Clinical trial NCT00326820: Ibandronate or Zoledronate in Treating Patients With Newly Diagnosed Bone Metastases From Breast Cancer
Official title: Zoledronate Versus Ibandronate Comparative Evaluation: A Randomized Phase III, Open-Label, Multicenter, Parallel Group Clinical Trial to Evaluate and Compare the Efficacy, Safety Profile and Tolerability of Oral Ibandronate Versus Intravenous Zoledronate in the Treatment of Breast Cancer Patients With Bone Metastases
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Breast Cancer
Hypercalcemia of Malignancy
Metastatic Cancer
Keywords: hypercalcemia of malignancy
stage IV breast cancer
bone metastases
recurrent breast cancer
male breast cancer
Lead sponsor: Wales Cancer Trials Unit
Sponsor class: OTHER
Collaborators: name: Velindre NHS Trust
First posted: 2006-05-17
Enrollment: 1404
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Ibandronate and zoledronate may help relieve some of the symptoms caused by bone metastases. It is not yet know whether ibandronate is more effective than zoledronate in treating bone metastases from breast cancer.

PURPOSE: This randomized phase III trial is studying ibandronate to see how well it works compared with zoledronate in treating patients with newly diagnosed bone metastases from breast cancer.

Detailed description: OBJECTIVES:

Primary

* Compare the efficacy, in terms of reducing frequency and timing of skeletal-related events (SREs), of ibandronate vs zoledronate in patients with newly diagnosed bone metastases secondary to breast cancer.

Secondary

* Compare the median time to first SRE in patients treated with these regimens.
* Compare the percentage of patients experiencing a SRE after treatment with these regimens.
* Compare the number of occult vertebral fractures present in patients at the end of treatment with these regimens.
* Compare the pain and analgesic scores and quality of life of patients treated with these regimens.
* Compare the number of patients developing renal dysfunction or hypocalcemia during the study period.
* Compare the number of patients developing osteonecrosis of the jaw during study treatment and follow-up.
* Compare the overall survival of these patients at 96 weeks and at 5 years.
* Compare the health-resource usage of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, parallel-group, controlled, multicenter study. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive zoledronate IV over 15 minutes on day 1. Treatment repeats every 21\* or 28 days for at least 96 weeks (24 or 32 courses) in the absence of disease progression or unacceptable toxicity.

NOTE: \*Patients who receive concurrent chemotherapy every 3 weeks receive study treatment every 21 days

* Arm II: Patients receive oral ibandronate once daily on days 1-28. Treatment repeats every 28 days for at least 96 weeks (24 courses) in the absence of disease progression or unacceptable toxicity. Patients with bone pain or hypercalcemia at study entry or those who require IV therapy due to hypercalcemia while on study may receive 1 treatment with ibandronate IV at the discretion of the supervising clinician.

Quality of life and pain are assessed at baseline, after every 3 courses, and at completion of study treatment.

After completion of study treatment, patients are followed annually for up to 3 years.

PROJECTED ACCRUAL: A total of 1,400 patients will be accrued for this study.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically proven breast cancer

  * Metastatic disease
  * Previous relapsed disease in sites other than bone allowed
* Newly diagnosed multiple bone metastases within the past 3 months, meeting all of the following criteria:

  * Painful or asymptomatic
  * Lytic, mixed, or purely sclerotic type
  * Radiological diagnosis
  * IV bisphosphonate therapy indicated
* No CNS metastases
* Hormone receptor status not specified

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Male or female
* Menopausal status not specified
* No known active peptic ulcer
* Not pregnant or nursing
* Fertile patients must use effective contraception
* No active dental problems, including infection of the teeth or jawbone (maxilla or mandible) or dental or fixture trauma
* No prior or current diagnosis of osteonecrosis of the jaw, exposed bone in the mouth, or slow healing after dental procedures
* Creatinine clearance ≥ 30 mL/min
* Bilirubin ≤ 1.5 x upper limit of normal (ULN)
* AST and ALT ≤ 1.5 times ULN
* No history of bisphosphonate hypersensitivity
* Able to comply with instructions relating to oral study medications
* Able to take oral study medications
* No psychiatric illness or other condition that would preclude giving informed consent

PRIOR CONCURRENT THERAPY:

* At least 6 months since prior bisphosphonate therapy
* At least 6 weeks since prior and no concurrent dental or jaw surgery (e.g., extractions or implants)

  * Concurrent unplanned dental extractions allowed provided study medication is discontinued for 8 weeks before and after the surgery
* Concurrent chemotherapy and/or hormone therapy for metastatic disease allowed
* No concurrent medications that affect bone metabolism (e.g., calcitonin or other nontrial bisphosphonates)

Primary outcomes:
measure: Frequency and timing of skeletal-related events (SREs)
timeFrame: 96 weeks
Secondary outcomes:
measure: Time to first SREs
timeFrame: 96 Weeks
measure: Proportion of patients with SREs
timeFrame: 96 Weeks
measure: Pain and analgesic score
timeFrame: 96 weeks
measure: Quality of life
timeFrame: 96 weeks
measure: Toxicity
timeFrame: 96 weeks
measure: Survival
timeFrame: 5 years
measure: Health resource usage and serum bone marker levels
timeFrame: 96 weeks
Other outcomes:
Locations:
city: Ashford
country: United Kingdom
facility: William Harvey Hospital
state: England
city: Barnstaple
country: United Kingdom
facility: North Devon District Hospital
state: England
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
state: England
city: Burnley
country: United Kingdom
facility: Burnley General Hospital
state: England
city: Burton-upon-Trent
country: United Kingdom
facility: Queen's Hospital
state: England
city: Canterbury
country: United Kingdom
facility: Kent and Canterbury Hospital
state: England
city: Chelmsford, Essex
country: United Kingdom
facility: Broomfield Hospital
state: England
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Oncology Centre at Cheltenham General Hospital
state: England
city: Chester
country: United Kingdom
facility: Countess of Chester Hospital
state: England
city: Colchester
country: United Kingdom
facility: Essex County Hospital
state: England
city: Coventry
country: United Kingdom
facility: Walsgrave Hospital
state: England
city: Dartford Kent
country: United Kingdom
facility: Darent Valley Hospital
state: England
city: Derby
country: United Kingdom
facility: Derbyshire Royal Infirmary
state: England
city: Dorchester
country: United Kingdom
facility: Dorset County Hospital
state: England
city: Durham
country: United Kingdom
facility: University Hospital of North Durham
state: England
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital
state: England
city: Gateshead
country: United Kingdom
facility: Queen Elizabeth Hospital
state: England
city: Grimsby
country: United Kingdom
facility: Diana Princess of Wales Hospital
state: England
city: Halifax
country: United Kingdom
facility: Calderdale Royal Hospital
state: England
city: Hartlepool, Cleveland
country: United Kingdom
facility: University Hospital of Hartlepool
state: England
city: High Wycombe
country: United Kingdom
facility: Wycombe General Hospital
state: England
city: Huddersfield, West Yorks
country: United Kingdom
facility: Huddersfield Royal Infirmary
state: England
city: Hull
country: United Kingdom
facility: Princess Royal Hospital at Hull and East Yorkshire NHS Trust
state: England
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: England
city: London
country: United Kingdom
facility: Whipps Cross Hospital
state: England
city: London
country: United Kingdom
facility: Saint Bartholomew's Hospital
state: England
city: London
country: United Kingdom
facility: St. George's Hospital
state: England
city: London
country: United Kingdom
facility: Royal Marsden - London
state: England
city: London
country: United Kingdom
facility: Charing Cross Hospital
state: England
city: Macclesfield
country: United Kingdom
facility: Macclesfield District General Hospital
state: England
city: Maidstone
country: United Kingdom
facility: Maidstone Hospital
state: England
city: Margate
country: United Kingdom
facility: Queen Elizabeth The Queen Mother Hospital
state: England
city: Newport
country: United Kingdom
facility: St. Mary's Hospital
state: England
city: Nottinghamshire
country: United Kingdom
facility: King's Mills Hospital
state: England
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
state: England
city: Nuneaton
country: United Kingdom
facility: George Eliot Hospital
state: England
city: Peterborough
country: United Kingdom
facility: Peterborough Hospitals Trust
state: England
city: Poole Dorset
country: United Kingdom
facility: Dorset Cancer Centre
state: England
city: Portsmouth
country: United Kingdom
facility: Portsmouth Oncology Centre at Saint Mary's Hospital
state: England
city: Preston
country: United Kingdom
facility: Rosemere Cancer Centre at Royal Preston Hospital
state: England
city: Redditch, Worcestershire
country: United Kingdom
facility: Alexandra Healthcare NHS
state: England
city: Saint Leonards-on-Sea
country: United Kingdom
facility: Conquest Hospital
state: England
city: Scarborough
country: United Kingdom
facility: Scarborough General Hospital
state: England
city: Scunthorpe
country: United Kingdom
facility: Scunthorpe General Hospital
state: England
city: Slough, Berkshire
country: United Kingdom
facility: Wexham Park Hospital
state: England
city: Solihull
country: United Kingdom
facility: Solihull Hospital
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Stockton-On-Tees
country: United Kingdom
facility: University Hospital of North Tees
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Torquay Devon
country: United Kingdom
facility: Torbay Hospital
state: England
city: Truro, Cornwall
country: United Kingdom
facility: Royal Cornwall Hospital
state: England
city: Tyne & Wear
country: United Kingdom
facility: South Tyneside District Hospital
state: England
city: Warrington
country: United Kingdom
facility: Warrington Hospital NHS Trust
state: England
city: Warwick, Warwickshire
country: United Kingdom
facility: South Warwickshire Hospital
state: England
city: Westcliff-On-Sea
country: United Kingdom
facility: Southend University Hospital NHS Foundation Trust
state: England
city: Wigan
country: United Kingdom
facility: Royal Albert Edward Infirmary
state: England
city: Winchester
country: United Kingdom
facility: Royal Hampshire County Hospital
state: England
city: Wirral
country: United Kingdom
facility: Clatterbridge Centre for Oncology
state: England
city: Worcester
country: United Kingdom
facility: Worcester Royal Hospital
state: England
city: Yeovil - Somerset
country: United Kingdom
facility: Yeovil District Hospital
state: England
city: East Kilbride
country: United Kingdom
facility: Hairmyres Hospital
state: Scotland
city: Falkirk
country: United Kingdom
facility: Falkirk and District Royal Infirmary
state: Scotland
city: Glasgow
country: United Kingdom
facility: Western Infirmary
state: Scotland
city: Kilmarnock
country: United Kingdom
facility: Crosshouse Hospital
state: Scotland
city: Wishaw
country: United Kingdom
facility: Wishaw General Hospital
state: Scotland
city: Abergavenny
country: United Kingdom
facility: Nevill Hall Hospital
state: Wales
city: Aberystwyth
country: United Kingdom
facility: Bronglais District General Hospital
state: Wales
city: Bangor
country: United Kingdom
facility: Ysbyty Gwynedd
state: Wales
city: Bridgend
country: United Kingdom
facility: Princess of Wales Hospital
state: Wales
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Center at Velindre Hospital
state: Wales
city: Carmarthen
country: United Kingdom
facility: West Wales General Hospital
state: Wales
city: Haverfordwest
country: United Kingdom
facility: Withybush General Hospital
state: Wales
city: Mid Glamorgan
country: United Kingdom
facility: Prince Charles Hospital
state: Wales
city: Newport Gwent
country: United Kingdom
facility: Royal Gwent Hospital
state: Wales
city: Rhyl, Denbighshire
country: United Kingdom
facility: Glan Clwyd Hospital
state: Wales
city: Swansea
country: United Kingdom
facility: South West Wales Cancer Institute
state: Wales
city: Wrexham
country: United Kingdom
facility: Wrexham Maelor Hospital
state: Wales
city: Llantrisant
country: United Kingdom
facility: Royal Glamorgan Hospital
Study officials:
affiliation: Velindre NHS Trust
name: Peter J. Barrett Lee, MD
role: STUDY_CHAIR
References:
citation: Gillespie D, Farewell D, Barrett-Lee P, Casbard A, Hawthorne AB, Hurt C, Murray N, Probert C, Stenson R, Hood K. The use of randomisation-based efficacy estimators in non-inferiority trials. Trials. 2017 Mar 9;18(1):117. doi: 10.1186/s13063-017-1837-3.
citation: Barrett-Lee P, Casbard A, Abraham J, Hood K, Coleman R, Simmonds P, Timmins H, Wheatley D, Grieve R, Griffiths G, Murray N. Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol. 2014 Jan;15(1):114-22. doi: 10.1016/S1470-2045(13)70539-4. Epub 2013 Dec 11.