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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02258451
Recruitment Status : Completed
First Posted : October 7, 2014
Results First Posted : March 10, 2022
Last Update Posted : November 8, 2022
Sponsor:
Information provided by (Responsible Party):
Bayer

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Breast Neoplasms Drug: Radium-223 dichloride (Xofigo, BAY88-8223) Drug: Placebo (saline) Drug: Exemestane Drug: Everolimus Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 283 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 4, 2015
Actual Primary Completion Date : January 22, 2020
Actual Study Completion Date : October 28, 2022

Resource links provided by the National Library of Medicine


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.
Drug: Radium-223 dichloride (Xofigo, BAY88-8223)
Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update)

Drug: Exemestane
One 25 mg tablet once daily after a meal.

Drug: Everolimus

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.
Drug: Placebo (saline)
Up to 6 cycles of saline injection

Drug: Exemestane
One 25 mg tablet once daily after a meal.

Drug: Everolimus

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.





Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: Up to 55 months ]
    The time from the date of randomization to the date of death due to any cause.

  2. 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

  3. 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.

  4. Time to Cytotoxic Chemotherapy [ Time Frame: Up to 55 months ]
    Time from the date of randomization to the date of the first cytotoxic chemotherapy

  5. 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.


  6. 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.

  7. 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.

  8. Number of Participants With Post-treatment Chemotherapy Related Adverse Events [ Time Frame: From post-treatment till end of study, up to 93 months ]
  9. 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 ]
  10. Number of Participants With New Primary Malignancies [ Time Frame: From first dosing till end of study, up to 93 months ]

Other Outcome Measures:
  1. 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.

  2. Number of Participants With Post-treatment Chemotherapy Related Adverse Events [ Time Frame: From post-treatment till primary analysis cutoff date, up to 55 months ]
  3. Number of Participants With Hematological Toxicities: Worst Grade Under Treatment [ Time Frame: From first dosing till primary analysis cutoff date, up to 55 months ]
  4. 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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02258451


Locations
Show Show 94 study locations
Sponsors and Collaborators
Bayer
Investigators
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Study Director: Bayer Study Director Bayer
  Study Documents (Full-Text)

Documents provided by Bayer:
Study Protocol  [PDF] December 4, 2019
Statistical Analysis Plan  [PDF] June 24, 2020

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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02258451    
Other Study ID Numbers: 17096
2014-002114-23 ( EudraCT Number )
First Posted: October 7, 2014    Key Record Dates
Results First Posted: March 10, 2022
Last Update Posted: November 8, 2022
Last Verified: November 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Breast Cancer
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Everolimus
Exemestane
Radium Ra 223 dichloride
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists