Study of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus in Subjects With Bone Predominant HER2 Negative Hormone Receptor Positive Metastatic Breast Cancer

July 25, 2023 updated by: Bayer

A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride in Combination With Exemestane and Everolimus Versus Placebo in Combination With Exemestane and Everolimus When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases

The objective of this study is to assess efficacy and safety of radium 223 dichloride in subjects with human epidermal growth factor receptor 2 (HER2) negative hormone receptor positive breast cancer with bone metastases treated with exemestane and everolimus

After implementation of CSP Amendment 10, only a limited number of subjects will remain in this study, in order to reduce the burden to study subjects, collection of data will be reduced and will focus mainly on acute safety, SSE, and OS. Once subjects are rolled over, the long-term safety will be collected and assessed entirely in the separate extended safety follow-up study.

Study Overview

Study Type

Interventional

Enrollment (Actual)

283

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Innsbruck, Austria, 6020
      • Anderlecht, Belgium, 1070
      • Edegem, Belgium, 2650
      • Kortrijk, Belgium, 8500
      • Leuven, Belgium, 3000
      • Angers Cedex, France, 49055
      • NIMES Cedex 9, France, 30029
      • Nantes, France, 44805
      • Saint Cloud, France, 92210
      • Tours, France, 37044
    • Nordrhein-Westfalen
      • Herne, Nordrhein-Westfalen, Germany, 44625
      • Chai Wan, Hong Kong
      • Hong Kong, Hong Kong
      • Kowloon, Hong Kong
      • Afula, Israel, 1834111
      • Beer Sheva, Israel, 8410101
      • Haifa, Israel, 3109601
      • Holon, Israel, 5822012
      • Jerusalem, Israel, 9112001
      • Jerusalem, Israel, 9103102
      • Ramat Gan, Israel, 5262000
      • Tel Aviv, Israel, 64239
      • Zrifin, Israel, 7030000
    • Emilia-Romagna
      • Bologna, Emilia-Romagna, Italy, 40138
      • Forlì Cesena, Emilia-Romagna, Italy, 47014
      • Modena, Emilia-Romagna, Italy, 41124
    • Lazio
      • Roma, Lazio, Italy, 00161
      • Roma, Lazio, Italy, 00149
    • Liguria
      • Genova, Liguria, Italy, 16128
    • Lombardia
      • Cremona, Lombardia, Italy, 26100
      • Milano, Lombardia, Italy, 20132
    • Puglia
      • Bari, Puglia, Italy, 70124
    • Toscana
      • Pisa, Toscana, Italy, 56126
      • Kagoshima, Japan, 892-0833
      • Osaka, Japan, 540-0006
    • Aichi
      • Nagoya, Aichi, Japan, 464-8681
    • Hokkaido
      • Sapporo, Hokkaido, Japan, 060-8648
    • Osaka
      • Osakasayama, Osaka, Japan, 589-8511
    • Saitama
      • Hidaka, Saitama, Japan, 350-1298
      • Kita-Adachigun, Saitama, Japan, 362-0806
    • Tokyo
      • Koto-ku, Tokyo, Japan, 135-8550
      • Busan, Korea, Republic of, 49241
      • Daegu, Korea, Republic of, 42601
      • Incheon, Korea, Republic of
      • Seoul, Korea, Republic of, 05505
    • Gyeonggido
      • Suwon-si, Gyeonggido, Korea, Republic of, 442-723
    • Seoul Teugbyeolsi
      • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 03080
      • Oslo, Norway, 0424
      • Bialystok, Poland, 15-027
      • Gdansk, Poland, 80-952
      • Gdynia, Poland, 81-519
      • Poznan, Poland, 61-485
      • Warszawa, Poland, 02-781
      • Singapore, Singapore, 119074
      • Singapore, Singapore, 169610
      • Singapore, Singapore, 258499
      • Barcelona, Spain, 08036
      • Barcelona, Spain, 08035
      • Barcelona, Spain, 08041
      • Madrid, Spain, 28046
      • Madrid, Spain, 28041
      • Madrid, Spain, 28033
      • Madrid, Spain, 28050
      • Pamplona, Spain, 31008
      • Sevilla, Spain, 41013
      • Sevilla, Spain, 41071
    • Illes Baleares
      • Palma de Mallorca, Illes Baleares, Spain, 07120
    • Aargau
      • Aarau, Aargau, Switzerland, 5001
      • Kaoshiung, Taiwan, 81346
      • Taichung, Taiwan, 40705
      • Taipei, Taiwan
      • Bristol, United Kingdom, BS2 8ED
      • Merseyside, United Kingdom, CH63 4JY
    • Cornwall
      • Truro, Cornwall, United Kingdom, TR1 3LJ
    • Devon
      • Plymouth, Devon, United Kingdom, PL6 8DH
    • Nottinghamshire
      • Nottingham, Nottinghamshire, United Kingdom, NG5 1PB
    • Somerset
      • Taunton, Somerset, United Kingdom, TA1 5DA
    • Arizona
      • Yuma, Arizona, United States, 85364
    • California
      • La Jolla, California, United States, 92093
      • Long Beach, California, United States, 90813
      • Los Angeles, California, United States, 90033
    • Connecticut
      • New Haven, Connecticut, United States, 06510
    • Florida
      • Hollywood, Florida, United States, 33021
    • Kentucky
      • Ashland, Kentucky, United States, 41101
    • Maryland
      • Rockville, Maryland, United States, 20850
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
      • Detroit, Michigan, United States, 48202
      • Pontiac, Michigan, United States, 48341
    • Minnesota
      • Rochester, Minnesota, United States, 55905
    • Missouri
      • Saint Louis, Missouri, United States, 63110
    • New Jersey
      • Newark, New Jersey, United States, 07103
    • New York
      • Jamaica, New York, United States, 11432
    • South Dakota
      • Watertown, South Dakota, United States, 57201
    • Washington
      • Spokane, Washington, United States, 99208-1129

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Women (≥18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy.
  • Documentation of histological or cytological confirmation of estrogen receptor positive (ER+) and HER2 negative adenocarcinoma of the breast must be available.
  • Documentation of menopausal status: postmenopausal subjects or pre-menopausal subjects with ovarian radiation or concomitant therapy with a luteinizing hormone-releasing hormone (LH-RH) agonist/antagonist are eligible.
  • Subjects with bone dominant disease with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by computed tomography (CT)/magnetic resonance imaging (MRI).
  • Subjects must have received at least one line of hormonal therapy in the metastatic setting.
  • Subjects who are eligible as per the Investigator's assessment and according to the local label for treatment with exemestane and everolimus as a second line or greater of hormone therapy in a metastatic setting.
  • Subjects must have experienced recurrent/progressive disease following treatment with a non-steroidal aromatase inhibitor (letrozole or anastrozole) in an adjuvant or metastatic setting
  • Subjects must have experienced no more than two skeletal-related events (SREs) prior to study entry defined as: need for external beam radiotherapy (EBRT) to bone pain, pathological bone fracture (excluding major trauma), spinal cord compression and/or orthopedic surgical procedure. Subjects with no prior SREs are not permitted.
  • Subjects must be on therapy with bisphosphonates or denosumab for at least 1 month before start of study treatment.
  • Adequate hematological, liver and kidney function.

Exclusion Criteria:

  • Subjects with Inflammatory breast cancer.
  • Patients with immediately life-threatening visceral disease for whom chemotherapy is preferred treatment option.
  • Subjects who have either received chemotherapy for metastatic disease or are considered by the treating investigator to be appropriate candidates for chemotherapy as current treatment for metastatic breast cancer are excluded. Chemotherapy administered for adjuvant/neo adjuvant disease is acceptable provided it was administered at least 1 year prior to study entry.
  • Subjects who received prior treatment or are already receiving everolimus treatment prior to study entry are not eligible.
  • Subjects with known or history of brain metastases or leptomeningeal disease: subjects with neurological symptoms must undergo a contrast CT scan or MRI of the brain within 28 days prior to randomization to exclude active brain metastasis. Imaging of the central nervous system (CNS) is otherwise not required.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Radium-223 dichloride + exemestane/everolimus
Up to 6 cycles of radium-223 dichloride 50kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.
Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update)
One 25 mg tablet once daily after a meal.

The recommended dose of everolimus administered in the study is 10 mg once daily with or without food.

Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.

Placebo Comparator: Placebo + exemestane/everolimus
Up to 6 cycles of saline injection (placebo) (randomized). Participants will also receive exemestane, 25-mg tablet once daily (after a meal), and everolimus, 10 mg once daily (with or without food), and supportive care as per the local or institutional standard of practice.
One 25 mg tablet once daily after a meal.

The recommended dose of everolimus administered in the study is 10 mg once daily with or without food.

Starting dose, dose modifications, and administration of exemestane and everolimus must be in compliance with the local labels in each of the participating countries and/or in line with local standard of practice.

Up to 6 cycles of saline injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Symptomatic Skeletal Event-free Survival (SSE-FS)
Time Frame: Up to 55 months
Time from date of randomization to occurrence of one of the following, whichever happened earlier: 1) an on study SSE, which was defined as the use of external beam radiotherapy (EBRT) to relieve skeletal symptoms, the occurrence of new symptomatic pathological bone fractures (vertebral or nonvertebral), the occurrence of spinal cord compression, a tumor related orthopedic surgical intervention; or 2) death from any cause
Up to 55 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: Up to 55 months
The time from the date of randomization to the date of death due to any cause.
Up to 55 months
Time to Opiate Use for Cancer Pain
Time Frame: Up to 55 months
Interval from the date of randomization to the date of opiate use
Up to 55 months
Time to Pain Progression
Time Frame: Up to 55 months
Time from randomization to the first date a participant experienced pain progression based on WPS. Pain progression was defined as an increase of 2 or more points in the BPI-SF "Worst pain in 24 hours" score from baseline observed at 2 consecutive evaluations ≥4 weeks apart or an increase in pain management (IPM) with respect to baseline, whichever occurred first. An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.
Up to 55 months
Time to Cytotoxic Chemotherapy
Time Frame: Up to 55 months
Time from the date of randomization to the date of the first cytotoxic chemotherapy
Up to 55 months
Radiological Progression-free Survival (rPFS)
Time Frame: Up to 55 months

Time from the date of randomization to the date of confirmed radiological progression in either soft tissue, viscera or bone, or death (if death occurs before progression).

Progression is defined using the modified RECIST 1.1 criteria (the modification refers to bone lesions assessment). Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or an unequivocal increase in non-target lesions, or the appearance of new lesions. All bone lesions are considered non-measurable and new bone lesions identified by bone scan should be confirmed by further imaging (CT/MRI). If a new bone lesion or unequivocal increase in size of bone lesions is only visible on a CT/MRI and not visible on a technetium-99m bone scan, progression should be declared without further confirmation.

Up to 55 months
Percentage of Participants With Pain Improvement
Time Frame: Up to 55 months
In the percentage of participants with confirmed pain improvement. Confirmed pain improvement is defined a 2-point decrease or more in BPI-SF WPS from baseline over 2 consecutive measurements conducted at least 4 weeks apart, without an increase in pain management (IPM). An IPM is defined as the initiation of any opioid in participants not taking opioids at baseline, the initiation of a strong opioid in participants taking a weak opioid at baseline, or the initiation of an additional strong opioid in participants taking a strong opioid at baseline.
Up to 55 months
Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)
Time Frame: From first dosing up to 30 days after the last administration of study treatments, up to 93 months
An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention.
From first dosing up to 30 days after the last administration of study treatments, up to 93 months
Number of Participants With Post-treatment Chemotherapy Related Adverse Events
Time Frame: From post-treatment till end of study, up to 93 months
From post-treatment till end of study, up to 93 months
Number of Participants With Hematological Oxicities: Worst Grade Under Treatment
Time Frame: From first dosing up to 30 days after the last administration of study treatments, up to 93 months
From first dosing up to 30 days after the last administration of study treatments, up to 93 months
Number of Participants With New Primary Malignancies
Time Frame: From first dosing till end of study, up to 93 months
From first dosing till end of study, up to 93 months

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Treatmemt-emergent Adverse Events (TEAEs)
Time Frame: From first dosing till primary analysis cutoff date, up to 55 months
An AE was any untoward medical occurrence (i.e. any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they started or worsened after first application of study intervention up to 30 days after end of treatment with study intervention. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening; persistent or significant disability/incapacity; congenital anomaly; another medical important serious event as judged by the investigator and an occurrence of any additional malignancies, including acute myelocytic leukemia or hematological conditions.
From first dosing till primary analysis cutoff date, up to 55 months
Number of Participants With Post-treatment Chemotherapy Related Adverse Events
Time Frame: From post-treatment till primary analysis cutoff date, up to 55 months
From post-treatment till primary analysis cutoff date, up to 55 months
Number of Participants With Hematological Toxicities: Worst Grade Under Treatment
Time Frame: From first dosing till primary analysis cutoff date, up to 55 months
From first dosing till primary analysis cutoff date, up to 55 months
Number of Participants With New Primary Malignancies During Study Treatment or Follow-up Period
Time Frame: From first dosing till primary analysis cutoff date, up to 55 months
From first dosing till primary analysis cutoff date, up to 55 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Director: Bayer Study Director, Bayer

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 4, 2015

Primary Completion (Actual)

January 22, 2020

Study Completion (Actual)

October 28, 2022

Study Registration Dates

First Submitted

September 30, 2014

First Submitted That Met QC Criteria

October 6, 2014

First Posted (Estimated)

October 7, 2014

Study Record Updates

Last Update Posted (Actual)

August 2, 2023

Last Update Submitted That Met QC Criteria

July 25, 2023

Last Verified

July 1, 2023

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Breast Neoplasms

Clinical Trials on Radium-223 dichloride (Xofigo, BAY88-8223)

3
Subscribe