and changes in, circulating tumour cells in peripheral blood taken pre-treatment, during treatment and following treatment
timeFrame: Pre-treatment, day 5, day 21, pre-surgery
Other outcomes:
Locations:
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust / Weston Park Hospital
state: South Yorkshire
Study officials:
affiliation: Academic Unit of Clinical Oncology, University of Sheffield
name: Robert E Coleman, MB BS, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jagdev SP, Coleman RE, Shipman CM, Rostami-H A, Croucher PI. The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer. 2001 Apr 20;84(8):1126-34. doi: 10.1054/bjoc.2001.1727.
citation: Neville-Webbe HL, Rostami-Hodjegan A, Evans CA, Coleman RE, Holen I. Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer. 2005 Jan 20;113(3):364-71. doi: 10.1002/ijc.20602.
citation: Ottewell PD, Jones M, Coleman RE, Holen I. Synergistic effects of cytotoxic drugs and anti-resorptive agents in vitro and in vivo. In 29th Annual San Antonio Breast Cancer Symposium Vol.100 Suppl.1 Abstract 6102, Breast Cancer Research and Treatment
citation: Winter MC, Wilson C, Syddall SP, Cross SS, Evans A, Ingram CE, Jolley IJ, Hatton MQ, Freeman JV, Mori S, Holen I, Coleman RE. Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer--a randomized biomarker pilot study. Clin Cancer Res. 2013 May 15;19(10):2755-65. doi: 10.1158/1078-0432.CCR-12-3235. Epub 2013 Mar 20.