| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Metastatic HER2 negative hormone receptor positive breast cancer subjects with bone metastases
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| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer subjects with bone metastases |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10055113 |
| E.1.2 | Term | Breast cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The objective of this study is to assess efficacy and safety of radium 223 dichloride in combination with exemestane and everolimus in subjects with human epidermal growth factor receptor 2 (HER2) negative, hormone receptor positive breast cancer with bone metastases. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Have provided written informed consent. Subjects must be able to understand and be willing to sign the written informed consent. A signed ICF must be appropriately obtained prior to the conduct of any trial-specific procedure.
• Documentation of histological or cytological confirmation of 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.
• Documentation of menopausal status: postmenopausal subjects.
o Post-menopausal status is defined either by:
*age ≥55 years and one year or more of amenorrhea,
*age <55 years and one year or more of amenorrhea with an estradiol assay <20 pg/mL
*bilateral oophorectomy
o Patients with ovarian radiation or concomitant treatment with a luteinizing hormone-releasing hormone (LHRH) agonist/antagonists must have a negative pregnancy test and agree to use an adequate method of contraception as recommended by their treating physicians
• 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 Tc99m bone scintigraphy and confirmed by CT/magnetic resonance imaging (MRI).
• Measurable or non-measurable disease (but radiologically evaluable) according to Response Evaluation Criteria in Solid Tumors (RECIST) 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 Tc99m bone scan should also be done at baseline for all subjects.
• CT/MRI done as part of the standard of practice within 6 weeks prior to randomization and standard-of-care Tc99m bone scans done within 6 weeks prior to randomization are acceptable.
• 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, for treatment with exemestane and everolimus as a second line or greater of hormone therapy in a metastatic setting. Subjects enrolled in the current study (signature of the informed consent), will start treatment with exemestane and everolimus, after randomization, either before or simultaneously to the first injection of radium-223 dichloride. Subjects already receiving exemestane and everolimus treatment prior to study entry are not eligible.
• Subjects must have experienced no more than two SREs prior to study entry defined as: EBRT for 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 3 months before start of study treatment.
• Asymptomatic or mildly symptomatic breast cancer.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
• Life expectancy ≥6 months
• Laboratory requirements:
o Absolute neutrophil count ≥1.5 x 109/L
o Platelet count ≥100 x109/L without platelet transfusion within 3weeks prior to randomization
o Hemoglobin (Hb) ≥9.0 g/dL (90 g/L; 5.6 mmol/L) without transfusion or erythropoietin within 6 weeks prior to randomization
o Total bilirubin level ≤1.5 x institutional upper limit of normal (ULN) (except for subjects with documented Gilbert’s disease)
o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x institutional ULN; AST and ALT values above the ULN must not be related to liver metastases
o Creatinine ≤1.5 x ULN
o Estimated glomerular filtration rate ≥60 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula
o International normalized ratio of prothrombin time (INR) and partial thromboplastin time (PTT) or activated PTT ≤1.5 x ULN. Subjects treated with warfarin or heparin will be allowed to participate in the study if no underlying abnormality in coagulation parameters exists per prior history; weekly evaluation of INR/PTT will be required until stability is achieved (as defined by local standard-of-care and based on prestudy INR/PTT values)
• Able to swallow oral medication |
|
| E.4 | Principal exclusion criteria |
• HER2-positive breast cancer (immunohistochemistry [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 with any of the following cancers:
o Inflammatory breast cancer
o Bilateral breast cancer or a history of 2 distinct breast cancers.
• History 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 ICF)
• 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 Hb, absolute neutrophil count, and platelets.
• Prior systemic radiotherapy with strontium-89, samarium-153, rhenium-186, or rhenium-188.
• ECOG PS ≥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 exemestane and everolimus as well as standard-of-care denosumab and bisphosphonates will apply. Subjects must be treated according to the local standard-of-care requirements.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Symptomatic skeletal event free survival(SSE-FS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The time from randomization to the occurrence of one of the following:
(1) An on-study SSE, which is defined as:
a. the use of EBRT to relieve skeletal symptoms
b. the occurrence of new symptomatic pathological bone fractures (vertebral or non-vertebral)
c. the occurrence of spinal cord compression
d. a tumor related orthopedic surgical intervention.
(2) Death from any cause
|
|
| E.5.2 | Secondary end point(s) |
1. Overall Survival
2. Time to pain progression
3. Time to cytotoxic chemotherapy
4. Time to opiate use for cancer pain
5. Radiological progression free survival (rPFS)
6. Safety, acute and long term, including new primary malignancies and hematopoietic reserve for tolerability of subsequent chemotherapy |
|
| E.5.2.1 | 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.
2. The interval from randomization to the first date a subject experiences pain progression based on WPS.
3. The time (days) from the date of randomization to the date of the first cytotoxic chemotherapy.
4. The interval from the date of randomization to the date of opiate use.
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).
6) To be reviewed throught the course of the study. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 118 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Canada |
| China |
| Czech Republic |
| France |
| Germany |
| Hong Kong |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study (EOS) will occur when the number of required events is met. All subjects on treatment at that time will be allowed to complete treatment. The 30-day safety follow-up visit is required for all subjects.
For each participating European Union (EU) country, the end of the study according to the EU Clinical Trial Directive will be reached when the last visit of the last subject in any site has occurred. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 22 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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