xml: <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/NCT05978024</url>
    </required_header>
    <id_info>
      <org_study_id>CCR5166</org_study_id>
      <nct_id>NCT05978024</nct_id>
    </id_info>
    <brief_title>Predicting Radiotherapy Response and Toxicities in Soft Tissue Sarcoma of the Extremities - Cohort B</brief_title>
    <acronym>PredicT-B</acronym>
    <official_title>Predicting Radiotherapy Response, Toxicities and Quality of Life Related Functional Outcome in Soft Tissue Sarcoma of the Extremities: a Prospective Observational Cohort Study</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Royal Marsden NHS Foundation Trust</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Royal Marsden NHS Foundation Trust</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        This is a multicentre prospective cohort study, primarily aimed at reporting the frequency&#xD;
        and intensity of radiotherapy side-effects of patients with soft tissues sarcoma of the&#xD;
        extremities (STSE).&#xD;
  &#xD;
        Two sub-studies are proposed within this study:&#xD;
  &#xD;
          -  MRI radiation response assessment Aimed at establishing whether changes in median&#xD;
             apparent diffusion coefficients (ADC) are predictive of pre-operative STSE response&#xD;
             measured using histopathology.&#xD;
  &#xD;
          -  Biomarker development and Immune mediators associated with radiotherapy Aimed at&#xD;
             establishing prognostic markers which may refine selection of cases for pre-operative,&#xD;
             palliative or no radiotherapy.&#xD;
  &#xD;
        Also, aimed at determining if radiotherapy stimulates the tumour microenvironment, resulting&#xD;
        in measurable change in anti-tumour immunity and if certain subtypes could potentially&#xD;
        benefit from the addition of immunotherapy with radiation.&#xD;
  &#xD;
        Patients participation in the sub-studies is optional.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is a multicentre prospective cohort study, primarily aimed at validating the dose-volume&#xD;
        parameters identified in the analyses of the VorteX and IMRiS trials datasets.&#xD;
  &#xD;
        • Delineation of healthy tissues&#xD;
  &#xD;
        Pre-defined outlining guidelines of normal tissues as bones, muscle compartments, joints,&#xD;
        lymph drainage basins and subcutaneous tissue from Predict A will be delineated in&#xD;
        radiotherapy planning computed tomography (CT) images. All cases will be delineated by a&#xD;
        single observer (Rita Simoes). Verification of all outlines will be carried out by Dr Aisha&#xD;
        Miah (clinical supervisor).&#xD;
  &#xD;
        • Dose-volume constraints validity testing&#xD;
  &#xD;
        Patients will be treated as per local protocol treatment technique.&#xD;
  &#xD;
        Radiotherapy, clinical and toxicities data will be collected, with no new intervention on the&#xD;
        treatment. Patients enrolled will receive standard radiation prescription doses as described&#xD;
        below:&#xD;
  &#xD;
          -  Pre-operative radiotherapy- 50 Gy in 25 fractions equivalent (pre-operative&#xD;
             radiotherapy). Where appropriate hypo-fractionated schedules as per institutional&#xD;
             guidelines can considered: eg. 25 Gy/ 5 daily fractions. In myxoid liposarcomas, 36 Gy&#xD;
             in 18 fractions can be considered where suitable;&#xD;
  &#xD;
          -  Post-operative radiotherapy- 60 Gy in 30 fractions or 66 Gy in 33 fractions (positive&#xD;
             resection margins); alternative hypo-fractionated schedules as per institutional&#xD;
             guidelines can be considered;&#xD;
  &#xD;
          -  Palliative radiotherapy- 30-36 Gy in 10-12 daily fractions, 40-45 Gy in 15 fractions,&#xD;
             30-36 Gy in 5-6 once weekly fractions or 25 Gy in 5 daily fractions.&#xD;
  &#xD;
        Toxicity will be assessed with the TESS and RTOG scoring instruments and Stern score for&#xD;
        lymphoedema. Patients enrolled in the study will fill in a specific quality-of-life&#xD;
        questionnaire to assess quality of life related functional outcomes following treatment for&#xD;
        STSE. This questionnaire is based on validated questions for assessing quality-of-life.&#xD;
        Patients will be followed up at 3, 6, 12, 18, and 24 months post-radiotherapy.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">April 16, 2021</start_date>
    <completion_date type="Anticipated">July 30, 2026</completion_date>
    <primary_completion_date type="Anticipated">July 30, 2024</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Cohort</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>The incidence of any RTOG grade ≥ 2 toxicities following treatment for STSE at 24 months</measure>
      <time_frame>24 Months</time_frame>
      <description>The primary objective is to report the frequency and intensity of radiotherapy side-effects in STSE.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>The ability of the fitted model from dose-volume constraints from PredicT A (IMRiS and Vortex analysis) to correctly predict the incidence of grade 2+ among PredicT B patients.</measure>
      <time_frame>24 Months</time_frame>
      <description>To report the differences in experienced by patients with STSE for whom dose-volume constraints were below or exceeded. Binary logistic regression will be used to quantify the differences using odds ratios (OR) from the fitted models. Univariate logistic regression models will be fitted to predict for the parameters relevant to toxicity grades in the RTOG, Stern's and TESS scales. ORs for each of the parameters will be used to judge for significant differences between the groups. There is no plan to fit multivariate model.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To report frequencies and proportions of radiotherapy-induced late toxicities</measure>
      <time_frame>24 Months</time_frame>
      <description>Frequencies and proportions of radiotherapy-induced late toxicities at the specified at 3, 6, 12, 18 and 24 months will be reported descriptively at each time point for the overall events and by types of events:&#xD;
  Subcutaneous tissue fibrosis&#xD;
  Lymphoedema&#xD;
  Bone fractures&#xD;
  Joint stiffness&#xD;
  Delayed wound healing following pre-operative RT</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To determine the time to developing early and late side-effects.</measure>
      <time_frame>24 Months</time_frame>
      <description>Time elapsed between day 1 of radiotherapy and the day to develop early and late side-effects using Kaplan-Meier methods. Median time to early side-effects with 95% confidence interval will be reported. Patients without any side-effects (on day 90 from end of RT) will be censored. Similarly, median time to late side-effects with 95% confidence interval will be reported. Patients without an event will be censored at the 24 months assessment visit or at last follow-up date known to be on the study without any event.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To determine radiological response rates to radiotherapy and where applicable chemo-radiotherapy for STSE of different histological subtypes.</measure>
      <time_frame>24 Months</time_frame>
      <description>Differences in the tumour volumes (in cc and %) will be calculated from CT and CBCT images at fractions 8, 16 and 25 for patients receiving pre-operative RT. Changes in target volumes during radiotherapy will be assessed by computing dissimilarity indices (e.g., Simpson's dissimilarity index) in sequential CBCT images captured during treatment compared to radiotherapy planning CT. Radiological: % volume change (RECIST), % cystic sold component).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To determine histological response rates to radiotherapy and where applicable chemo-radiotherapy for STSE of different histological subtypes.</measure>
      <time_frame>24 Months</time_frame>
      <description>Differences in the response rates will be assessed according to: histopathological semi-quantitative scores (pathological: % viable cells). Tumour factors are tumour histotype, staging and tumour size.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To determine quality of life-related functional outcomes and explore correlations with dose-volume parameters for patients who have received pre, post-operative or palliative radiotherapy for STSE.</measure>
      <time_frame>24 Months</time_frame>
      <description>Correlations between functional outcomes (expressed in TESS and EORT-QLQ- C30 and QLQ-FA12 fatigue questionnaire scores) with dose-volume parameters (expressed in Gy/volume, where volume will be defined in % of total volume and cc) will be calculated using Spearman's correlation method. Patients will be categorised according to dose volume constraints and compare the groups using t-test or Mann-Whitney non-parametric test as appropriate.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To determine predictive and prognostic factors for local and distant recurrence and overall survival for patients receiving pre-operative and palliative RT.</measure>
      <time_frame>24 Months</time_frame>
      <description>Percentage of patients responding to treatment will be calculated, this will be reported in the overall patients and for dose-volume constraints groups. Local control rates, disease-free survival rates and overall survival at 2 years will be calculated using Kaplan-Meier methods. Disease free survival events are local or distance disease recurrence and death from disease related causes. Overall survival events are death from any causes.</description>
    </secondary_outcome>
    <enrollment type="Anticipated">150</enrollment>
    <condition>Soft Tissue Sarcoma of the Extremities</condition>
    <biospec_retention>Samples With DNA</biospec_retention>
    <biospec_descr>
      <textblock>
        -  Tumour tissue for histopathological markers, immune function and DNA damage response&#xD;
             from the area receiving radiotherapy (both biopsies and surgical resection specimens)&#xD;
  &#xD;
          -  Blood samples for immune function analysis (Up to 50 ml at each time point).&#xD;
      </textblock>
    </biospec_descr>
    <eligibility>
      <study_pop>
        <textblock>
          The study population to be enrolled in this observational study will have had been&#xD;
          diagnosed with STSE and referred to receive a course of radiotherapy either in the primary,&#xD;
          palliative, pre-operative or post-operative settings.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Histopathological diagnosis of soft tissue sarcoma of the upper or lower limb or limb&#xD;
               girdle;&#xD;
  &#xD;
            -  Patients receiving pre-operative (neo-adjuvant), post-operative (adjuvant) or&#xD;
               palliative radiotherapy;&#xD;
  &#xD;
            -  Patients receiving radiotherapy planned as per local protocols (neoadjuvant&#xD;
               chemotherapy will be allowed). Neoadjuvant chemotherapy patients may be approached as&#xD;
               they commence chemotherapy;&#xD;
  &#xD;
            -  WHO performance status 0-2;&#xD;
  &#xD;
            -  Aged ≥16 years;&#xD;
  &#xD;
            -  Patients fit enough to undergo radiotherapy treatment and willing to attend follow up&#xD;
               visits, during two years;&#xD;
  &#xD;
            -  Female patients of child-bearing potential and male patients with partners of&#xD;
               child-bearing potential must agree to use adequate contraception methods, which must&#xD;
               be continued for 3 months after completion of treatment;&#xD;
  &#xD;
            -  Capable of giving written informed consent.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Previous radiotherapy to the same site;&#xD;
  &#xD;
            -  Pregnancy;&#xD;
  &#xD;
            -  Patients with concurrent or previous malignancy that could compromise assessment of&#xD;
               primary and secondary endpoints of the trial.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>16 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Aisha Miah</last_name>
      <role>Principal Investigator</role>
      <affiliation>The Royal Marsden Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Thuy-Giang Nguyen</last_name>
      <phone>02078118090</phone>
      <email>Thuy-Giang.Nguyen@rmh.nhs.uk</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Stephanie Elston</last_name>
      <phone>02078118395</phone>
      <email>stephanie.elston@rmh.nhs.uk</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Addenbrooke's Hospital</name>
        <address>
          <city>Cambridge</city>
          <zip>CB2 0QQ</zip>
          <country>United Kingdom</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Katy Cooper</last_name>
      </contact>
      <investigator>
        <last_name>Sarah Prewett</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>The Royal Marsden NHS Foundation Trust</name>
        <address>
          <city>London</city>
          <zip>SW3 6JJ</zip>
          <country>United Kingdom</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Thuy-Giang Nguyen</last_name>
        <phone>+442078118090</phone>
        <email>Thuy-Giang.Nguyen@rmh.nhs.uk</email>
      </contact>
      <investigator>
        <last_name>Aisha Miah</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location>
      <facility>
        <name>University College London</name>
        <address>
          <city>London</city>
          <zip>WC1E 6BT</zip>
          <country>United Kingdom</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Carla Dalton</last_name>
      </contact>
      <investigator>
        <last_name>Mahbubl Ahmed</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United Kingdom</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 14, 2023</study_first_submitted>
    <study_first_submitted_qc>July 27, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 7, 2023</study_first_posted>
    <last_update_submitted>July 27, 2023</last_update_submitted>
    <last_update_submitted_qc>July 27, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Sarcoma</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>Patient outcomes data will be utilised to publish study endpoints. However specific participant data will not be shared.&#xD;
  We aim to publish protocol, and study results in the form of peer-reviewed publications and guidelines</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05978024
  org study id: CCR5166
  nct id: NCT05978024
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  This is a multicentre prospective cohort study, primarily aimed at reporting the frequency
        and intensity of radiotherapy side-effects of patients with soft tissues sarcoma of the
        extremities (STSE).
  
        Two sub-studies are proposed within this study:
  
          -  MRI radiation response assessment Aimed at establishing whether changes in median
             apparent diffusion coefficients (ADC) are predictive of pre-operative STSE response
             measured using histopathology.
  
          -  Biomarker development and Immune mediators associated with radiotherapy Aimed at
             establishing prognostic markers which may refine selection of cases for pre-operative,
             palliative or no radiotherapy.
  
        Also, aimed at determining if radiotherapy stimulates the tumour microenvironment, resulting
        in measurable change in anti-tumour immunity and if certain subtypes could potentially
        benefit from the addition of immunotherapy with radiation.
  
        Patients participation in the sub-studies is optional.
  This is a multicentre prospective cohort study, primarily aimed at validating the dose-volume
        parameters identified in the analyses of the VorteX and IMRiS trials datasets.
  
        • Delineation of healthy tissues
  
        Pre-defined outlining guidelines of normal tissues as bones, muscle compartments, joints,
        lymph drainage basins and subcutaneous tissue from Predict A will be delineated in
        radiotherapy planning computed tomography (CT) images. All cases will be delineated by a
        single observer (Rita Simoes). Verification of all outlines will be carried out by Dr Aisha
        Miah (clinical supervisor).
  
        • Dose-volume constraints validity testing
  
        Patients will be treated as per local protocol treatment technique.
  
        Radiotherapy, clinical and toxicities data will be collected, with no new intervention on the
        treatment. Patients enrolled will receive standard radiation prescription doses as described
        below:
  
          -  Pre-operative radiotherapy- 50 Gy in 25 fractions equivalent (pre-operative
             radiotherapy). Where appropriate hypo-fractionated schedules as per institutional
             guidelines can considered: eg. 25 Gy/ 5 daily fractions. In myxoid liposarcomas, 36 Gy
             in 18 fractions can be considered where suitable;
  
          -  Post-operative radiotherapy- 60 Gy in 30 fractions or 66 Gy in 33 fractions (positive
             resection margins); alternative hypo-fractionated schedules as per institutional
             guidelines can be considered;
  
          -  Palliative radiotherapy- 30-36 Gy in 10-12 daily fractions, 40-45 Gy in 15 fractions,
             30-36 Gy in 5-6 once weekly fractions or 25 Gy in 5 daily fractions.
  
        Toxicity will be assessed with the TESS and RTOG scoring instruments and Stern score for
        lymphoedema. Patients enrolled in the study will fill in a specific quality-of-life
        questionnaire to assess quality of life related functional outcomes following treatment for
        STSE. This questionnaire is based on validated questions for assessing quality-of-life.
        Patients will be followed up at 3, 6, 12, 18, and 24 months post-radiotherapy.
  observational model: Cohort
  time perspective: Prospective
  measure: The incidence of any RTOG grade ≥ 2 toxicities following treatment for STSE at 24 months
  time frame: 24 Months
  description: The primary objective is to report the frequency and intensity of radiotherapy side-effects in STSE.
  measure: The ability of the fitted model from dose-volume constraints from PredicT A (IMRiS and Vortex analysis) to correctly predict the incidence of grade 2+ among PredicT B patients.
  time frame: 24 Months
  description: To report the differences in experienced by patients with STSE for whom dose-volume constraints were below or exceeded. Binary logistic regression will be used to quantify the differences using odds ratios (OR) from the fitted models. Univariate logistic regression models will be fitted to predict for the parameters relevant to toxicity grades in the RTOG, Stern's and TESS scales. ORs for each of the parameters will be used to judge for significant differences between the groups. There is no plan to fit multivariate model.
  measure: To report frequencies and proportions of radiotherapy-induced late toxicities
  time frame: 24 Months
  description: Frequencies and proportions of radiotherapy-induced late toxicities at the specified at 3, 6, 12, 18 and 24 months will be reported descriptively at each time point for the overall events and by types of events:
  Subcutaneous tissue fibrosis
  Lymphoedema
  Bone fractures
  Joint stiffness
  Delayed wound healing following pre-operative RT
  measure: To determine the time to developing early and late side-effects.
  time frame: 24 Months
  description: Time elapsed between day 1 of radiotherapy and the day to develop early and late side-effects using Kaplan-Meier methods. Median time to early side-effects with 95% confidence interval will be reported. Patients without any side-effects (on day 90 from end of RT) will be censored. Similarly, median time to late side-effects with 95% confidence interval will be reported. Patients without an event will be censored at the 24 months assessment visit or at last follow-up date known to be on the study without any event.
  measure: To determine radiological response rates to radiotherapy and where applicable chemo-radiotherapy for STSE of different histological subtypes.
  time frame: 24 Months
  description: Differences in the tumour volumes (in cc and %) will be calculated from CT and CBCT images at fractions 8, 16 and 25 for patients receiving pre-operative RT. Changes in target volumes during radiotherapy will be assessed by computing dissimilarity indices (e.g., Simpson's dissimilarity index) in sequential CBCT images captured during treatment compared to radiotherapy planning CT. Radiological: % volume change (RECIST), % cystic sold component).
  measure: To determine histological response rates to radiotherapy and where applicable chemo-radiotherapy for STSE of different histological subtypes.
  time frame: 24 Months
  description: Differences in the response rates will be assessed according to: histopathological semi-quantitative scores (pathological: % viable cells). Tumour factors are tumour histotype, staging and tumour size.
  measure: To determine quality of life-related functional outcomes and explore correlations with dose-volume parameters for patients who have received pre, post-operative or palliative radiotherapy for STSE.
  time frame: 24 Months
  description: Correlations between functional outcomes (expressed in TESS and EORT-QLQ- C30 and QLQ-FA12 fatigue questionnaire scores) with dose-volume parameters (expressed in Gy/volume, where volume will be defined in % of total volume and cc) will be calculated using Spearman's correlation method. Patients will be categorised according to dose volume constraints and compare the groups using t-test or Mann-Whitney non-parametric test as appropriate.
  measure: To determine predictive and prognostic factors for local and distant recurrence and overall survival for patients receiving pre-operative and palliative RT.
  time frame: 24 Months
  description: Percentage of patients responding to treatment will be calculated, this will be reported in the overall patients and for dose-volume constraints groups. Local control rates, disease-free survival rates and overall survival at 2 years will be calculated using Kaplan-Meier methods. Disease free survival events are local or distance disease recurrence and death from disease related causes. Overall survival events are death from any causes.
  -  Tumour tissue for histopathological markers, immune function and DNA damage response
             from the area receiving radiotherapy (both biopsies and surgical resection specimens)
  
          -  Blood samples for immune function analysis (Up to 50 ml at each time point).
  study pop: 
  sampling method: Probability Sample
  criteria: 
  gender: All
  minimum age: 16 Years
  maximum age: N/A
  healthy volunteers: Accepts Healthy Volunteers
  last name: Aisha Miah
  role: Principal Investigator
  affiliation: The Royal Marsden Hospital
  last name: Thuy-Giang Nguyen
  phone: 02078118090
  email: Thuy-Giang.Nguyen@rmh.nhs.uk
  last name: Stephanie Elston
  phone: 02078118395
  email: stephanie.elston@rmh.nhs.uk
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  facility: 
  status: Recruiting
  contact: 
  investigator: 
  country: United Kingdom
  responsible party type: Sponsor
  mesh term: Sarcoma
  sharing ipd: No
  ipd description: Patient outcomes data will be utilised to publish study endpoints. However specific participant data will not be shared.
  We aim to publish protocol, and study results in the form of peer-reviewed publications and guidelines