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

NCT02258451 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 170962014-002114-23
• Study Type: interventional
• Target: 283
• Locations: 17 countries
• Sites: 92

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.

Conditions

Breast Neoplasms

Keywords

Breast Cancer

Outcome Measures

Primary Outcomes (1)

• 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. Per Protocol Amendment 10, following primary analysis completion, further assessments were focused on safety, and only limited efficacy data including SSE and survival were collected and not designed to support reconsideration of the primary analysis efficacy conclusions. Accordingly, no formal statistical analyses were performed for primary and secondary efficacy outcomes in the final analysis. All primary and secondary efficacy outcome measures presented in this document came from the primary completion analysis.

  Up to 55 months

Secondary Outcomes (10)

• Overall Survival

  Up to 55 months

• Time to Opiate Use for Cancer Pain

  Up to 55 months

• Time to Pain Progression

  Up to 55 months

• Time to Cytotoxic Chemotherapy

  Up to 55 months

• Radiological Progression-free Survival (rPFS)

  Up to 55 months

Other Outcomes (4)

• Number of Participants With Treatment-emergent Adverse Events (TEAEs) (From First Dosing Till Primary Analysis)

  From first dosing till primary analysis cutoff date, up to 55 months

• Number of Participants With Post-treatment Chemotherapy Related Adverse Events (From First Dosing Till Primary Analysis)

  From post-treatment till primary analysis cutoff date, up to 55 months

• Number of Participants With Hematological Toxicities: Worst Grade Under Treatment (From First Dosing Till Primary Analysis)

  From first dosing till primary analysis cutoff date, up to 55 months

Study Arms (2)

Radium-223 dichloride + exemestane/everolimus

EXPERIMENTAL

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); Drug: Exemestane; Drug: Everolimus

Placebo + exemestane/everolimus

PLACEBO COMPARATOR

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); Drug: Exemestane; Drug: Everolimus

Interventions

Radium-223 dichloride (Xofigo, BAY88-8223) DRUG

Up to 6 cycles of radium-223 dichloride 50kBq/kg body (55 kBq/kg after implementation of NIST update)

Radium-223 dichloride + exemestane/everolimus

Placebo (saline) DRUG

Up to 6 cycles of saline injection

Placebo + exemestane/everolimus

Exemestane DRUG

One 25 mg tablet once daily after a meal.

Placebo + exemestane/everolimus; Radium-223 dichloride + exemestane/everolimus

Everolimus DRUG

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 + exemestane/everolimus; Radium-223 dichloride + exemestane/everolimus

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Bayer: lead

Study Sites (92)

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La Jolla, California, 92093, United States

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Los Angeles, California, 90033, United States

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New Haven, Connecticut, 6510, United States

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Hollywood, Florida, 33021, United States

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Ashland, Kentucky, 41101, United States

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Rockville, Maryland, 20850, United States

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Ann Arbor, Michigan, 48109, United States

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Detroit, Michigan, 48202, United States

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Pontiac, Michigan, 48341, United States

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Rochester, Minnesota, 55905, United States

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St Louis, Missouri, 63110, United States

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Newark, New Jersey, 07103, United States

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Jamaica, New York, 11432, United States

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Watertown, South Dakota, 57201, United States

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Spokane, Washington, 99208-1129, United States

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Innsbruck, 6020, Austria

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Brussels, 1070, Belgium

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Edegem, 2650, Belgium

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Kortrijk, 8500, Belgium

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Leuven, 3000, Belgium

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Angers, 49055, France

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Nantes, 44805, France

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Nîmes, 30029, France

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Saint-Cloud, 92210, France

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Tours, 37044, France

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Herne, North Rhine-Westphalia, 44625, Germany

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Chai Wan, Hong Kong

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Hong Kong, Hong Kong

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Kowloon, Hong Kong

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Afula, 1834111, Israel

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Beersheba, 8410101, Israel

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Haifa, 3109601, Israel

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Holon, 5822012, Israel

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Jerusalem, 9103102, Israel

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Jerusalem, 9112001, Israel

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Ramat Gan, 5262000, Israel

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Tel Aviv, 64239, Israel

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Zrifin, 7030000, Israel

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Bari, Apulia, 70124, Italy

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Bologna, Emilia-Romagna, 40138, Italy

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Forlì Cesena, Emilia-Romagna, 47014, Italy

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Modena, Emilia-Romagna, 41124, Italy

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Rome, Lazio, 00149, Italy

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Rome, Lazio, 00161, Italy

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Genoa, Liguria, 16128, Italy

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Cremona, Lombardy, 26100, Italy

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Milan, Lombardy, 20132, Italy

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Pisa, Tuscany, 56126, Italy

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Nagoya, Aichi-ken, 464-8681, Japan

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Sapporo, Hokkaido, 060-8648, Japan

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Sayama, Osaka, 589-8511, Japan

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Hidaka, Saitama, 350-1298, Japan

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Kita-Adachigun, Saitama, 362-0806, Japan

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Koto-ku, Tokyo, 135-8550, Japan

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Kagoshima, 892-0833, Japan

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Osaka, 540-0006, Japan

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Oslo, 0424, Norway

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Bialystok, 15-027, Poland

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Gdansk, 80-952, Poland

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Gdynia, 81-519, Poland

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Poznan, 61-485, Poland

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Warsaw, 02-781, Poland

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Singapore, 119074, Singapore

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Singapore, 168583, Singapore

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Singapore, 258499, Singapore

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Suwon, Gyeonggido, 442-723, South Korea

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Seoul, Seoul Teugbyeolsi, 03080, South Korea

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Busan, 49241, South Korea

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Daegu, 42601, South Korea

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Incheon, South Korea

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Seoul, 05505, South Korea

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Palma de Mallorca, Illes Baleares, 07120, Spain

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Barcelona, 08023, Spain

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Barcelona, 08041, Spain

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Barcelona, 8036, Spain

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Madrid, 28033, Spain

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Madrid, 28041, Spain

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Madrid, 28046, Spain

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Madrid, 28050, Spain

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Pamplona, 31008, Spain

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Seville, 41013, Spain

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Seville, 41071, Spain

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Aarau, Canton of Aargau, 5001, Switzerland

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Kaohsiung City, 813414, Taiwan

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Taichung, 40705, Taiwan

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Taipei, 114, Taiwan

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Taipei, Taiwan

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Truro, Cornwall, TR1 3LJ, United Kingdom

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Plymouth, Devon, PL6 8DH, United Kingdom

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Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

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Taunton, Somerset, TA1 5DA, United Kingdom

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Bristol, BS2 8ED, United Kingdom

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Related Publications (1)

• Rugo HS, Van Poznak CH, Neven P, Danielewicz I, Lee SC, Campone M, Chik JYK, Vega Alonso E, Naume B, Brain E, Siegel JM, Li R, Uema D, Wagner VJ, Coleman RE. Radium-223 in women with hormone receptor-positive bone-metastatic breast cancer receiving endocrine therapy: pooled analysis of two international, phase 2, randomized, double-blind, placebo-controlled trials. Breast Cancer Res Treat. 2024 Apr;204(2):249-259. doi: 10.1007/s10549-023-07147-z. Epub 2023 Dec 20.

  PMID: 38123789 DERIVED

Related Links

• Click here to find information about studies related to Bayer Healthcare products conducted in Europe
• Click here to find further information and, after study completion, the study results according to Bayer's transparency standards

MeSH Terms

Conditions

Breast Neoplasms

Interventions

radium Ra 223 dichloride; Sodium Chloride; exemestane; Everolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Sirolimus; Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

Due to reassessment of the Primary Completion date (PCD) conditions, PCD was moved back to 22 January 2020. Interim survival data on patients transferring from this study to study 16996 (NCT02312960), as of analysis cutoff, was pooled with this study's data to increase the reliability of efficacy results. This pooling was specified in a supplemental SAP dated 24 Jun 2020. All other primary and secondary analysis details were specified in the main study SAP dated 14 Feb 2020.

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayer.com

(+) 1-888-8422937

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2014
• First Posted: October 7, 2014
• Study Start: June 4, 2015
• Primary Completion: January 22, 2020
• Study Completion: October 28, 2022
• Last Updated: November 24, 2023
• Results First Posted: March 10, 2022

Record last verified: 2023-11

Locations

NO (1); ES (11); GB (5); DE (1); IT (10); PL (5); AU (1); US (15); KR (6); IL (9); SG (3); TW (4); HK (3); BE (4); FR (5); JP (8); CH (1)