A Phase IIR/III Trial of Standard of Care Therapy With or Without Stereotactic Body Radiotherapy (SBRT) and/or Surgical Ablation for Newly Oligometastatic Breast Cancer (NGR BR002)

Standard of Care Therapy With or Without Stereotactic Radiosurgery and/or Surgery in Treating Patients With Limited Metastatic Breast Cancer

This randomized phase II/III trial studies how well standard of care therapy with stereotactic radiosurgery and/or surgery works and compares it to standard of care therapy alone in treating patients with breast cancer that has spread to one or two locations in the body (limited metastatic) that are previously untreated. Standard of care therapy comprising chemotherapy, hormonal therapy, biological therapy, and others may help stop the spread of tumor cells. Radiation therapy and/or surgery is usually only given with standard of care therapy to relieve pain; however, in patients with limited metastatic breast cancer, stereotactic radiosurgery, also known as stereotactic body radiation therapy, may be able to send x-rays directly to the tumor and cause less damage to normal tissue and surgery may be able to effectively remove the metastatic tumor cells. It is not yet known whether standard of care therapy is more effective with stereotactic radiosurgery and/or surgery in treating limited metastatic breast cancer.

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Breast Cancer

Learn More

To learn more, visit ClinicalTrials.Gov or contact Clinical Research at 864-560-6812.

Principal Investigator(s)

Jeremy Kilburn, MD

Sponsor(s)

NRG Oncology

Key Trial Criteria

For a patient to be eligible for participation in this study, all of the following criteria must apply.
- Pathologically confirmed metastatic breast cancer
- Known estrogen, progesterone, and HER2 status of either primary tumor or metastasis
- ≤ 4 metastases seen on standard imaging within 60 days prior to registration when all metastatic disease is located within the following sites:
  - peripheral lung
  - osseous (bone)
  - spine
  - central lung
  - abdominal-pelvic(lymph node/adrenal gland)
  - liver
  - mediastinal/cervical lymph node
- All known disease amenable to metastasis-directed therapy with either SBRT or resection
  - NOTE: Symptomatic bone metastasis are allowed if ablative therapy can be delivered
  - NOTE: Sites for possible surgical excision include lung, liver, adrenal gland, bone, small intestine, large intestine, ovary, and amenable nodal disease sites
  - NOTE: Surgical stabilization is allowed for a metastasis if it is followed by conventionally fractionated external beam radiotherapy
- Maximum diameter of individual metastasis in any dimension ≤ 5 cm
- There are no restrictions on distance between the metastases
- Patients must be registered within 365 days of the initial metastatic breast cancer diagnosis. First-line standard systemic therapy (chemotherapy, anti-endocrine therapy, anti-HER2 or other standard targeted therapy) for metastatic breast cancer must be given or planned to be given. If given before study entry, it cannot have exceeded a duration of 12 months at the time of registration. (Note: Sequencing of ablative therapy (surgery or SBRT) relative to systemic therapy, for patients randomized to Arm 2, is at the discretion of the treating physician.)
- The primary tumor site must be controlled prior to registration
  - For those who present with synchronous primary and oligometastatic disease:
- Primary must be controlled prior to registration. The definition of control is definitive surgery by excision or mastectomy (+/- radiotherapy) per institution preference
- For those who present with local recurrence and oligometastatic disease, local recurrence must be controlled prior to registration The definition of control is definitive surgery by excision or mastectomy (+/- radiotherapy) per institution preference
  - Appropriate stage for study entry based on the following diagnostic workup:
- History/physical examination within 60 days prior to registration
- Clinical grade computed tomography (CT) scans of the chest, abdomen, and pelvis with radionuclide bone scan OR whole body positron emission tomography (PET)/CT within 60 days prior to study registration
  - Zubrod performance status ≤ 2 within 60 days prior to registration
  - Absolute neutrophil count (ANC) ≥ 500 cells/mm^3
  - Platelets ≥ 50,000 cells/mm^3
  - Hemoglobin ≥ 8.0 g/dl (note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] ≥ 8.0 g/dl is acceptable)
  - For females of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to study registration
A patient will not be eligible for participation in this study if any of the following criteria apply.
- T4 tumors including inflammatory breast cancer
- Definitive clinical or radiologic evidence of metastatic disease; required imaging studies must have been performed within 90 days prior to randomization
- Synchronous or previous contralateral invasive breast cancer; (patients with synchronous and/or previous contralateral DCIS or LCIS are eligible)
- Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS; (patients with synchronous or previous ipsilateral LCIS are eligible)
- History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization
- Previous therapy with anthracyclines or taxanes for any malignancy
- Chemotherapy administered for the currently diagnosed breast cancer prior to randomization
- Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy; patients are eligible if these medications are discontinued prior to randomization
- Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens; this includes but is not confined to:
  - Active cardiac disease
    - Symptomatic pericarditis
    - Valvular disease with documented compromise in cardiac function; or
    - Conduction abnormality requiring a pacemaker;
    - Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
    - Ventricular arrhythmias except for benign premature ventricular contractions;
    - Angina pectoris that requires the current use of anti-anginal medication;
    - History of cardiac disease
      Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricle (LV) function;
      History of documented congestive heart failure (CHF); or
      Documented cardiomyopathy
- Uncontrolled hypertension defined as sustained systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg; (patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria)
- Active hepatitis B or hepatitis C with abnormal liver function tests
- Patients known to be human immunodeficiency virus (HIV) positive with a baseline cluster of differentiation (CD)4 count of < 250 cells/mm^3 or have a history of acquired immune deficiency syndrome (AIDS) indicator conditions
- Intrinsic lung disease resulting in dyspnea
- History of hospitalization in past 12 months for diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic nonketotic syndrome (HHNS)
- Active infection or chronic infection requiring chronic suppressive antibiotics
- Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0
- Conditions that would prohibit administration of corticosteroids
- Chronic daily treatment with corticosteroids with a dose of >= 10 mg/day methylprednisolone equivalent (excluding inhaled steroids)
- Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor® EL
- Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up
- Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
- Pregnancy or lactation at the time of study entry; (note: pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to randomization)
- Use of any investigational product within 4 weeks prior to randomization
- Pathologic evidence of local/regional breast tumor recurrence at the time of registration
- Co-existing or prior invasive malignancy (except non-melanomatous skin cancer), unless disease free for a minimum of 3 years; previous RT dose, date, fraction size, must be reported
- Metastases with indistinct borders making targeting not feasible
  - NOTE: A potential issue with bone metastases is that they often are not discrete. Since many patients on this protocol will have bone metastases, this will be an important issue. Theoretically, Houndsfield units might provide an appropriate measure; however, a sclerotic lesion against dense cortical bone will not have a sharp demarcation based on Houndsfield units (HU). Therefore, we acknowledge that such determinations will pose a challenge and thus the physician's judgment will be required
- Prior palliative radiation treatment for metastatic disease (including radiopharmaceuticals)
- Metastases located within 3 cm of the previously irradiated structures:
  - Spinal cord previously irradiated to > 40 Gy (delivered in ≤ 3 Gy/fraction)
  - Brachial plexus previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction)
  - Small intestine, large intestine, or stomach previously irradiated to > 45 Gy (delivered in ≤ 3 Gy/fraction)
  - Brainstem previously irradiated to > 50 Gy (delivered in ≤ 3 Gy/fraction)
  - Whole lung previously irradiated with prior V20Gy > 30% (delivered in ≤ 3 Gy/fraction)
  - Primary tumor irradiated with SBRT
  - Metastasis irradiated with SBRT
- Brain metastases
- Exudative, bloody, or cytological proven malignant effusions
- Severe, active co-morbidity defined as follows:
  - Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months
  - Transmural myocardial infarction within the last 6 months
  - Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  - Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
- Pregnancy; lactating females must cease expression of milk prior to signing consent to be eligible
- Human immunodeficiency virus (HIV) positive with cluster of differentiation (CD)4 count < 200 cells/microliter; note that patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count ≥ 200 cells/microliter within 30 days prior to registration; note also that HIV testing is not required for eligibility for this protocol

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