Study of Radium-223 Dichloride Versus Placebo and Hormonal Treatment as Background Therapy in Subjects With Bone Predominant HER2 (Human Epidermal Growth Factor Receptor 2) Negative Hormone Receptor Positive Metastatic Breast Cancer

Study Overview
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Brief Summary
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The objective of this study was to assess efficacy and safety of radium-223 dichloride in subjects with human epidermal growth factor receptor 2 negative (HER2 negative) hormone receptor positive breast cancer with bone metastases treated with hormonal treatment background therapy

Official Title
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A Phase II Randomized, Double-blind, Placebo-controlled Trial of Radium-223 Dichloride Versus Placebo When Administered to Metastatic HER2 Negative Hormone Receptor Positive Breast Cancer Subjects With Bone Metastases Treated With Hormonal Treatment Background Therapy

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
* Drug: Placebo (saline)
* Other: Background hormonal therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documentation of histological or cytological confirmation of estrogen receptor positive (ER+) and HER2 negative adenocarcinoma of the breast must be available. Women (≥18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy. Documentation of menopausal status: post menopausal or premenopausal subjects are eligible. Subjects with bone dominant disease with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI). Presence of metastases in soft tissue (skin, subcutaneous, muscle, fat, lymph nodes)and/or visceral metastases is allowed. Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Subjects must have received at least one line of hormonal therapy in the metastatic setting Subjects who are eligible for further standard of care endocrine treatment. Subjects enrolled in the current study must start treatment with the single hormone agent either within 15 days prior to randomization or after randomization (before or simultaneously to the first injection of Ra-223/placebo). Subjects must have experienced no more than two skeletal-related events (SREs) prior to study entry defined as: Need for external beam radiotherapy (EBRT) tor bone, 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 bisphosphonate and denosumab. and are required to have been on such therapy for at least 1 month before start of study treatment. Adequate hematological, liver and kidney function. Exclusion Criteria: Subjects with Inflammatory breast cancer. 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. 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. Known presence of osteonecrosis of jaw. Patients with immediately life-threatening visceral disease, for whom chemotherapy is the preferred treatment option. Lymphangitic carcinomatosis. Patients with ascites requiring paracentesis within 2 weeks prior to study entry (signature of informed consent) and during the screening period.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radium 223 dichloride<br>Participants treated with a single hormonal agent as background therapy received 50 kBq/kg body weight (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update) of Radium 223 dichloride intravenously for a maximum of 6 cycles at intervals of 4 weeks | Drug: Radium-223 dichloride (Xofigo, BAY88-8223)<br>* Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of National Institute of Standards and Technology [NIST] update)<br>Other: Background hormonal therapy<br>* Prescribed by PI and was provided as long as patient can tolerate treatment. It must be prescribed as per local label in country participating.<br>|
| Placebo Comparator: Placebo<br>Participants treated with a single hormonal agent as background therapy received isotonic saline (0.9% sodium chloride solution for injection) intravenously for a maximum of 6 cycles at intervals of 4 weeks | Drug: Placebo (saline)<br>* Up to 6 cycles of saline injection<br>Other: Background hormonal therapy<br>* Prescribed by PI and was provided as long as patient can tolerate treatment. It must be prescribed as per local label in country participating.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic Skeletal Event Free Survival (SSE-FS) | 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 approximately 51 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization to death from any cause | Up to approximately 51 months | 
| Time to Opiate Use for Cancer Pain | Interval from the date of randomization to the date of opiate use | Up to approximately 51 months | 
| Time to Pain Progression | Time from randomization to the first date a participants (only in participants with baseline WPS ≤8) experiences pain progression based on worst pain score (WPS) ranging from 0 to 10 and analgesic use. Pain progression is defined as an increase of 2 or more points in the 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 occurs first | Up to approximately 51 months | 
| Pain Improvement Rate | The percentage of participants (baseline WPS>=2) with confirmed pain improvement at any time point. Confirmed pain improvement is defined as a 2 point decrease in worst pain score (WPS) from baseline over 2 consecutive assessment periods conducted at least 4 weeks apart | Up to approximately 51 months | 
| Time to Cytotoxic Chemotherapy | Time from the date of randomization to the date of the first cytotoxic chemotherapy | Up to approximately 51 months | 
| Radiological Progression-free Survival (rPFS) | Time from the date of randomization to the date of first radiological progression or death (if death occurs before progression) | Up to approximately 51 months | 
| Number of Participants With Treatment-emergent Adverse Events | Any event arising or worsening after the start of study drug administration until 30 days after the last study medication intake | Up to approximately 7 months | 
| Number of Participants With Post-treatment Adverse Events Including Additional Malignancies and Chemotherapy Related Adverse Events | AEs related to the study drug, all occurrences of additional malignancies, febrile neutropenia and hemorrhage in subjects receiving chemotherapy, bone fractures and bone associated events (regardless of severity and relationship to study drug), and some symptoms needed for the characterization of an symptomatic skeletal event | From 30 days after the last dose of study treatment until the end of study, assessed up to approximately 44 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer