Clinical trial NCT03664687: Comparing a Single-Dose vs. Twice Yearly Zoledronate in Patients With Early Stage Breast Cancer (REaCT-ZOL)
Official title: A Randomised, Multicentre, Pragmatic Trial Comparing a Single-Dose vs. Twice Yearly Zoledronate in Patients With Early Stage Breast Cancer (REaCT-ZOL)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Early-stage Breast Cancer
Keywords: Adjuvant Zoledronate
Lead sponsor: Ottawa Hospital Research Institute
Sponsor class: OTHER
First posted: 2018-09-10
Enrollment: 211
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: REaCT ZOL will compare one 4 mg dose of Zoledronate vs. one 4 mg dose of Zoledronate given every 6 months for 3 years.

Detailed description: Breast cancer patients are at an increased risk of recurrence in bone and bone density loss (osteopenia/osteoporosis) and consequently fragility fractures due to: age, systemic therapy with aromatase inhibitors, and premature induction of menopause by chemotherapy or ovarian ablation. Bone is the most common site of breast cancer recurrence. The use of bone modifying agents, such as Zoledronate may reduce the risk of bone metastases and fragility fractures. Despite the widespread use of adjuvant Zoledronate, it is not known what the optimal number of infusions is to reduce the risk of bone metastases and the risk of fragility fractures. Indeed, the recent CCO and ASCO Practice Guideline, 'Bottom line recommendations' specifically states, "More research is recommended comparing different bone-modifying agents, doses, dosing intervals, and durations." In the metastatic setting, for nearly 2 decades biphosphonates (i.e. Zoledronate) have been given to patients every 3-4 weeks. This dosing interval was selected based on convenience of co-administration with standard anti-cancer agents and not on the long biological effect of these agents on osteoclasts, the cells responsible for excess bone breakdown. Furthermore, in the bone density preservation setting, despite the usual administration of Zoledronate once a year a single dose of Zoledronate was associated with a sustained increase in bone mineral density 5 years later. A recent systematic review in the adjuvant setting, showed that BTA at any particular dose or route of administration showed superiority over the other. In other words, the lowest dose appears to be just as good as the highest dose. This study will compare the single dose of Zoledronate to Zoledronate given every 6 months for 3 years. The primary outcome for this study will be feasibility of conducting this trial. The secondary outcome will assess bone-metastasis risk, fragility rates, quality of life, and cost-effectiveness.

In this study it is hypothesized that a single dose of Zoledronate will be non-inferior to every 6 months in terms of bone-metastasis free survival, time to first bone metastasis and fragility fractures. It is also hypothesized that a single dose of Zoledronate will have less toxicities associated with Zoledronate compared to every 6 months.

Eligibility criteria: Inclusion Criteria:

* Commencing zoledronate within 3 months of starting neoadjuvant or adjuvant endocrine therapy or within 3 months of completion of neoadjuvant or adjuvant chemotherapy for early stage breast cancer
* Patients receiving any intravenous or oral biphosphonates, or subcutaneous denosumab for the treatment of osteoporosis must discontinue treatment prior to baseline evaluation
* ECOG performance status equal or less than 2 and life expectancy of more than 12 months
* Serum creatinine greater than 30 ml/min and corrected serum calcium equal or greater than 2 mmol/l within 4 weeks before first zoledronate infusion
* Age equal or greater than 18 years
* Able to provide written consent

Exclusion Criteria:

* Metastatic disease
* History of osteonecrosis of the jaw
* Known hypersensitivity to trial drug or hypersensitivity to any other component of the trial drug (e.g. fructose)
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol
* Pregnancy or risk of pregnancy (this includes participants that are not willing to practice active contraception for the duration of the study)\* \*Women/men of child bearing potential must have agreed to use two effective contraceptive methods while on study. A women is considered to be of 'childbearing potential' if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods. 'effective contraception' also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as complete hysterectomy, bilateral oophorectomy or bilateral tubal ligation, or vasectomy/vasectomized partner. However, if at any point a previously celibate participant chooses to become heterosexually active during the period for use of contraceptive measures outlined in the protocol, she is responsible for beginning contraceptive measures. Examples of effective methods of contraception: Male condom plus spermicide; Cap plus spermicide; Diaphragm plus spermicide; intrauterine device (Copper T, Progesterone T; Levonorgestrel-releasing intrauterine system (i.e. Mirena); hormonal methods (implants, hormonal shot or injection, combined pill, minipill, patch).

Primary outcomes:
measure: Multiple Site Activation
timeFrame: 12 months
measure: Time to Activate Six Sites
timeFrame: 12 months
measure: Medical Oncologist Active Participation
timeFrame: Through to end of accrual, average 2 years
measure: Patient Enrollment
timeFrame: 9 months
Secondary outcomes:
measure: Bone-Metastasis-Free Survival
timeFrame: Through to end of study, average of 3 years
measure: Time to first bone metastasis
timeFrame: Through to end of study, average of 3 years
measure: Fragility fractures rates
timeFrame: Through to end of study, average of 3 years
measure: Direct Estimation of Health Utility Values
timeFrame: Through to end of study, average of 3 years
measure: Incremental Cost-Effectiveness Ratio
timeFrame: Through to study completion, an average of 3 years
Other outcomes:
Locations:
city: Brampton
country: Canada
facility: William Osler Health System, Brampton Civic Hospital
state: Ontario
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: Markham
country: Canada
facility: Markham Stouffville Hospital
state: Ontario
city: Newmarket
country: Canada
facility: Southlake Regional Health Centre
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
Study officials:
affiliation: Ottawa Hospital Research Institute
name: Mark Clemons, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Awan A, Ng T, Conter H, Raskin W, Stober C, Simos D, Pond G, Dhesy-Thind S, Mates M, Kumar V, Fergusson D, Hutton B, Saunders D, Vandermeer L, Clemons M; REaCT Investigators. Feasibility outcomes of a randomised, multicentre, pilot trial comparing standard 6-monthly dosing of adjuvant zoledronate with a single one-time dose in patients with early stage breast cancer. J Bone Oncol. 2020 Dec 13;26:100343. doi: 10.1016/j.jbo.2020.100343. eCollection 2021 Feb.
citation: McGee S, Alzahrani M, Vandermeer L, Cole K, Larocque G, Awan A, Hutton B, Pond G, Saunders D, Clemons M. Adjuvant bisphosphonate use in patients with early stage breast cancer: a physician survey. Breast Cancer Res Treat. 2021 Jun;187(2):477-486. doi: 10.1007/s10549-021-06147-1. Epub 2021 Mar 23.
citation: McGee S, AlZahrani M, Stober C, Ng TL, Cole K, Larocque G, Awan A, Sehdev S, Hilton J, Vandermeer L, Hutton B, Pond G, Saunders D, Clemons M. Adjuvant bisphosphonate use in patients with early stage breast cancer: Patient perspectives on treatment acceptability and potential de-escalation. J Bone Oncol. 2021 Feb 19;27:100351. doi: 10.1016/j.jbo.2021.100351. eCollection 2021 Apr.