<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/NCT03294122</url>
  </required_header>
  <id_info>
    <org_study_id>INT 11/17</org_study_id>
    <nct_id>NCT03294122</nct_id>
  </id_info>
  <brief_title>Predictors of Normal Tissue Response From the Microenvironment in Radiotherapy for Prostate and Head-and-neck Cancer</brief_title>
  <acronym>MICROLEARNER</acronym>
  <official_title>Microbiota, Inflammatory Environment, Clinical and Radiomic Features as Predictors of Normal Tissue Response in Radiotherapy for Prostate and Head-and-neck Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</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>
      The main idea behind MICRO-LEARNER is to provide new insights about the response of healthy&#xD;
      tissues to radiation by using information from the micro-environment obtained by biological&#xD;
      measurements and imaging. This new knowledge will be included in current available predictive&#xD;
      models of radio-induced toxicity, thus allowing to add unique biological characteristics of&#xD;
      patients to dosimetry and treatment/clinical related variables.&#xD;
&#xD;
      MICRO-LEARNER focuses on prostate cancer (PCa) and head-and-neck cancer (HNCa). For both&#xD;
      cancers, radiotherapy is effectively used as curative treatment, in single modality or within&#xD;
      a multidisciplinary approach including surgery (PCa) and/or chemotherapy (HNCa). Prediction&#xD;
      and reduction of radio-induced side effects are becoming a priority: for PCa, high survival&#xD;
      rates should be accompanied by a very low rate of moderate/severe toxicities; for HNCa, there&#xD;
      is the need to tailor radiation dose according to disease recurrence risk profile. The shared&#xD;
      aim of both cancers is to balance the improvement in outcome with a well-tolerated toxicity&#xD;
      profile.&#xD;
&#xD;
      Recent research indicates that the intestinal/salivary bacteria are strongly suspected of&#xD;
      being very important in mediating the response to inflammation and lesions. Although their&#xD;
      balance deeply changes during radiotherapy, studies done so far in the field of the&#xD;
      microbiota-host relationship in radiotherapy have not addressed their role in insurgence of&#xD;
      radiation toxicity.&#xD;
&#xD;
      In this study, the investigators will assess how microbial populations evolve and how this&#xD;
      influences the host and radiation induced toxicity in a significant number of patients.&#xD;
      Moreover, the individual response at the tissue microstructure level, through analysis of&#xD;
      images with advanced bioengineering techniques, will be determined.&#xD;
&#xD;
      Results from this research, besides suggesting new ways to predict patients at risk of&#xD;
      relevant side-effects, may also suggest possible treatments to change the baseline microbiota&#xD;
      of patients at high risk or to modify it during therapy, in order to mitigate toxicity.&#xD;
      Understanding the microbiota-radiotherapy interaction may thus lead to novel, effective and&#xD;
      inexpensive ways of assessing and managing complications of cancer treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      **Prospective Clinical Trial: discovery population**&#xD;
&#xD;
      130 PCa and 130 HNCa consecutive patients will be enrolled in 18 months. All patients will&#xD;
      receive radiotherapy at radical curative doses at the National Cancer Institute in Milan, and&#xD;
      follow-up visits at the same centre.&#xD;
&#xD;
      Detailed pre-treatment evaluation will include: recording of demographic features, clinical&#xD;
      history, comorbidities and habits, evaluation of normal tissue functioning by the health&#xD;
      practitioner (CTCAE scoring system), evaluation of quality of life and normal tissue&#xD;
      functioning through validated patient reported outcome (PROs) questionnaires, evaluation of&#xD;
      organ functioning by instrumental measures (i.e. baseline swallowing screening with flexible&#xD;
      endoscopic evaluation of swallowing - FEES - and unstimulated salivary flow for HNCa&#xD;
      patients), biochemical examinations, gut (PCa)/salivary (HNCa) microbiome measurement,&#xD;
      determination of baseline level of plasma/salivary inflammatory markers, baseline&#xD;
      multi-parametric magnetic resonance imaging (MRI).&#xD;
&#xD;
      Patients will receive radiotherapy and possible adjuvant (hormone or chemo) therapies as&#xD;
      foreseen by international guidelines. In this aspect the here proposed trial is an&#xD;
      observational study, no modification to standard regimens is considered. Radiotherapy is&#xD;
      performed with 6 MV photon beams delivered with Volumetric Modulated arc Therapy (VMAT)&#xD;
      technique at conventional fractionations.&#xD;
&#xD;
      Evaluation during treatment will include weekly assessment of toxicity, as measured by the&#xD;
      clinician (according to CTCAE v 4.0) and by PROs and biochemical measurements, and evaluation&#xD;
      of inflammatory markers (plasmatic and salivary cytokines) after a dose of 20 Gy. For a&#xD;
      subpopulation of 60 oropharyngeal cancer patients treated with definitive radiotherapy +/-&#xD;
      chemotherapy an additional MRI study during the second week of treatment is foreseen.&#xD;
&#xD;
      Assessment at the end of radiotherapy will include evaluation of toxicity by the clinician&#xD;
      and by PROs, FEES and unstimulated salivary flow for HNCa patients, biochemical examinations,&#xD;
      gut/salivary microbiome measurement.&#xD;
&#xD;
      Evaluation at 3, 6 and 12 months will include: evaluation of toxicity by the clinician and by&#xD;
      PROs, FEES and unstimulated salivary flow for HNCa patients and biochemical examinations.&#xD;
&#xD;
      Minimum follow-up is set to 12 months for the specific purpose of evaluation of acute and&#xD;
      mid-term toxicity, which are the endpoints considered in this project. Nevertheless,&#xD;
      follow-up will continue until 3 years after the end of radiotherapy (beyond the end of the&#xD;
      project) in order to allow evaluation of incidence, prevalence and patterns of late&#xD;
      side-effects, as well as for survival outcome assessment. After 12 months, follow-up will be&#xD;
      performed every 6 months and limited to assessment of toxicity by the clinician and by PROs.&#xD;
&#xD;
      Follow-up MRI studies will be performed at 3, 12 and 24 months for HNCa patients and at 12&#xD;
      months for PCa patients.&#xD;
&#xD;
      **Prospective Clinical Trial: validation population**&#xD;
&#xD;
      70 PCa and 70 HNCa consecutive patients will be enrolled in 12 months, starting immediately&#xD;
      after the end of enrolment of the discovering population.&#xD;
&#xD;
      The specific aim of this second phase is validation of results on microbiota, specifically on&#xD;
      association between selected baseline microbiota profiles and the risk of acute toxicity (for&#xD;
      the purpose of this project) and for mid-term/late toxicity (beyond this projects). This&#xD;
      result should be the more significant from the clinical point of view, allowing development&#xD;
      of a therapeutic algorithm to be used before treatment and permitting introduction ways of&#xD;
      changing the make-up of gut/salivary bacteria in patients at high risk of toxicity.&#xD;
&#xD;
      Baseline assessment, treatment and follow-up evaluation of toxicity by the clinician and by&#xD;
      PROs will follow the scheme described for the developing population. Microbioma measurement&#xD;
      will be only performed at baseline, due to the higher clinical interest in having a test&#xD;
      determining patient radiosensitivity before treatment. Imaging and assessment of inflammatory&#xD;
      marker levels will not be accomplished in the validation population.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 2, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2019</completion_date>
  <primary_completion_date type="Anticipated">July 31, 2019</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>Acute toxicity</measure>
    <time_frame>&lt;90 days after radiotherapy</time_frame>
    <description>If any, acute (&lt;within 90 days from radiotherapy completion) Grade 1, Grade 2, Grade 3-4 disorder, according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system, and its association with clinical variables, absorbed dose, microbioma characteristics and radiomic features.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Late toxicity</measure>
    <time_frame>3 months - 3 years after radiotherapy</time_frame>
    <description>If any, late (&gt; 90 days after radiotherapy completion) Grade 1, Grade 2, Grade 3-4 disorder, according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system, and its association with clinical variables, absorbed dose, microbioma characteristics and radiomic features.</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">400</enrollment>
  <condition>Prostate Cancer</condition>
  <condition>Head and Neck Cancer</condition>
  <arm_group>
    <arm_group_label>PCa patients - Discovery cohort</arm_group_label>
    <description>External beam radiotherapy for prostate cancer</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HNCa patients - Discovery cohort</arm_group_label>
    <description>External beam radiotherapy for head and neck cancer</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PCa patients - Validation cohort</arm_group_label>
    <description>External beam radiotherapy for prostate cancer</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HNCa patients - Validation cohort</arm_group_label>
    <description>External beam radiotherapy for head and neck cancer</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>External beam radiotherapy for prostate cancer</intervention_name>
    <description>Patients will receive radiotherapy for prostate cancer and possible adjuvant hormone therapies as foreseen by international guidelines. No modification of standard regimens is considered. PCa patients are treated with 78 Gy, 2Gy/fraction, in exclusive setting and with 70 Gy, 2Gr/fraction in the post-prostatectomy setting. Lymph node irradiation is performed (50 Gy, 2Gy/fraction) when indicated by risk class.</description>
    <arm_group_label>PCa patients - Discovery cohort</arm_group_label>
    <arm_group_label>PCa patients - Validation cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>External beam radiotherapy for head and neck cancer</intervention_name>
    <description>Patients will receive radiotherapy for head and neck cancer and possible concomitant chemotherapies as foreseen by international guidelines. No modification of standard regimens is considered. In curative setting, HNCa patients are treated at a total dose of 70 Gy, 59.4 Gy and 56.1 Gy in 33 fractions to high risk Planning Target Volume (PTV), intermediate risk and low risk PTV, respectively. In high risk post-operative setting they are treated with 66 Gy (according to histopathological features), 60 Gy and 56.1 Gy to high, intermediate and low risk PTV, respectively; while, in intermediate risk post-operative case, intermediate and low risk PTV are irradiated with 60 Gy and 54 Gy, respectively. Chemotherapy will be platinum based (weekly or 3-weekly cisplatin).</description>
    <arm_group_label>HNCa patients - Discovery cohort</arm_group_label>
    <arm_group_label>HNCa patients - Validation cohort</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Whole blood samples of all patients, stool samples of prostate cancer patients, salivary&#xD;
      samples of head and neck cancer patients&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients undergoing external beam radiotherapy for prostate or head and neck cancer at the&#xD;
        Radiation Oncology 1 and Radiation Oncology 2 units of the Istituto Nazionale dei Tumori.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria (PCa patients in discovery and validation cohorts):&#xD;
&#xD;
          -  Patients with histologically confirmed diagnosis of PCa candidate to exclusive or&#xD;
             post-surgical radiotherapy, in both case it can be associated to hormone therapy&#xD;
&#xD;
          -  Prognostic risk included in the very low, low, intermediate or high risk classes&#xD;
             following the NCCN Clinical Practice Guidelines in Oncology and patients with&#xD;
             oligometastatic disease treated with curative doses to the prostate (≥70 Gy at 2 Gy&#xD;
             per fraction)&#xD;
&#xD;
          -  Written informed consent to the study&#xD;
&#xD;
        Exclusion Criteria (PCa patients in discovery and validation cohorts):&#xD;
&#xD;
          -  Previous pelvic radiotherapy&#xD;
&#xD;
          -  Autoimmune disease (scleroderma,Chron's disease and ulcerative colitis), chronic&#xD;
             kidney disease requiring dyalis&#xD;
&#xD;
          -  Patients with malignant neoplasm in treatment with local or systemic therapies, except&#xD;
             for patients with PCa and skin cancers&#xD;
&#xD;
          -  Refusal to accept the study participation modalities&#xD;
&#xD;
        Inclusion Criteria (HNCa patients in discovery and validation cohorts):&#xD;
&#xD;
          -  ECOG PS ≤ 3&#xD;
&#xD;
          -  Histologically confirmed diagnosis of squamous cell carcinoma of the head and neck&#xD;
             (oral cavity, pharynx, larynx, paranasal sinuses and nasal cavity, salivary glands)&#xD;
&#xD;
          -  Non-metastatic stage III-IV cancer of the pharinx, larynx according to AJCC VII&#xD;
             edition. Patients with stage III-IV cancer of salivary glands o paranasal sinuses.&#xD;
             Patients with stage I-II cancer of pharinx and larynx only if neck lymph nodes or oral&#xD;
             mucosa are included in the irradiated volume&#xD;
&#xD;
          -  Indication to exclusive or post-surgical radiotherapy (associated or not to systemic&#xD;
             therapy according to internal guidelines)&#xD;
&#xD;
          -  Written informed consent to the study&#xD;
&#xD;
        Exclusion Criteria (HNCa patients in discovery and validation cohorts):&#xD;
&#xD;
          -  Previous head and neck radiotherapy&#xD;
&#xD;
          -  Connective tissue disease (lupus erythematosus or scleroderma) or other concomitant&#xD;
             head and neck cancers, except for in situ skin cancers not requiring radiotherapy or&#xD;
             systemic therapies.&#xD;
&#xD;
          -  Refusal to accept the study participation modalities&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Riccardo Valdagni, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ester Orlandi, MD</last_name>
    <role>Study Director</role>
    <affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nice Bedini, MD</last_name>
    <role>Study Director</role>
    <affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Loris De Cecco, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Nadia Zaffaroni, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tiziana Rancati, MS</last_name>
    <role>Study Director</role>
    <affiliation>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Riccardo Valdagni, MD, PhD</last_name>
    <phone>+0039 02-23903034</phone>
    <email>riccardo.valdagni@istitutotumori.mi.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Tiziana Rancati, MS</last_name>
    <phone>+0039 02-23903786</phone>
    <email>tiziana.rancati@istitutotumori.mi.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Fondazione IRCCS Istituto Nazionale Tumori</name>
      <address>
        <city>Milan</city>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Riccardo Valdagni, MD, PhD</last_name>
      <phone>+39 02-23903034</phone>
      <email>riccardo.valdagni@istitutotumori.mi.it</email>
    </contact>
    <contact_backup>
      <last_name>Tiziana Rancati, MS</last_name>
      <phone>+39 02-23903786</phone>
      <email>tiziana.rancati@istitutotumori.mi.it</email>
    </contact_backup>
    <investigator>
      <last_name>Riccardo Valdagni, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Valdagni R, Kattan MW, Rancati T, Yu C, Vavassori V, Fellin G, Cagna E, Gabriele P, Mauro FA, Baccolini M, Bianchi C, Menegotti L, Monti AF, Stasi M, Giganti MO, Fiorino C. Is it time to tailor the prediction of radio-induced toxicity in prostate cancer patients? Building the first set of nomograms for late rectal syndrome. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1957-66. doi: 10.1016/j.ijrobp.2011.03.028. Epub 2011 Jun 2.</citation>
    <PMID>21640511</PMID>
  </reference>
  <reference>
    <citation>Palorini F, Rancati T, Cozzarini C, Improta I, Carillo V, Avuzzi B, Casanova Borca V, Botti A, Degli Esposti C, Franco P, Garibaldi E, Girelli G, Iotti C, Maggio A, Palombarini M, Pierelli A, Pignoli E, Vavassori V, Valdagni R, Fiorino C. Multi-variable models of large International Prostate Symptom Score worsening at the end of therapy in prostate cancer radiotherapy. Radiother Oncol. 2016 Jan;118(1):92-8. doi: 10.1016/j.radonc.2015.11.036. Epub 2016 Jan 6.</citation>
    <PMID>26777123</PMID>
  </reference>
  <reference>
    <citation>Bossi P, Bergamini C, Miceli R, Cova A, Orlandi E, Resteghini C, Locati L, Alfieri S, Imbimbo M, Granata R, Mariani L, Iacovelli NA, Huber V, Cavallo A, Licitra L, Rivoltini L. Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy. Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):959-966. doi: 10.1016/j.ijrobp.2016.08.047. Epub 2016 Sep 6.</citation>
    <PMID>27745982</PMID>
  </reference>
  <reference>
    <citation>Orlandi E, Giandini T, Iannacone E, De Ponti E, Carrara M, Mongioj V, Stucchi C, Tana S, Bossi P, Licitra L, Fallai C, Pignoli E. Radiotherapy for unresectable sinonasal cancers: dosimetric comparison of intensity modulated radiation therapy with coplanar and non-coplanar volumetric modulated arc therapy. Radiother Oncol. 2014 Nov;113(2):260-6. doi: 10.1016/j.radonc.2014.11.024. Epub 2014 Nov 29.</citation>
    <PMID>25467003</PMID>
  </reference>
  <reference>
    <citation>De Cecco L, Nicolau M, Giannoccaro M, Daidone MG, Bossi P, Locati L, Licitra L, Canevari S. Head and neck cancer subtypes with biological and clinical relevance: Meta-analysis of gene-expression data. Oncotarget. 2015 Apr 20;6(11):9627-42. doi: 10.18632/oncotarget.3301.</citation>
    <PMID>25821127</PMID>
  </reference>
  <reference>
    <citation>Doldi V, Callari M, Giannoni E, D'Aiuto F, Maffezzini M, Valdagni R, Chiarugi P, Gandellini P, Zaffaroni N. Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation. Oncotarget. 2015 Oct 13;6(31):31441-60. doi: 10.18632/oncotarget.5056.</citation>
    <PMID>26375444</PMID>
  </reference>
  <reference>
    <citation>Ferreira MR, Muls A, Dearnaley DP, Andreyev HJ. Microbiota and radiation-induced bowel toxicity: lessons from inflammatory bowel disease for the radiation oncologist. Lancet Oncol. 2014 Mar;15(3):e139-47. doi: 10.1016/S1470-2045(13)70504-7.</citation>
    <PMID>24599929</PMID>
  </reference>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>July 25, 2017</study_first_submitted>
  <study_first_submitted_qc>September 20, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 26, 2017</study_first_posted>
  <last_update_submitted>October 2, 2017</last_update_submitted>
  <last_update_submitted_qc>October 2, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 3, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Radiotherapy</keyword>
  <keyword>Adverse effects</keyword>
  <keyword>Prostate cancer</keyword>
  <keyword>Head and neck cancer</keyword>
  <keyword>Patient risk stratification</keyword>
  <keyword>Mathematical models</keyword>
  <keyword>Microbiome</keyword>
  <keyword>Inflammatory cytokines</keyword>
  <keyword>Magnetic Resonance Imaging</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
    <mesh_term>Head and Neck Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 19, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/22/NCT03294122/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 20, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/22/NCT03294122/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03294122
org study id: INT 11/17
nct id: NCT03294122
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The main idea behind MICRO-LEARNER is to provide new insights about the response of healthy
      tissues to radiation by using information from the micro-environment obtained by biological
      measurements and imaging. This new knowledge will be included in current available predictive
      models of radio-induced toxicity, thus allowing to add unique biological characteristics of
      patients to dosimetry and treatment/clinical related variables.

      MICRO-LEARNER focuses on prostate cancer (PCa) and head-and-neck cancer (HNCa). For both
      cancers, radiotherapy is effectively used as curative treatment, in single modality or within
      a multidisciplinary approach including surgery (PCa) and/or chemotherapy (HNCa). Prediction
      and reduction of radio-induced side effects are becoming a priority: for PCa, high survival
      rates should be accompanied by a very low rate of moderate/severe toxicities; for HNCa, there
      is the need to tailor radiation dose according to disease recurrence risk profile. The shared
      aim of both cancers is to balance the improvement in outcome with a well-tolerated toxicity
      profile.

      Recent research indicates that the intestinal/salivary bacteria are strongly suspected of
      being very important in mediating the response to inflammation and lesions. Although their
      balance deeply changes during radiotherapy, studies done so far in the field of the
      microbiota-host relationship in radiotherapy have not addressed their role in insurgence of
      radiation toxicity.

      In this study, the investigators will assess how microbial populations evolve and how this
      influences the host and radiation induced toxicity in a significant number of patients.
      Moreover, the individual response at the tissue microstructure level, through analysis of
      images with advanced bioengineering techniques, will be determined.

      Results from this research, besides suggesting new ways to predict patients at risk of
      relevant side-effects, may also suggest possible treatments to change the baseline microbiota
      of patients at high risk or to modify it during therapy, in order to mitigate toxicity.
      Understanding the microbiota-radiotherapy interaction may thus lead to novel, effective and
      inexpensive ways of assessing and managing complications of cancer treatment.
**Prospective Clinical Trial: discovery population**

      130 PCa and 130 HNCa consecutive patients will be enrolled in 18 months. All patients will
      receive radiotherapy at radical curative doses at the National Cancer Institute in Milan, and
      follow-up visits at the same centre.

      Detailed pre-treatment evaluation will include: recording of demographic features, clinical
      history, comorbidities and habits, evaluation of normal tissue functioning by the health
      practitioner (CTCAE scoring system), evaluation of quality of life and normal tissue
      functioning through validated patient reported outcome (PROs) questionnaires, evaluation of
      organ functioning by instrumental measures (i.e. baseline swallowing screening with flexible
      endoscopic evaluation of swallowing - FEES - and unstimulated salivary flow for HNCa
      patients), biochemical examinations, gut (PCa)/salivary (HNCa) microbiome measurement,
      determination of baseline level of plasma/salivary inflammatory markers, baseline
      multi-parametric magnetic resonance imaging (MRI).

      Patients will receive radiotherapy and possible adjuvant (hormone or chemo) therapies as
      foreseen by international guidelines. In this aspect the here proposed trial is an
      observational study, no modification to standard regimens is considered. Radiotherapy is
      performed with 6 MV photon beams delivered with Volumetric Modulated arc Therapy (VMAT)
      technique at conventional fractionations.

      Evaluation during treatment will include weekly assessment of toxicity, as measured by the
      clinician (according to CTCAE v 4.0) and by PROs and biochemical measurements, and evaluation
      of inflammatory markers (plasmatic and salivary cytokines) after a dose of 20 Gy. For a
      subpopulation of 60 oropharyngeal cancer patients treated with definitive radiotherapy +/-
      chemotherapy an additional MRI study during the second week of treatment is foreseen.

      Assessment at the end of radiotherapy will include evaluation of toxicity by the clinician
      and by PROs, FEES and unstimulated salivary flow for HNCa patients, biochemical examinations,
      gut/salivary microbiome measurement.

      Evaluation at 3, 6 and 12 months will include: evaluation of toxicity by the clinician and by
      PROs, FEES and unstimulated salivary flow for HNCa patients and biochemical examinations.

      Minimum follow-up is set to 12 months for the specific purpose of evaluation of acute and
      mid-term toxicity, which are the endpoints considered in this project. Nevertheless,
      follow-up will continue until 3 years after the end of radiotherapy (beyond the end of the
      project) in order to allow evaluation of incidence, prevalence and patterns of late
      side-effects, as well as for survival outcome assessment. After 12 months, follow-up will be
      performed every 6 months and limited to assessment of toxicity by the clinician and by PROs.

      Follow-up MRI studies will be performed at 3, 12 and 24 months for HNCa patients and at 12
      months for PCa patients.

      **Prospective Clinical Trial: validation population**

      70 PCa and 70 HNCa consecutive patients will be enrolled in 12 months, starting immediately
      after the end of enrolment of the discovering population.

      The specific aim of this second phase is validation of results on microbiota, specifically on
      association between selected baseline microbiota profiles and the risk of acute toxicity (for
      the purpose of this project) and for mid-term/late toxicity (beyond this projects). This
      result should be the more significant from the clinical point of view, allowing development
      of a therapeutic algorithm to be used before treatment and permitting introduction ways of
      changing the make-up of gut/salivary bacteria in patients at high risk of toxicity.

      Baseline assessment, treatment and follow-up evaluation of toxicity by the clinician and by
      PROs will follow the scheme described for the developing population. Microbioma measurement
      will be only performed at baseline, due to the higher clinical interest in having a test
      determining patient radiosensitivity before treatment. Imaging and assessment of inflammatory
      marker levels will not be accomplished in the validation population.
observational model: Cohort
time perspective: Prospective
measure: Acute toxicity
time frame: <90 days after radiotherapy
description: If any, acute (<within 90 days from radiotherapy completion) Grade 1, Grade 2, Grade 3-4 disorder, according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system, and its association with clinical variables, absorbed dose, microbioma characteristics and radiomic features.
measure: Late toxicity
time frame: 3 months - 3 years after radiotherapy
description: If any, late (> 90 days after radiotherapy completion) Grade 1, Grade 2, Grade 3-4 disorder, according to the Common Terminology Criteria for Adverse Events (CTCAE) grading system, and its association with clinical variables, absorbed dose, microbioma characteristics and radiomic features.
arm group label: PCa patients - Discovery cohort
description: External beam radiotherapy for prostate cancer
arm group label: HNCa patients - Discovery cohort
description: External beam radiotherapy for head and neck cancer
arm group label: PCa patients - Validation cohort
description: External beam radiotherapy for prostate cancer
arm group label: HNCa patients - Validation cohort
description: External beam radiotherapy for head and neck cancer
intervention type: Radiation
intervention name: External beam radiotherapy for prostate cancer
description: Patients will receive radiotherapy for prostate cancer and possible adjuvant hormone therapies as foreseen by international guidelines. No modification of standard regimens is considered. PCa patients are treated with 78 Gy, 2Gy/fraction, in exclusive setting and with 70 Gy, 2Gr/fraction in the post-prostatectomy setting. Lymph node irradiation is performed (50 Gy, 2Gy/fraction) when indicated by risk class.
arm group label: PCa patients - Discovery cohort
arm group label: PCa patients - Validation cohort
intervention type: Radiation
intervention name: External beam radiotherapy for head and neck cancer
description: Patients will receive radiotherapy for head and neck cancer and possible concomitant chemotherapies as foreseen by international guidelines. No modification of standard regimens is considered. In curative setting, HNCa patients are treated at a total dose of 70 Gy, 59.4 Gy and 56.1 Gy in 33 fractions to high risk Planning Target Volume (PTV), intermediate risk and low risk PTV, respectively. In high risk post-operative setting they are treated with 66 Gy (according to histopathological features), 60 Gy and 56.1 Gy to high, intermediate and low risk PTV, respectively; while, in intermediate risk post-operative case, intermediate and low risk PTV are irradiated with 60 Gy and 54 Gy, respectively. Chemotherapy will be platinum based (weekly or 3-weekly cisplatin).
arm group label: HNCa patients - Discovery cohort
arm group label: HNCa patients - Validation cohort
Whole blood samples of all patients, stool samples of prostate cancer patients, salivary
      samples of head and neck cancer patients
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Riccardo Valdagni, MD, PhD
role: Principal Investigator
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
last name: Ester Orlandi, MD
role: Study Director
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
last name: Nice Bedini, MD
role: Study Director
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
last name: Loris De Cecco, PhD
role: Study Director
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
last name: Nadia Zaffaroni, PhD
role: Study Director
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
last name: Tiziana Rancati, MS
role: Study Director
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
last name: Riccardo Valdagni, MD, PhD
phone: +0039 02-23903034
email: riccardo.valdagni@istitutotumori.mi.it
last name: Tiziana Rancati, MS
phone: +0039 02-23903786
email: tiziana.rancati@istitutotumori.mi.it
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Italy
citation: Valdagni R, Kattan MW, Rancati T, Yu C, Vavassori V, Fellin G, Cagna E, Gabriele P, Mauro FA, Baccolini M, Bianchi C, Menegotti L, Monti AF, Stasi M, Giganti MO, Fiorino C. Is it time to tailor the prediction of radio-induced toxicity in prostate cancer patients? Building the first set of nomograms for late rectal syndrome. Int J Radiat Oncol Biol Phys. 2012 Apr 1;82(5):1957-66. doi: 10.1016/j.ijrobp.2011.03.028. Epub 2011 Jun 2.
PMID: 21640511
citation: Palorini F, Rancati T, Cozzarini C, Improta I, Carillo V, Avuzzi B, Casanova Borca V, Botti A, Degli Esposti C, Franco P, Garibaldi E, Girelli G, Iotti C, Maggio A, Palombarini M, Pierelli A, Pignoli E, Vavassori V, Valdagni R, Fiorino C. Multi-variable models of large International Prostate Symptom Score worsening at the end of therapy in prostate cancer radiotherapy. Radiother Oncol. 2016 Jan;118(1):92-8. doi: 10.1016/j.radonc.2015.11.036. Epub 2016 Jan 6.
PMID: 26777123
citation: Bossi P, Bergamini C, Miceli R, Cova A, Orlandi E, Resteghini C, Locati L, Alfieri S, Imbimbo M, Granata R, Mariani L, Iacovelli NA, Huber V, Cavallo A, Licitra L, Rivoltini L. Salivary Cytokine Levels and Oral Mucositis in Head and Neck Cancer Patients Treated With Chemotherapy and Radiation Therapy. Int J Radiat Oncol Biol Phys. 2016 Dec 1;96(5):959-966. doi: 10.1016/j.ijrobp.2016.08.047. Epub 2016 Sep 6.
PMID: 27745982
citation: Orlandi E, Giandini T, Iannacone E, De Ponti E, Carrara M, Mongioj V, Stucchi C, Tana S, Bossi P, Licitra L, Fallai C, Pignoli E. Radiotherapy for unresectable sinonasal cancers: dosimetric comparison of intensity modulated radiation therapy with coplanar and non-coplanar volumetric modulated arc therapy. Radiother Oncol. 2014 Nov;113(2):260-6. doi: 10.1016/j.radonc.2014.11.024. Epub 2014 Nov 29.
PMID: 25467003
citation: De Cecco L, Nicolau M, Giannoccaro M, Daidone MG, Bossi P, Locati L, Licitra L, Canevari S. Head and neck cancer subtypes with biological and clinical relevance: Meta-analysis of gene-expression data. Oncotarget. 2015 Apr 20;6(11):9627-42. doi: 10.18632/oncotarget.3301.
PMID: 25821127
citation: Doldi V, Callari M, Giannoni E, D'Aiuto F, Maffezzini M, Valdagni R, Chiarugi P, Gandellini P, Zaffaroni N. Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation. Oncotarget. 2015 Oct 13;6(31):31441-60. doi: 10.18632/oncotarget.5056.
PMID: 26375444
citation: Ferreira MR, Muls A, Dearnaley DP, Andreyev HJ. Microbiota and radiation-induced bowel toxicity: lessons from inflammatory bowel disease for the radiation oncologist. Lancet Oncol. 2014 Mar;15(3):e139-47. doi: 10.1016/S1470-2045(13)70504-7.
PMID: 24599929
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Head and Neck Neoplasms
sharing ipd: No
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