The ODYSSEY TRIAL Phase IV Trial Evaluating the Palliative Benefit of Pamidronate or Zoledronic Acid in Breast Cancer (ER11-03)

A Randomized, Double-blind, Placebo-controlled, Phase IV Trial Evaluating the Palliative Benefit of Either Continuing Pamidronate or Switching to Second-line Zoledronic Acid in Breast Cancer Patients With High-risk Bone Metastases.

Metastatic breast cancer patients with bone involvement who are at high-risk of subsequent skeletal related event (SRE), defined as radiotherapy or surgery to the bone, pathological fracture, spinal cord compression, or hypercalcemia (as reflected through: elevated sCTX or bone pain or a prior SRE despite receiving standard bisphosphonate therapy) should experience a decrease in the surrogate marker, sCTX, at week 12 if switched to zoledronic acid compared with those patients who continue on intravenous pamidronate (i.e. current standard of care). The investigators propose that a drop in sCTX will correlate with improved pain, quality of life and a reduced incidence of further SREs.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: placebo; Drug: Pamidronate; Drug: Zoledronic acid

Detailed Description

This study will be a prospective, randomized, double-blind, placebo controlled, Phase IV study of pamidronate vs. zoledronic acid in women with breast cancer and bone metastases. Patients who are at high-risk of subsequent SREs will be screened for entry into this study. High-risk will be defined as fulfilling one or more of the following criteria: elevated sCTX (>400ng/L) and/or bone pain and/or a prior SRE and/or progression of bone disease (by imaging) despite at least 3 months of pamidronate therapy. Patients who meet the eligibility criteria, will be randomized to receive 3 cycles of intravenous zoledronic acid (4mg intravenously over 15 minutes) or to continue their standard dose of pamidronate. Both treatments will be given at 4 week intervals. Patients will be stratified according to whether or not they have had a SRE prior to study entry, progressive bone disease or bone pain. In order for the study to be double-blind, patients will receive two infusions simultaneously, at each study visit, one of the active drug and another of the placebo. After completing 3 cycles of study treatment, patients will resume their monthly intravenous pamidronate infusions as per current standard of care.

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital Cancer Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Metastatic breast cancer to the bone with radiologically confirmed bone metastases
2. High-risk of subsequent SRE as reflected through either: elevated serum CTX (> 400ng/L) and/or bone pain (using BPI) and/or prior SRE while on bisphosphonate therapy and/or progressive bone metastasis (by imaging)
3. On pamidronate therapy for at least 3 months
4. ECOG ≤ 2 and life expectancy > 3 months
5. Serum creatinine ≤ 2.0 × ULN (zoledronic acid or pamidronate to be renal dosed as per institution standard)
6. No changes in systemic treatment in the 4 weeks prior to study entry or anticipated changes in the 4 weeks after entering the study. Markers of bone formation can be affected by a change in systemic therapies
7. Ability to take calcium and Vitamin D as per Health Canada recommended daily doses for the duration of the study
8. Ability to provide informed consent and complete study evaluations.

Exclusion Criteria:

1. Patients with acute symptomatic pathological fractures or acute spinal cord compression until such time as the appropriate management (surgery and/or radiotherapy) has been completed
2. Acute hypercalcemia (>3.5 mmol/L)
3. Hypersensitivity to any bisphosphonate
4. Patients with rapidly progressive non-bone metastases for whom delaying a change in systemic anti-cancer treatment for the 1 month biochemical marker evaluation period could have a detrimental impact on patient outcome.
5. Renal dysfunction (≥ 2x creatinine of the upper limit of normal )
6. Pregnancy or lactation
7. Patients with dental abscesses or patients potentially requiring tooth extraction while on study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Pamidronate and placebo; Patients will receive two infusions simultaneously, at each study visit, one of Pamidronate and another of the placebo. After completing 3 cycles of study treatment, patients will resume their monthly intravenous pamidronate infusions as per current standard of care.	Drug: placebo; Drug: Pamidronate; 90mg IV once every 4 weeks for 3 cycles; Other Names: ADP Sodium; Aredia®
ACTIVE_COMPARATOR: Zoledronic acid and placebo; Patients will receive two infusions simultaneously, at each study visit, one of Zoledronic acid and another of the placebo. After completing 3 cycles of study treatment, patients will resume their monthly intravenous pamidronate infusions as per current standard of care.	Drug: placebo; Drug: Zoledronic acid; 4mg IV every 4 weeks for 3 cycles; Other Names: Reclast; Zometa; Aclasta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
sCTX values	To compare the proportion of high-risk metastatic breast cancer patients with bone metastases that will achieve a decrease in sCTX (surrogate for decrease risk of SREs) in the zoledronic and pamidronate treatment arms.	baseline, 1 week post treatment, week 4, week 8, week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Palliative response	To determine the proportion of high-risk metastatic breast cancer patients that will achieve a significant improvement in palliative response (18) (defined as a two unit drop in their worst pain score, based on a brief pain inventory questionnaire for two consecutive measurements at least one month apart) in the zoledronic and pamidronate treatment arms.	baseline, week 1, week 4, week 8, week 12.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
predictor of pain benefit	To assess whether a drop in sCTX one week post infusion of zoledronic acid is a predictor of pain benefit at week 12. We will test the strength of the association in sCTX drop (any drop from baseline level) at week 1 and palliative response when measured at week 12, using the validated BPI and FACT-BP questionnaires	week 1 and week 12

Collaborators and Investigators

• Sponsor: Ottawa Hospital Research Institute
• Collaborators: Canadian Breast Cancer Foundation
• Investigators: Principal Investigator: Mark Clemons, Dr., The Ottawa Hospital

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (ACTUAL): January 1, 2016
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: July 22, 2013
• First Submitted That Met QC Criteria: July 24, 2013
• First Posted (ESTIMATE): July 25, 2013

Study Record Updates

• Last Update Posted (ACTUAL): July 7, 2017
• Last Update Submitted That Met QC Criteria: July 5, 2017
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: pain; breast; bone
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid; Pamidronate
• Other Study ID Numbers: 2011349-01H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: results will be published.