ER+ve HER-ve breast cancer with bone metastases MedDRA version: 21.1 Level: LLT Classification code 10006280 Term: Breast neoplasm benign female System Organ Class: 100000004864
Conditions
Interventions
Trade Name: Xofigo
Product Name: Xofigo
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Radium-223 dichloride
CAS Number: 444811-40-9
Current Sponsor code: BAY 88-8223
Concentration u
Sponsors
Sheffield Teaching Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Female patients >=18 years, with histological evidence of ER+ve, HER2-ve primary breast cancer 2. Radiological evidence of bone metastasis (with or without metastasis at other sites) to include plain radiograph, bone scan, CT or MRI and assessed according to RECIST v1.1, with at least 2 bone metastatic lesions on screening investigations performed at least 6 weeks prior to confirmation of eligibility 3. Measurable disease by RECIST 1.1 (including bone scans – see above) 4. 2-5 prior chemotherapy treatments for advanced disease, including an anthracycline and a taxane, unless contraindicated or patient has declined previous treatment or alternative treatment. 5. ECOG Performance Status 0, 1 or 2. 6. Life expectancy >6 months 7. Adequate haematological, renal and hepatic function and bone marrow function. Laboratory requirements within 14 days prior to confirmation of eligibility and start of trial treatment as follows; a. Neutrophil count =1.5 x10^9/L b. Platelet count =100 x10^9/L c. Haemoglobin =9.0 g/dL d. Total bilirubin level =1.5 xULN in treating institution (or =3.0 xULN for patients with Gilbert’s syndrome) e. AST or ALT =3 xULN in treating institution f. Calculated creatinine clearance or estimated GFR >40mls/min (Cockcroft and Gault or Wright formula may be used according to local practice) 8. Patient on bone targeted therapy (e.g. bisphosphonates or denosumab) for >6 weeks before confirmation of eligibility and starting treatment. No change to bone targeted therapy anticipated during study 9. Able to provide an archival primary tumour biopsy for assay of PD-1 expression (Please note that for Phase IIa participants only, provision of a biopsy from a metastatic lesion if already available, or optional provision of a new metastatic biopsy) 10. Patient must be fully informed about the study and has signed the informed consent form. 11. Patient must be willing and able to comply with the protocol, have mental capacity and (if relevant) use effective contraception throughout treatment and for 6 months after treatment completion. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 12
Exclusion criteria
Exclusion criteria: 1. Presence of other currently active (diagnosis within the last 5 years) malignancy (except treated non-melanoma skin cancer (basal or squamous), carcinoma in situ of cervix and superficial bladder cancers). 2. External beam radiotherapy within 4 weeks of confirmation of eligibility and starting treatment. 3. Past medical history of autoimmune disorders or organ transplant including but not limited to myasthenia gravis,myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, poorly controlled type 1 diabetes, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis 4. Previous treatment with immune checkpoint inhibitors 5. Active hepatitis B or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Testing must be performed within 12 months prior to confirmation of eligibility. 6. HIV positive tested within 12 months prior to confirmation of eligibility. 7. Active tuberculosis based on clinical findings. 8. Receipt of an active live vaccine within 4 weeks of confirmation of eligibility and starting treatment. 9. Treatment with systemic immune stimulants or suppressors (including systemic steroids) within 2 weeks of confirmation of eligibility and starting treatment. 10. Requirement for ongoing steroids in the context of active/symptomatic brain/leptomeningeal metastases. 11. Presence of imminent or established spinal cord compression based on clinical findings and/or MRI 12. Known history of clinically significant cardiac disease as documented in the medical records 13. Positive pregnancy test at eligibility assessment for women of childbearing potential or breast-feeding women 14. Known hypersensitivity to any of the excipients of avelumab or radium-223 as documented in the medical records 15. Inability to tolerate antihistamine or antipyretic (e.g. paracetamol) as documented in the medical records 16. Coagulation dysfunction that is deemed by the investigator to be likely to interfere with trial treatment as identified by clotting panel (APTT and INR) within 12 months prior to confirmation of eligibility. 17. Thyroid dysfunction that is deemed by the investigator to be likely to interfere with trial treatment as identified by TSH, free T3 and free T4 within 6 months prior to confirmation of eligibility. Patients with a history of autoimmune-mediated hypothyroidism on a stable dose of thyroid replacement hormone are eligible. 18. Erythropoietin treatment within the 4 weeks prior to confirmation of eligibility and start of treatment
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib: initial safety phase • To determine whether avelumab can be safely combined with radium-223 in patients with ER+ve and HER2-ve metastatic breast cancer patients. (ER+ve and HER2-ve are genetic characteristics that we know affect the likely response to treatment. Metastatic means that the cancer has spread to one or more other locations in the body) Phase IIa: randomised expansion phase • To assess whether the activity of avelumab immunotherapy in metastatic ER+ve HER2-ve breast cancer is enhanced by radium-223.;Secondary Objective: Secondary objectives • To evaluate the longer-term safety and toxicity of the combination of radium-223 and avelumab in patients with ER+ve, HER2-ve metastatic breast cancer • To further evaluate the efficacy of the combination in terms of additional measures of anti-tumour activity. • To evaluate the effect of the combination of radium-223 and avelumab on bone turnover markers (PINP and uNTX:creatinine ratio). • To evaluate time to first symptomatic skeletal-related event (SSE). • To evaluate time to progression of bone disease and time to first documented disease progression (clinical or radiological). • To evaluate quality of life in patients with ER+ve and HER2-ve metastatic breast cancer (efficacy is the ability to produce the desired effect, toxicity is a measure of unwanted effects of treatment (eg fever, seizure), examples of symptomatic skeletal-related events are fractures or severe bone pain, quality of life will be measure using participant questionnaires) Exploratory t;Primary end point(s): Phase Ib initial safety phase The number of dose limiting toxicities (DLTs) observed during the DLT period. This will confirm the safety of radium-223 in combination with avelumab. Randomised expansion phase • Objective response rate (ORR) – this will be calculated as the proportion of participants achieving at least a partial response (according to RECIST 1.1 (to include bone response)) within 24 weeks of | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety and toxicity as assessed by the occurrence of SAEs, SARs, SUSARs, ARs and AEs Tumour response according to RECISTS 1.1 and where appropriate immune-RECIST, including maximum objective response of measurable non-osseous lesions, assessed within 24 weeks of cycle 1 day 1 Time to progression of bone disease, based on either unequivocal progression of existing bone lesion(s) or appearance of one or more new osteolytic bone lesions Time to first documented disease progression either clinical or radiological Disease control rate and duration of clinical benefit Treatment compliance as assessed by dose omissions/delays Change in bone turnover markers in serum (PINP) and urine (uNTX:creatinine ratio) from baseline to prior to cycle 4 Time to occurrence of first SSE Quality of life as measured using EORTC QLQ-C30 and QLQ-BM22 ;Timepoint(s) of evaluation of this end point: End of trial- when all patients have been followed up for at least 12 months | — |
Countries
United Kingdom
Contacts
Public ContactJamie Oughton
Clinical Trials Research Unit, University of Leeds
Outcome results
None listed