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

NCT02364557

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Standard of Care Therapy With or Without Stereotactic Radiosurgery and/or Surgery in Treating Patients With Limited Metastatic Breast Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: NRG-BR002
  • SECONDARY ID: NCI-2014-01810
  • SECONDARY ID: NRG-BR002
  • SECONDARY ID: NRG-BR002
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT02364557

Conditions

  • Dyspnea
  • Fatigue
  • Nausea and Vomiting
  • Pain
  • Stage IV Breast Cancer

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine whether ablation (through stereotactic body radiation therapy [SBRT]
      [stereotactic radiosurgery] and/or surgical resection of all known metastases) in
      oligometastatic breast cancer patients provides a sufficient signal for improved
      progression-free survival (PFS) to warrant full accrual to the Phase III portion of the
      trial. (Phase II-R) II. To determine whether ablation (through SBRT and/or surgical
      resection of all known metastases) in oligometastatic breast cancer patients significantly
      improves overall survival (OS). (Phase III)

      SECONDARY OBJECTIVES:

      I. To evaluate treated metastasis control according to tumor receptor status (estrogen
      receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor [HER]-2),
      use of chemotherapy, surgery vs. ablative therapy, and solitary metastasis vs. 2 metastasis
      (may expand to >= 2 to =< 4 following completion of a Phase I trial).

      II. To evaluate whether the addition of ablative metastasis directed therapy significantly
      reduces the number of distant recurrences (new metastases) in patients who progress
      according to tumor receptor status (ER, PR, HER-2); use of chemotherapy, and solitary
      metastasis vs. 2 metastases (may expand to >= 2 to =< 4 following completion of the Phase I
      NRG-BR001 trial).

      III. To evaluate adverse events in patients who receive ablative metastasis-directed therapy
      to all known metastases in addition to standard medical therapy alone.

      IV. To explore the most appropriate and clinically relevant technological parameters to
      ensure quality and effectiveness throughout the radiation therapy processes, including
      imaging, simulation, target and critical structure definition, treatment planning, image
      guidance, and delivery.

      TERTIARY OBJECTIVES:

      I. To determine whether < 5 circulating tumor cells (CTCs) (per 7.5 ml of blood) is an
      independent prognostic (outcome) marker for improved PFS and OS in oligometastatic breast
      cancer.

      II. To determine whether < 5 CTCs (per 7.5 ml of blood) is an independent predictive
      (response to therapy) marker for improved PFS and OS in oligometastatic breast cancer.

      III. To determine whether eliminating CTCs (0/7.5 ml of blood in patients with at least 2
      CTCs at registration) is both a prognostic and predictive marker for improved PFS and OS.

      IV. To evaluate the prognostic and predictive properties of CTC count as a continuous
      measure of PFS and OS.

      V. To store material for retrospective analysis of circulating tumor deoxyribonucleic acid
      (ctDNA).

      VI. To store material for retrospective analysis of circulating micro-ribonucleic acid
      (RNA).

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM 1: Patients continue to receive their current planned systemic therapy at the discretion
      of the treating physician.

      ARM 2: Patients continue to receive their current planned systemic therapy at the discretion
      of the treating physician. Patients also undergo stereotactic radiosurgery in 1, 3, or 5
      fractions within 3 weeks and/or surgery at the discretion of the treating physician.

      ARM 1: Patients are followed every 3 months from randomization to 2 years. ARM 2: Patients
      are followed 25-35 days post-ablation, every 3 months from randomization to 2 years, and
      then yearly thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1 (standard of care)No InterventionPatients continue to receive their current planned systemic therapy at the discretion of the treating physician.
    Arm 2 (stereotactic radiosurgery, surgery)ExperimentalPatients continue to receive their current planned systemic therapy at the discretion of the treating physician. Patients also undergo stereotactic radiosurgery in 1, 3, or 5 fractions within 3 weeks and/or surgery at the discretion of the treating physician.

      Eligibility Criteria

              Inclusion Criteria:
      
                -  Pathologically confirmed metastatic breast cancer within 270 days prior to
                   registration
      
                -  Known estrogen, progesterone, and HER2 status of either primary tumor or metastasis
      
                -  =< 2 metastases seen on standard imaging within 30 days prior to registration
      
                -  Controlled primary tumor site defined as >= 3 months (90 days) recurrence-free
                   interval since completion of definitive surgical management
      
                -  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
      
                -  Metastases must be > 5 cm away from each other (defined as Edge to Edge of tumor)
      
                     -  NOTE: If metastases are =< 5 cm away from each other, consider enrollment in
                        NRG-BR001
      
                -  First-line standard systemic therapy (chemotherapy, anti-endocrine therapy, anti-HER2
                   or other standard targeted therapy) for metastatic breast cancer not to have exceeded
                   a duration of 6 months at the time of registration
      
                -  Appropriate stage for study entry based on the following diagnostic workup:
      
                     -  History/physical examination within 30 days prior to registration
      
                     -  Computed tomography (CT) scans of the chest, abdomen, and pelvis with
                        radionuclide bone scan OR whole body positron emission tomography (PET)/CT
                        within 30 days prior to study registration
      
                -  Zubrod performance status =< 2 within 30 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
      
                -  The patient must provide study-specific informed consent prior to study entry
      
              Exclusion Criteria:
      
                -  Pathologic evidence of local/regional breast tumor recurrence
      
                -  Co-existing or prior invasive malignancy (except non-melanomatous skin cancer),
                   unless disease free for a minimum of 3 years
      
                -  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
      
                -  Metastases located within 3 cm of the previously irradiated structures:
      
                     -  Spinal cord previously irradiated to > 40 Gy
      
                     -  Brachial plexus previously irradiated to > 50 Gy
      
                     -  Small intestine, large intestine, or stomach previously irradiated to > 45 Gy
      
                     -  Brainstem previously irradiated to > 50 Gy
      
                     -  Lung previously irradiated with prior V20Gy > 30%
      
                -  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
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Progression-free survival (failure: progression or death due to any cause) (Phase II-R)
      Time Frame:From the date of randomization to the date of first PFS failure or last follow-up; assessed up to 3 years
      Safety Issue:
      Description:Progression-free survival will be estimated by the Kaplan-Meier method, with progression defined as: progression of initial/treated metastases (using the revised Response Evaluation Criteria in Solid Tumors [RECIST] guideline), appearance of new metastases, or death due to any cause. The distribution of PFS estimates between the two arms will be compared using the log rank test.

      Secondary Outcome Measures

      Measure:Appearance of new metastases
      Time Frame:From the date of randomization to the date of the first appearance of any new metastases; assessed up to 8 years
      Safety Issue:
      Description:Failure for this endpoint will be the appearance of any new metastases. The cumulative probability of new metastases in the presence of competing failure events will be estimated by the cumulative incidence method. The cumulative incidence distributions between the two arms will be compared using Gray's test. The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, that may be associated with the incidence of new metastases.
      Measure:Incidence of adverse events graded according to National Cancer Institute CTCAE version 4
      Time Frame:From the date of randomization to the date of death or last follow-up; assessed up to 2 years
      Safety Issue:
      Description:The frequencies and severity of adverse events by treatment arm will be analyzed.
      Measure:Initial presence of CTCs in blood samples
      Time Frame:Baseline
      Safety Issue:
      Description:The prognostic effect of the initial presence of CTCs at baseline on PFS (OS) will be evaluated using the Cox proportional hazards model, controlling for treatment effect and stratification factors. The hypothesis tests will be two-sided and will use an alpha level of 0.05 to determine significance.
      Measure:Presence of CTCs after treatment in blood samples
      Time Frame:Up to 3 months
      Safety Issue:
      Description:The interaction between treatment effect and the initial presence of CTCs at baseline on PFS (OS) will be evaluated in the Cox model, which will include an indicator for treatment group, an indicator for presence of CTCs (>= 5 per 7.5 ml of blood), and their interaction term. The analysis will be adjusted for the stratification factors.
      Measure:Change in CTC count in blood samples
      Time Frame:Baseline to up to 3 months
      Safety Issue:
      Description:The effect of change in CTC count from CTC >= 2 per 7.5 ml of blood at baseline to CTC = 0 at follow-up after initial treatment on PFS (OS) will be evaluated using the Cox proportional hazards model, controlling for treatment effect and stratification factors. The analyses will be conditional on a patient's event-free survival up to post-treatment evaluation. The interaction between treatment effect and change in CTC count will be evaluated in the Cox model, which will include an indicator for treatment group, an indicator for change of CTCs, and their interaction term.
      Measure:Levels of ctDNA in plasma samples
      Time Frame:Up to 3 months
      Safety Issue:
      Description:The prognostic effect of dichotomized ctDNA on PFS (OS) will be evaluated using the Cox proportional hazards model, controlling for treatment effect and stratification factors. In addition, the presence of the interaction between treatment effect and dichotomized ctDNA will be evaluated (predictive effect). Spearman rank correlation coefficient will be used to correlate the levels of CTCs and ctDNA.

      Details

      Phase:Phase 2/Phase 3
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:NRG Oncology

      Last Updated

      June 17, 2016