<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02212860</url>
  </required_header>
  <id_info>
    <org_study_id>SIGNAL</org_study_id>
    <nct_id>NCT02212860</nct_id>
  </id_info>
  <brief_title>Stereotactic Image-Guided Neoadjuvant Ablative Radiation Then Lumpectomy</brief_title>
  <acronym>SIGNAL 2</acronym>
  <official_title>Clinical Trial to Evaluate Single Dose Versus Three Doses of Stereotactic Radiation Therapy (SBRT) Prior to Surgery for Early Stage Breast Carcinoma: SIGNAL 2.0 (Stereotactic Image-Guided Neoadjuvant Ablative Radiation Then Lumpectomy) Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Lawson Health Research Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Weill Medical College of Cornell University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sunnybrook Health Sciences Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Ontario Institute for Cancer Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Lawson Health Research Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Radiation therapy after surgery to remove breast cancer improves control of the breast&#xD;
      cancer. Standard therapy after breast conservation surgery is five to six weeks of radiation&#xD;
      to the entire breast.&#xD;
&#xD;
      This clinical trial will evaluate the effectiveness of conformal radiation therapy delivered&#xD;
      only to the area in the breast where the lumpectomy will be performed.&#xD;
&#xD;
      This study will determine if radiation therapy delivered in this manner will prevent the&#xD;
      cancer from coming back and eliminate the need for five to six weeks of radiation. Eligible&#xD;
      participants will be randomized to one of two arms; Arm 1 which is comprised of one&#xD;
      neoadjuvant radiation treatment, or Arm 2 which is comprised of three neoadjuvant radiation&#xD;
      treatments.&#xD;
&#xD;
      The study will also gather information about the safety and effects (good and bad) this&#xD;
      radiation has, the immune priming effects of this radiation, and on patient satisfaction with&#xD;
      the appearance of the breast.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Our proposal represents the convergence of several recent developments in the treatment of&#xD;
      patients with low-risk carcinoma of the breast. For the selected subset of patients with&#xD;
      low-risk disease, it appears that intra-operative radiotherapy with a single fraction leads&#xD;
      to acceptable clinical outcomes in terms of local control, overall survival and toxicity.&#xD;
      There have also been a few Phase I dose escalation trials demonstrating safety with single&#xD;
      fraction breast radiation.&#xD;
&#xD;
      In this study, we propose the delivery of radiotherapy using stereotactic body radiation&#xD;
      therapy in two different regimens; a single 21 Gy fraction, or 3 10Gy fractions. Radiation&#xD;
      will be delivered using Volumetric-modulated arc therapy (VMAT), planned on coregistered MRI&#xD;
      (with a subset having a 3T PET-MRI) and CT imaging, and delivered prone. Our approach will&#xD;
      potentially have numerous benefits, including significantly shortened treatment time,&#xD;
      convenience and potentially reduced health care costs. It would significantly improve the&#xD;
      quality of life of many patients.&#xD;
&#xD;
      This study will also provide a unique opportunity for pathologic assessment of the impact of&#xD;
      radiation at a microscopic level and on tumour and immune markers without the confounding&#xD;
      impact of systemic treatments, comparing pre- to post-radiation biopsy specimens for imaging&#xD;
      and histologic predictors of radiation sensitivity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>March 2015</start_date>
  <completion_date type="Anticipated">April 2023</completion_date>
  <primary_completion_date type="Actual">April 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Immune priming will be measured</measure>
    <time_frame>1.5 years</time_frame>
    <description>Immune priming effects of both treatment arms will be evaluated by quantifying tumour infiltrating lymphocytes (CD8) into tumour specimen, as well as the expression of immune markers (PDL1, Fox3) and immune panel in blood (CD4, CD8, neutrophil, and macrophage counts).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Angiogenesis will be measured</measure>
    <time_frame>1.5 years</time_frame>
    <description>Angiogenesis will be examined using the CD31 or VEGF-a cell markers</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proliferation markers will be measured</measure>
    <time_frame>1.5 years</time_frame>
    <description>Proliferation will be examined using the Ki67 marker, hypoxia will be examined using the Carbonic Anhydrase 9 (CAH IX), or HIF1/HIF2 markers, apoptosis will be examined using the Caspase-3, or Tunnel markers, invasion will be analyzed using the vimentin, or SDF1-a markers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hypoxia markers will be measured</measure>
    <time_frame>1.5 years</time_frame>
    <description>Hypoxia will be examined using the Carbonic Anhydrase 9 (CAH IX), or HIF1/HIF2 markers, apoptosis will be examined using the Caspase-3, or Tunnel markers, invasion will be analyzed using the vimentin, or SDF1-a markers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Apoptosis markers will be measured</measure>
    <time_frame>1.5 years</time_frame>
    <description>Apoptosis will be examined using the Caspase-3, or Tunnel markers, invasion will be analyzed using the vimentin, or SDF1-a markers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Invasion markers will be measured</measure>
    <time_frame>1.5 years</time_frame>
    <description>Invasion will be analyzed using the vimentin, or SDF1-a markers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Toxicity resulting from radiation treatment</measure>
    <time_frame>1.5 years</time_frame>
    <description>Toxicity resulting from radiation treatment will be collected and graded according to the Common Terminology Criteria for Adverse Events, version 4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cosmesis of the treated breast</measure>
    <time_frame>1.5 years</time_frame>
    <description>cosmetic result of treated breast as judged by the patient, surgeon, and radiation oncologist. Patients will self-assess cosmesis using the Modified Harvard-Harris Cosmetic Scale. The surgeon and radiation oncologist will assess cosmesis using photographs and the Modified Harvard-Harris Cosmetic Scale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-Free Survival</measure>
    <time_frame>8.5 years</time_frame>
    <description>Disease recurrences will be recorded. Any tumor recurrence or death is considered a treatment failure.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mastectomy-Free Survival</measure>
    <time_frame>8.5 years</time_frame>
    <description>All surgical interventions will be recorded. Mastectomy and death will be considered treatment failures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>8.5 years</time_frame>
    <description>Death from any cause is considered a treatment failure.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">139</enrollment>
  <condition>Early Stage Breast Carcinoma</condition>
  <arm_group>
    <arm_group_label>Single Fraction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Stereotactic neoadjuvant ablative radiation give in one single dose of 21 Gy. Lumpectomy to follow within 14-20 from radiation treatment date.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Three Fractions</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Stereotactic neoadjuvant ablative radiation give in three doses of 10 Gy (30 Gy given in 3 fractions, one treatment every second business day). Lumpectomy to follow within 14-20 days from last radiation treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic Body Radiation Then Surgery</intervention_name>
    <description>Stereotactic image-guided neoadjuvant ablative radiation (randomized to single dose of 21 Gy or three 10 Gy doses) followed by lumpectomy for early stage breast carcinoma</description>
    <arm_group_label>Single Fraction</arm_group_label>
    <arm_group_label>Three Fractions</arm_group_label>
    <other_name>Neoadjuvant radiation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 50 years and postmenopausal&#xD;
&#xD;
          -  Tumor size &lt; 3cm on pre-treatment imaging&#xD;
&#xD;
          -  Any grade of disease, estrogen receptor (ER) positive&#xD;
&#xD;
          -  Unicentric/unifocal disease&#xD;
&#xD;
          -  Invasive ductal carcinoma or other favorable subtypes of epithelial breast malignancy&#xD;
             (lobular, medullary, papillary, colloid, mucinous, or tubular) .&#xD;
&#xD;
          -  Clinically node-negative (based upon pre-treatment physical examination and/or&#xD;
             axillary ultrasound).&#xD;
&#xD;
          -  Surgical expectation that a &gt; 2mm margin can be obtained.&#xD;
&#xD;
          -  Lesion is 1 cm or greater from the skin surface.&#xD;
&#xD;
          -  Able to have surgery within 14-20 days of radiation therapy.&#xD;
&#xD;
          -  Able to lie comfortably in the prone position with arms raised above the head for&#xD;
             extended periods of time.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous RT to the same breast&#xD;
&#xD;
          -  Evidence of suspicious diffuse microcalcifications in the breast prior to the start of&#xD;
             radiation.&#xD;
&#xD;
          -  Local metastatic spread into ipsilateral axilla and/or supraclavicular region and/or&#xD;
             neck nodes and/or internal mammary nodes diagnosed on clinical examination or any&#xD;
             imaging assessment (unless such sites can be confirmed as negative following biopsy)&#xD;
&#xD;
          -  Distant metastases&#xD;
&#xD;
          -  Involvement of contralateral axillary, supraclavicular, infraclavicular or internal&#xD;
             mammary nodes (unless there is histologic confirmation that these nodes are negative)&#xD;
&#xD;
          -  Prior non-hormonal therapy or radiation therapy for the current breast cancer&#xD;
&#xD;
          -  Patients with Paget's disease of the nipple.&#xD;
&#xD;
          -  Skin involvement, regardless of tumor size.&#xD;
&#xD;
          -  Patients with a breast technically unsatisfactory for radiation therapy.&#xD;
&#xD;
          -  Inability to lie prone with arms raised above head for extended periods of time.&#xD;
&#xD;
          -  Patients not appropriate for breast conserving surgery due to expectation of poor&#xD;
             cosmetic result, even without RT&#xD;
&#xD;
          -  Collagen vascular disease (particularly lupus, scleroderma, dermatomyositis)&#xD;
&#xD;
          -  Inability or unwillingness to provide informed consent.&#xD;
&#xD;
          -  Any other malignancy at any site (except non-melanomatous skin cancer) &lt; 5 years prior&#xD;
             to study enrollment&#xD;
&#xD;
          -  Patients who are pregnant or lactating&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Muriel Brackstone, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Lawson Health Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>London Regional Cancer Program of the Lawson Health Research Institute</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 4L6</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>August 5, 2014</study_first_submitted>
  <study_first_submitted_qc>August 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 8, 2014</study_first_posted>
  <last_update_submitted>May 13, 2022</last_update_submitted>
  <last_update_submitted_qc>May 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Lawson Health Research Institute</investigator_affiliation>
    <investigator_full_name>Muriel Brackstone</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>neoadjuvant</keyword>
  <keyword>radiation</keyword>
  <keyword>breast</keyword>
  <keyword>cancer</keyword>
  <keyword>hypofractionation</keyword>
  <keyword>stereotactic</keyword>
  <keyword>preoperative</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02212860
org study id: SIGNAL
nct id: NCT02212860
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
Radiation therapy after surgery to remove breast cancer improves control of the breast
      cancer. Standard therapy after breast conservation surgery is five to six weeks of radiation
      to the entire breast.

      This clinical trial will evaluate the effectiveness of conformal radiation therapy delivered
      only to the area in the breast where the lumpectomy will be performed.

      This study will determine if radiation therapy delivered in this manner will prevent the
      cancer from coming back and eliminate the need for five to six weeks of radiation. Eligible
      participants will be randomized to one of two arms; Arm 1 which is comprised of one
      neoadjuvant radiation treatment, or Arm 2 which is comprised of three neoadjuvant radiation
      treatments.

      The study will also gather information about the safety and effects (good and bad) this
      radiation has, the immune priming effects of this radiation, and on patient satisfaction with
      the appearance of the breast.
Our proposal represents the convergence of several recent developments in the treatment of
      patients with low-risk carcinoma of the breast. For the selected subset of patients with
      low-risk disease, it appears that intra-operative radiotherapy with a single fraction leads
      to acceptable clinical outcomes in terms of local control, overall survival and toxicity.
      There have also been a few Phase I dose escalation trials demonstrating safety with single
      fraction breast radiation.

      In this study, we propose the delivery of radiotherapy using stereotactic body radiation
      therapy in two different regimens; a single 21 Gy fraction, or 3 10Gy fractions. Radiation
      will be delivered using Volumetric-modulated arc therapy (VMAT), planned on coregistered MRI
      (with a subset having a 3T PET-MRI) and CT imaging, and delivered prone. Our approach will
      potentially have numerous benefits, including significantly shortened treatment time,
      convenience and potentially reduced health care costs. It would significantly improve the
      quality of life of many patients.

      This study will also provide a unique opportunity for pathologic assessment of the impact of
      radiation at a microscopic level and on tumour and immune markers without the confounding
      impact of systemic treatments, comparing pre- to post-radiation biopsy specimens for imaging
      and histologic predictors of radiation sensitivity.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Immune priming will be measured
time frame: 1.5 years
description: Immune priming effects of both treatment arms will be evaluated by quantifying tumour infiltrating lymphocytes (CD8) into tumour specimen, as well as the expression of immune markers (PDL1, Fox3) and immune panel in blood (CD4, CD8, neutrophil, and macrophage counts).
measure: Angiogenesis will be measured
time frame: 1.5 years
description: Angiogenesis will be examined using the CD31 or VEGF-a cell markers
measure: Proliferation markers will be measured
time frame: 1.5 years
description: Proliferation will be examined using the Ki67 marker, hypoxia will be examined using the Carbonic Anhydrase 9 (CAH IX), or HIF1/HIF2 markers, apoptosis will be examined using the Caspase-3, or Tunnel markers, invasion will be analyzed using the vimentin, or SDF1-a markers.
measure: Hypoxia markers will be measured
time frame: 1.5 years
description: Hypoxia will be examined using the Carbonic Anhydrase 9 (CAH IX), or HIF1/HIF2 markers, apoptosis will be examined using the Caspase-3, or Tunnel markers, invasion will be analyzed using the vimentin, or SDF1-a markers.
measure: Apoptosis markers will be measured
time frame: 1.5 years
description: Apoptosis will be examined using the Caspase-3, or Tunnel markers, invasion will be analyzed using the vimentin, or SDF1-a markers.
measure: Invasion markers will be measured
time frame: 1.5 years
description: Invasion will be analyzed using the vimentin, or SDF1-a markers.
measure: Toxicity resulting from radiation treatment
time frame: 1.5 years
description: Toxicity resulting from radiation treatment will be collected and graded according to the Common Terminology Criteria for Adverse Events, version 4.0
measure: Cosmesis of the treated breast
time frame: 1.5 years
description: cosmetic result of treated breast as judged by the patient, surgeon, and radiation oncologist. Patients will self-assess cosmesis using the Modified Harvard-Harris Cosmetic Scale. The surgeon and radiation oncologist will assess cosmesis using photographs and the Modified Harvard-Harris Cosmetic Scale.
measure: Disease-Free Survival
time frame: 8.5 years
description: Disease recurrences will be recorded. Any tumor recurrence or death is considered a treatment failure.
measure: Mastectomy-Free Survival
time frame: 8.5 years
description: All surgical interventions will be recorded. Mastectomy and death will be considered treatment failures.
measure: Overall Survival
time frame: 8.5 years
description: Death from any cause is considered a treatment failure.
arm group label: Single Fraction
arm group type: Experimental
description: Stereotactic neoadjuvant ablative radiation give in one single dose of 21 Gy. Lumpectomy to follow within 14-20 from radiation treatment date.
arm group label: Three Fractions
arm group type: Experimental
description: Stereotactic neoadjuvant ablative radiation give in three doses of 10 Gy (30 Gy given in 3 fractions, one treatment every second business day). Lumpectomy to follow within 14-20 days from last radiation treatment.
intervention type: Radiation
intervention name: Stereotactic Body Radiation Then Surgery
description: Stereotactic image-guided neoadjuvant ablative radiation (randomized to single dose of 21 Gy or three 10 Gy doses) followed by lumpectomy for early stage breast carcinoma
arm group label: Single Fraction
arm group label: Three Fractions
other name: Neoadjuvant radiation
criteria: 
gender: Female
minimum age: 50 Years
maximum age: N/A
healthy volunteers: No
last name: Muriel Brackstone, MD, PhD
role: Principal Investigator
affiliation: Lawson Health Research Institute
facility: 
country: Canada
responsible party type: Principal Investigator
investigator affiliation: Lawson Health Research Institute
investigator full name: Muriel Brackstone
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Breast Neoplasms
sharing ipd: No