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

• 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: Bayer
• Information provided by (Responsible Party): Bayer

Study Description

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

Study Design

• 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

Arms and Interventions

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.

Outcome Measures

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 ]

Eligibility Criteria

• 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.

Contacts and Locations

Locations

United States, Arizona

Yuma, Arizona, United States, 85364

United States, California

La Jolla, California, United States, 92093

Long Beach, California, United States, 90813

Los Angeles, California, United States, 90033

United States, Connecticut

New Haven, Connecticut, United States, 06510

United States, Florida

Hollywood, Florida, United States, 33021

United States, Kentucky

Ashland, Kentucky, United States, 41101

United States, Maryland

Rockville, Maryland, United States, 20850

United States, Michigan

Ann Arbor, Michigan, United States, 48109

Detroit, Michigan, United States, 48202

Pontiac, Michigan, United States, 48341

United States, Minnesota

Rochester, Minnesota, United States, 55905

United States, Missouri

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Newark, New Jersey, United States, 07103

United States, New York

Jamaica, New York, United States, 11432

United States, South Dakota

Watertown, South Dakota, United States, 57201

United States, Washington

Spokane, Washington, United States, 99208-1129

Austria

Innsbruck, Austria, 6020

Belgium

Anderlecht, Belgium, 1070

Edegem, Belgium, 2650

Kortrijk, Belgium, 8500

Leuven, Belgium, 3000

France

Angers Cedex, France, 49055

Nantes, France, 44805

NIMES Cedex 9, France, 30029

Saint Cloud, France, 92210

Tours, France, 37044

Germany

Herne, Nordrhein-Westfalen, Germany, 44625

Hong Kong

Chai Wan, Hong Kong

Hong Kong, Hong Kong

Kowloon, Hong Kong

Israel

Afula, Israel, 1834111

Beer Sheva, Israel, 8410101

Haifa, Israel, 3109601

Holon, Israel, 5822012

Jerusalem, Israel, 9103102

Jerusalem, Israel, 9112001

Ramat Gan, Israel, 5262000

Tel Aviv, Israel, 64239

Zrifin, Israel, 7030000

Italy

Bologna, Emilia-Romagna, Italy, 40138

Forlì Cesena, Emilia-Romagna, Italy, 47014

Modena, Emilia-Romagna, Italy, 41124

Roma, Lazio, Italy, 00149

Roma, Lazio, Italy, 00161

Genova, Liguria, Italy, 16128

Cremona, Lombardia, Italy, 26100

Milano, Lombardia, Italy, 20132

Bari, Puglia, Italy, 70124

Pisa, Toscana, Italy, 56126

Japan

Nagoya, Aichi, Japan, 464-8681

Sapporo, Hokkaido, Japan, 060-8648

Osakasayama, Osaka, Japan, 589-8511

Hidaka, Saitama, Japan, 350-1298

Kita-Adachigun, Saitama, Japan, 362-0806

Koto-ku, Tokyo, Japan, 135-8550

Kagoshima, Japan, 892-0833

Osaka, Japan, 540-0006

Korea, Republic of

Suwon-si, Gyeonggido, Korea, Republic of, 442-723

Seoul, Seoul Teugbyeolsi, Korea, Republic of, 03080

Busan, Korea, Republic of, 49241

Daegu, Korea, Republic of, 42601

Incheon, Korea, Republic of

Seoul, Korea, Republic of, 05505

Norway

Oslo, Norway, 0424

Poland

Bialystok, Poland, 15-027

Gdansk, Poland, 80-952

Gdynia, Poland, 81-519

Poznan, Poland, 61-485

Warszawa, Poland, 02-781

Singapore

Singapore, Singapore, 119074

Singapore, Singapore, 169610

Singapore, Singapore, 258499

Spain

Palma de Mallorca, Illes Baleares, Spain, 07120

Barcelona, Spain, 08035

Barcelona, Spain, 08036

Barcelona, Spain, 08041

Madrid, Spain, 28033

Madrid, Spain, 28041

Madrid, Spain, 28046

Madrid, Spain, 28050

Pamplona, Spain, 31008

Sevilla, Spain, 41013

Sevilla, Spain, 41071

Switzerland

Aarau, Aargau, Switzerland, 5001

Taiwan

Kaoshiung, Taiwan, 81346

Taichung, Taiwan, 40705

Taipei, Taiwan

United Kingdom

Truro, Cornwall, United Kingdom, TR1 3LJ

Plymouth, Devon, United Kingdom, PL6 8DH

Nottingham, Nottinghamshire, United Kingdom, NG5 1PB

Taunton, Somerset, United Kingdom, TA1 5DA

Bristol, United Kingdom, BS2 8ED

Merseyside, United Kingdom, CH63 4JY

Sponsors and Collaborators

Bayer

Investigators

• 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

More Information

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

• 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:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Everolimus; Exemestane; Radium Ra 223 dichloride; MTOR Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists