Investigating the Biological Effects of the Addition of Zoledronic Acid to Pre-operative Chemotherapy in Breast Cancer

NCT00525759 | Completed Phase 2

• 1 other identifier: STH14707
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

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.

Conditions

Breast Cancer

Keywords

Breast cancer; Zoledronic acid; Neoadjuvant chemotherapy; Synergy; Apoptosis

Outcome Measures

Primary Outcomes (1)

• Increase in apoptotic index between diagnostic core biopsy and repeat core biopsy taken on day 5

  Repeat biopsy on day 5 (+/- day 21)

Secondary Outcomes (4)

• Reduction in Ki67 immunostaining between preoperative core biopsy, repeat core biopsy on day 5, +/- day 21, and operative specimen

  Day 5, +/- Day 21, surgical specimen

• Changes in serum angiogenesis markers between pre-treatment and operative time points

  Pre-treatment, Day 5, day 21, pre-surgery

• Changes in bone biochemical markers between pre-treatment, treatment and operative timepoints

  Pre-treatment, Day 5, day 21, pre-surgery

• Detection of, and changes in, circulating tumour cells in peripheral blood taken pre-treatment, during treatment and following treatment

  Pre-treatment, day 5, day 21, pre-surgery

Study Arms (2)

A

ACTIVE COMPARATOR

Neoadjuvant chemotherapy alone

Drug: 5-FU, Epirubicin, Cyclophosphamide, Docetaxel

B

EXPERIMENTAL

Neoadjuvant chemotherapy + zoledronic acid

Drug: 5-FU, Epirubicin, Cyclophosphamide, Docetaxel, Zoledronic acid

Interventions

5-FU, Epirubicin, Cyclophosphamide, Docetaxel DRUG

3 cycles of FEC q3w, followed by 3 cycles of docetaxel q3w FEC: 5FU 500mg/m2 intravenous bolus D1, Epirubicin 100mg/m2 intravenous bolus D1, Cyclophosphamide 500mg/m2 intravenous bolus D1) every 21 days Docetaxel: (100mg/ m2 intravenous infusion) every 21 days

A

5-FU, Epirubicin, Cyclophosphamide, Docetaxel, Zoledronic acid DRUG

3 cycles of FEC q3w, followed by 3 cycles of docetaxel q3w FEC: 5FU 500mg/m2 intravenous bolus D1, Epirubicin 100mg/m2 intravenous bolus D1, Cyclophosphamide 500mg/m2 intravenous bolus D1) every 21 days Docetaxel: (100mg/ m2 intravenous infusion) every 21 days Zoledronic acid: 4mg intravenous infusion Day 2, AFTER FIRST CYCLE CHEMOTHERAPY ONLY

B

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Sheffield Teaching Hospitals NHS Foundation Trust: lead
• University of Sheffield: collaborator

Study Sites (1)

Sheffield Teaching Hospitals NHS Foundation Trust / Weston Park Hospital

Sheffield, South Yorkshire, S10 2SJ, United Kingdom

Location

Related Publications (5)

• 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.

  PMID: 11308265 BACKGROUND

• 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.

  PMID: 15455384 BACKGROUND

• 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

  BACKGROUND

• Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

  PMID: 38979716 DERIVED

• 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.

  PMID: 23515409 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Fluorouracil; Epirubicin; Cyclophosphamide; Docetaxel; Zoledronic Acid

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Diphosphonates; Organophosphonates; Imidazoles; Azoles

Study Officials

• Robert E Coleman, MB BS, MD

  Academic Unit of Clinical Oncology, University of Sheffield

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: September 5, 2007
• First Posted: September 6, 2007
• Study Start: July 1, 2007
• Primary Completion: January 1, 2010
• Study Completion: January 1, 2010
• Last Updated: November 24, 2023

Record last verified: 2023-11

Locations

GB (1)