Study of radium-223 dichloride versus placebo and hormonal treatment as background therapy in subjects with bone predominant HER2 negative hormone receptor positive metastatic breast cancer.
- Conditions
- HER2 negative hormone receptor positive metastatic breast cancer with bone metastases treated with standard of care hormonal treatment.MedDRA version: 17.1Level: PTClassification code 10055113Term: Breast cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2014-002113-39-NO
- Lead Sponsor
- Bayer HealthCare AG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- Female
- Target Recruitment
- 227
• Have provided written informed consent. Subjects must be able to understand and be willing to sign the written informed consent. A signed informed consent form must be appropriately obtained prior to the conduct of any study-specific procedure.
• Documentation of histological or cytological confirmation of estrogen receptor positive (ER+) and HER2 negative adenocarcinoma of the breast must be available. HER2 status should be determined by an accredited/Ministry of Health approved laboratory by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), or chromogenic in situ hybridization (CISH).
• Tumors (from either primary or metastatic sites) must be ER+ defined as =10% positive tumor nuclei in the analyzed sample. ER+/progesterone receptor positive (PR+) and ER+/ progesterone receptor negative (PR-) subjects are eligible whereas estrogen receptor negative (ER- )/PR+ and ER-/PR- disease will not be eligible.
• Women (=18 years of age) with metastatic breast cancer not amenable to curative treatment by surgery or radiotherapy. Women of reproductive potential and their male partners must agree to use adequate contraception during treatment and for 6 months following the completion of treatment with radium-223 dichloride/placebo.
• Documentation of menopausal status: post-menopausal or pre-menopausal subjects are eligible.
o Pre-menopausal subjects as well as subjects with ovarian radiation or concomitant treatment with an LH-RH agonist/antagonist must have a negative pregnancy test and agree to use an adequate method of contraception as recommended by their treating physicians
o Post-menopausal status is defined either by:
o age =55 years and one year or more of amenorrhea,
o age <55 years and one year or more of amenorrhea with an estradiol assay <20 pg/mL
o bilateral oophorectomy
• Subjects with bone dominant disease (with or without metastases in soft tissue including lymph nodes) with at least 2 skeletal metastases identified at baseline by bone scintigraphy and confirmed by computed tomography (CT)/magnetic resonance imaging (MRI).
• Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors v1.1 criteria. All disease burden must be assessed at baseline by CT or MRI of chest, pelvis and abdomen and any additional fields as needed. A bone scan should also be done at baseline for all subjects.
CT/MRI done as part of the standard of practice within 6 weeks of randomization and standard of care bone scans done within 6 weeks of randomization are acceptable.
18F-sodium fluoride positron emission tomography/CT scan is acceptable as an alternative to technetium-99m bone scintigraphy if it is the standard of care at the institution, provided the same bone imaging modality is used throughout the study.
• 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 with any of the following administered as in second line or greater of hormone therapy in metastatic setting:
o Selective estrogen receptors modulators such as tamoxifen and toremifene
o Non-steroidal aromatase inhibitors such as anastrozole and letrozole
o Steroidal aromatase inhibitors such as exemestane
o Estrogen receptor down-regulators such as fulvestrant
Subjects enrolled in the current study (signature of the informed consent) will start treatment w
• HER2-positive breast cancer (IHC=3+, positive FISH, or positive CISH); equivocal or unknown HER2 status
Note: Subjects with 3+ by IHC cannot be chosen regardless of their FISH/CISH status and those with positive FISH/CISH (=2 amplifications) cannot be chosen either, regardless of the IHC findings. Subjects with 2+ by IHC will not be eligible if no negative FISH/CISH is available.
• Subjects eligible for treatment with everolimus
• Subjects with any of the following cancers:
o Inflammatory breast cancer
o Bilateral breast cancer or a history of 2 distinct breast cancers
• History and/or presence of visceral metastases
• 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 with any previous untreated or concurrent cancer that is distinct in primary site or histology from the cancer under study, except treated basal cell carcinoma or superficial bladder tumor (Ta and Tis, American Joint Committee on Cancer, 7th edition). Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before enrollment are allowed. All cancer treatments must be completed at least 3 years prior to study entry (i.e., signature date of informed consent form).
• 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 is otherwise not required.
• Imminent or established untreated spinal cord compression based on clinical findings and/or MRI. Following treatment of spinal cord compression, the subject may be eligible if all other eligibility criteria are fulfilled.
• Prior treatment with radium-223 dichloride
• Prior hemibody external radiotherapy. Subjects who received other types of prior external radiotherapy are allowed provided that bone marrow function is assessed and meets the protocol requirements for hemoglobin, absolute neutrophil count, and platelets.
• Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188
• ECOG Performance Status =2
• Blood transfusions or use of erythropoietin within 6 weeks prior to randomization. Platelet transfusions are not allowed within 3 weeks prior to randomization.
• Use of biologic response modifiers, such as granulocyte macrophage colony-stimulating factor or granulocyte colony-stimulating factor, within 6 weeks prior to randomization.
• Treatment with an investigational drug or with any anti cancer treatments not permitted by the protocol, within 4 weeks prior to randomization
• Chronic conditions associated with non-malignant abnormal bone growth (e.g., confirmed Paget’s disease of bone)
• Any other serious illness or medical condition such as, but not limited to:
o Any uncontrolled infection
o Cardiac failure New York Heart Association Class III or IV
o Crohn’s disease or ulcerative colitis
o Bone marrow dysplasia
• Previous assignment to treatment in this study
All local label specific criteria for the standard of care hormonal treatment as well as denosumab an
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To assess the efficacy and safety of radium-223 dichloride in subjects with HER2 negative, hormone receptor positive breast cancer with bone metastases treated with hormonal treatment background therapy.;Secondary Objective: Not applicable. ;Primary end point(s): • Symptomatic skeletal event free survival(SSE-FS);Timepoint(s) of evaluation of this end point: The time from randomization to the occurrence of one of the following:<br>(1) An on-study SSE, which is defined as:<br>a. the use of EBRT to relieve skeletal symptoms<br>b. the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral)<br>c. the occurrence of spinal cord compression<br>d. a tumor related orthopedic surgical intervention.<br>(2) Death from any cause
- Secondary Outcome Measures
Name Time Method Secondary end point(s): 1. Overall survival (OS)<br>2. Time to opiate use for cancer pain <br>3. Time to pain progression<br>4. Time to cytotoxic chemotherapy<br>5. Radiological progression free survival (rPFS)<br>6. Safety, acute and long term, including new primary malignancies and hematopoietic reserve for tolerability of subsequent chemotherapy;Timepoint(s) of evaluation of this end point: 1. The time (days) from the date of randomization to the date of death due to any cause.<br>2. The interval from the date of randomization to the date of opiate use.<br>3. The interval from randomization to the first date a subject experiences pain progression based on WPS.<br>4. The time (days) from the date of randomization to the date of the first cytotoxic chemotherapy.<br>5. The time (days) 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).<br>6. To be reviewed throughout the course of the study.<br>