<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/NCT03001570</url>
  </required_header>
  <id_info>
    <org_study_id>European Institute of Oncology</org_study_id>
    <nct_id>NCT03001570</nct_id>
  </id_info>
  <brief_title>Accelerated Modulated Fractionation (SIB-IMRT) for Head and Neck District</brief_title>
  <acronym>FAMOSO</acronym>
  <official_title>Accelerated Modulated Fractionation (SIB-IMRT) for the Treatment of Locally Advanced Squamous Cell Carcinoma From Head and Neck District</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>European Institute of Oncology</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>European Institute of Oncology</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Nowadays the association between radiotherapy and the anti- Epidermal Growth Factor Receptor&#xD;
      (anti-EGFR) monoclonal antibody Cetuximab represents a valid option in the treatment of head&#xD;
      and neck locally advanced squamous neoplasm and, particularly, of oropharynx carcinoma. Up to&#xD;
      date we have only indirect comparison with the standard curative treatment (i.e. concurrent&#xD;
      radiochemotherapy) and the preliminary data show equivalent efficacy of both regimens. For&#xD;
      this reason, concurrent Cetuximab and radiotherapy is administered in patients not eligible&#xD;
      to chemoradiotherapy. The introduction of Cetuximab has been associated to new kind of&#xD;
      toxicities, especially cutaneous, that have increasingly reported.&#xD;
&#xD;
      The aim of our study is to improve the toxicity/benefit ratio in patients receiving&#xD;
      concurrent radiotherapy and cetuximab for locally advanced head and neck neoplasm. Hence,&#xD;
      this improvement could be achieved by modulating radiation therapy dose per fraction&#xD;
      following Cetuximab pharmacokinetics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Radiobiological rationale Overexpression of EGFR has been found to be involved into two&#xD;
      different mechanisms of response to ionizing radiations: the former is related to the&#xD;
      increased cell proliferation rate, the latter leading to lower radiosensitivity.&#xD;
&#xD;
        1. Increasing of cell proliferation rate From an analysis of the already reported&#xD;
           evidences, we quantified the effect of a higher cell proliferation rate due to&#xD;
           overexpression of EGFR. These findings were reported in patients affected with squamous&#xD;
           carcinoma of head and neck district and evaluated for EGFR status. In those patients,&#xD;
           local recurrence was compared in patients with different length of treatment but at the&#xD;
           same fractionation. Consequently, the real doubling time in the subgroups with high and&#xD;
           low EGFR expression was extrapolated . From these extrapolated values, equivalent doses&#xD;
           of each day of non-delivered treatment have been calculated for patients who received&#xD;
           accelerated schedule. Furthermore, doses were reported in relation to the different&#xD;
           primary sites (oropharynx, larynx, oral cavity, hypopharynx).&#xD;
&#xD;
           Modification of doubling time (TD) of neoplastic cell population in patients with Low&#xD;
           and High EGFR expression.&#xD;
&#xD;
        2. Reduction of radiosensitivity Unfortunately, how radiosensitizing drugs can modify&#xD;
           radiosensitivity cannot be evaluated retrospectively. Actually, the efficacy is&#xD;
           evaluated on the basis of an overall effect of the treatment but radiosensitivity&#xD;
           changes day by day in radiation and pharmacological concurrent treatment. However, these&#xD;
           changing in radiosensitivity can be analysed in pre-clinical setting. In many reports, a&#xD;
           progressively higher radiosensitivity has been shown in cellular survival curves by&#xD;
           increasing EGFR inhibitor concentration. Nevertheless, the concentrations of EGFR&#xD;
           inhibitor do not correspond to in vivo concentration during radiotherapy delivery.&#xD;
           Fortunately, this data is obtainable from Cetuximab pharmacokinetic curve. Therefore,&#xD;
           cell survival curves corresponding to drug concentration were obtained by performing a&#xD;
           graphic interpolation. From these curves, daily radiosensitivity parameters were found.&#xD;
&#xD;
      Subsequently, daily doses with respect to daily radiosensitivity were identified by&#xD;
      radiobiological calculation model. This fractionation, designed on Cetuximab&#xD;
      pharmacokinetics, have been calculated to be equivalent to curative treatment (70Gy given&#xD;
      with conventional schedule).&#xD;
&#xD;
      At the same time, lower cutaneous toxicity is expected with this &quot;modulated&quot; schedule due to&#xD;
      the possibly increased cellular repair. Pharmacokinetics data of Cetuximab we found on the&#xD;
      population: Vmax 4.38mg/h (15.4%), Km 74g/ml, central compartment volume Vl 2.83 l (18.6%),&#xD;
      peripheral compartment volume 2.43 l (56.4%) and intercompartmental clearance 0.103 l/h&#xD;
      (97.2%). Those parameters remain unmodified also during prolonged therapies. Administrated&#xD;
      doses have been found to be adequate to cell wall receptors saturation.&#xD;
&#xD;
      A definition of overexpression of EGFR is still lacking. Different cut-offs have been&#xD;
      proposed to distinguish patients with &quot;high expression&quot; from patients with &quot;low expression&quot;&#xD;
      of EGFR. In a recent study the adoption of accelerated fractionation showed an advantage for&#xD;
      those patients with an expression of EGFR&gt;50%. Thus, we adopted this cut-off in our study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>January 2014</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Actual">December 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients who experienced acute toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG / EORTC)</measure>
    <time_frame>up to 7 days during RT treatment</time_frame>
    <description>During radiotherapy, patients will be assessed weekly for acute toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale.&#xD;
Furthermore pain (NRS pain scale) nutritional assessment (weight in kilograms ) will be performed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients who experienced late toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale RTOG / EORTC</measure>
    <time_frame>up to 6-8 weeks after treatment completion and then up to 2 years</time_frame>
    <description>Patients will be assessed weekly for late toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who experienced local or distance recurrence of disease assessed through clinical and radiological controls</measure>
    <time_frame>up to 6-8 weeks after treatment completion and then up to 2 years</time_frame>
    <description>Clinical assessment will be performed through:&#xD;
Otolaryngology examination and laryngoscopy&#xD;
Radiological assessment will be performed through:&#xD;
Facial skeleton and neck MRI with and without contrast or CT with and without contrast if MRI is unfeasible.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">10</enrollment>
  <condition>Carcinoma of the Head and Neck</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Radiotherapy treatment associated with concurrent Cetuximab administration.&#xD;
Patients candidate to curative concurrent Cetuximab and Radiotherapy are eligible for this study. After expressing written informed consent, patients will perform CT simulation. Then an IMRT-SIB (Simultaneous Integrated Boost) treatment plan will be elaborated and deliver the following Cetuximab pharmacokinetic:&#xD;
Length: 6 weeks; 1 fraction daily (From Monday to Friday) 30 Total Fractions (5 per week, 6 weeks of treatment). Cetuximab will be administered weekly from a week before starting radiotherapy until the end of treatment for 7 subsequent administration accordingly to the standard schedule (1 before and 6 during radiotherapy).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cetuximab plus Radiotherapy</intervention_name>
    <description>Standard dose of a curative radiotherapy treatment is 70Gy given with conventional fractionation (2G daily) in an overall length of 7 weeks. In this study, the fractionation has been modified accordingly Cetuximab pharmacokinetics. Cetuximab will be administered with standard schedule: charge dose of 400mg/mq a week before the beginning of concurrent treatment, then weekly doses of 250mg/mq intravenous for 7 administration. This schedule to obtain the same biological efficacy on tumour with lower toxicity on healthy tissues.</description>
    <arm_group_label>Arm 1</arm_group_label>
    <other_name>Radiotherapy, IMRT</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with histological proof of locally advanced squamous carcinoma of oropharynx,&#xD;
             larynx, hypopharynx (stage III and Iva)&#xD;
&#xD;
          -  Overexpression of EGFR (&gt;50%)&#xD;
&#xD;
          -  Patients previously considered non-eligible for curative radio-chemotherapy for&#xD;
             clinical reasons.&#xD;
&#xD;
          -  Performance Status (ECOG) ≤ 2&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Possibility of correct administration of treatment&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Distant metastases&#xD;
&#xD;
          -  Oral cavity or rhinopharynx neoplasm&#xD;
&#xD;
          -  Need of cutaneous bolus&#xD;
&#xD;
          -  Previous treatments on head and neck district&#xD;
&#xD;
          -  Collagenopathies or other severe systemic disease&#xD;
&#xD;
          -  Severe cardiopathies or myocardial infarction in the previous 12 months, serious&#xD;
             hepatopathies or other diseases with heavy impact on general conditions.&#xD;
&#xD;
          -  Psychiatric disorders or other conditions preventing from expressing informed consent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Roberto Orecchia, Prof</last_name>
    <role>Study Director</role>
    <affiliation>European Institute of Oncology</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Roberto Orecchia, Prof.</last_name>
    <email>roberto.orecchia@ieo.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Daniela Alterio, MD</last_name>
    <email>daniela.alterio@ieo.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Division of Radiotherapy European Institute of Oncology</name>
      <address>
        <city>Milan</city>
        <state>MI</state>
        <zip>20141</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Daniela Alterio, MD</last_name>
      <email>daniela.alterio@ieo.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>December 12, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <last_update_submitted>June 27, 2023</last_update_submitted>
  <last_update_submitted_qc>June 27, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 28, 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>Carcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cetuximab</mesh_term>
  </intervention_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/NCT03001570
org study id: European Institute of Oncology
nct id: NCT03001570
lead sponsor: 
has dmc: No
Nowadays the association between radiotherapy and the anti- Epidermal Growth Factor Receptor
      (anti-EGFR) monoclonal antibody Cetuximab represents a valid option in the treatment of head
      and neck locally advanced squamous neoplasm and, particularly, of oropharynx carcinoma. Up to
      date we have only indirect comparison with the standard curative treatment (i.e. concurrent
      radiochemotherapy) and the preliminary data show equivalent efficacy of both regimens. For
      this reason, concurrent Cetuximab and radiotherapy is administered in patients not eligible
      to chemoradiotherapy. The introduction of Cetuximab has been associated to new kind of
      toxicities, especially cutaneous, that have increasingly reported.

      The aim of our study is to improve the toxicity/benefit ratio in patients receiving
      concurrent radiotherapy and cetuximab for locally advanced head and neck neoplasm. Hence,
      this improvement could be achieved by modulating radiation therapy dose per fraction
      following Cetuximab pharmacokinetics.
Radiobiological rationale Overexpression of EGFR has been found to be involved into two
      different mechanisms of response to ionizing radiations: the former is related to the
      increased cell proliferation rate, the latter leading to lower radiosensitivity.

        1. Increasing of cell proliferation rate From an analysis of the already reported
           evidences, we quantified the effect of a higher cell proliferation rate due to
           overexpression of EGFR. These findings were reported in patients affected with squamous
           carcinoma of head and neck district and evaluated for EGFR status. In those patients,
           local recurrence was compared in patients with different length of treatment but at the
           same fractionation. Consequently, the real doubling time in the subgroups with high and
           low EGFR expression was extrapolated . From these extrapolated values, equivalent doses
           of each day of non-delivered treatment have been calculated for patients who received
           accelerated schedule. Furthermore, doses were reported in relation to the different
           primary sites (oropharynx, larynx, oral cavity, hypopharynx).

           Modification of doubling time (TD) of neoplastic cell population in patients with Low
           and High EGFR expression.

        2. Reduction of radiosensitivity Unfortunately, how radiosensitizing drugs can modify
           radiosensitivity cannot be evaluated retrospectively. Actually, the efficacy is
           evaluated on the basis of an overall effect of the treatment but radiosensitivity
           changes day by day in radiation and pharmacological concurrent treatment. However, these
           changing in radiosensitivity can be analysed in pre-clinical setting. In many reports, a
           progressively higher radiosensitivity has been shown in cellular survival curves by
           increasing EGFR inhibitor concentration. Nevertheless, the concentrations of EGFR
           inhibitor do not correspond to in vivo concentration during radiotherapy delivery.
           Fortunately, this data is obtainable from Cetuximab pharmacokinetic curve. Therefore,
           cell survival curves corresponding to drug concentration were obtained by performing a
           graphic interpolation. From these curves, daily radiosensitivity parameters were found.

      Subsequently, daily doses with respect to daily radiosensitivity were identified by
      radiobiological calculation model. This fractionation, designed on Cetuximab
      pharmacokinetics, have been calculated to be equivalent to curative treatment (70Gy given
      with conventional schedule).

      At the same time, lower cutaneous toxicity is expected with this "modulated" schedule due to
      the possibly increased cellular repair. Pharmacokinetics data of Cetuximab we found on the
      population: Vmax 4.38mg/h (15.4%), Km 74g/ml, central compartment volume Vl 2.83 l (18.6%),
      peripheral compartment volume 2.43 l (56.4%) and intercompartmental clearance 0.103 l/h
      (97.2%). Those parameters remain unmodified also during prolonged therapies. Administrated
      doses have been found to be adequate to cell wall receptors saturation.

      A definition of overexpression of EGFR is still lacking. Different cut-offs have been
      proposed to distinguish patients with "high expression" from patients with "low expression"
      of EGFR. In a recent study the adoption of accelerated fractionation showed an advantage for
      those patients with an expression of EGFR>50%. Thus, we adopted this cut-off in our study.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients who experienced acute toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer (RTOG / EORTC)
time frame: up to 7 days during RT treatment
description: During radiotherapy, patients will be assessed weekly for acute toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale.
Furthermore pain (NRS pain scale) nutritional assessment (weight in kilograms ) will be performed.
measure: Number of patients who experienced late toxicity with Grade 3 or Grade 4 adverse events according to Scala CTCAE v4.0 toxicity criteria and scale RTOG / EORTC
time frame: up to 6-8 weeks after treatment completion and then up to 2 years
description: Patients will be assessed weekly for late toxicity using validated international scales.acute toxicity will be assessed with CTCAE V 4.03 (Common Terminology Criteria of Adverse Events Version 4.03) scale.
measure: Number of patients who experienced local or distance recurrence of disease assessed through clinical and radiological controls
time frame: up to 6-8 weeks after treatment completion and then up to 2 years
description: Clinical assessment will be performed through:
Otolaryngology examination and laryngoscopy
Radiological assessment will be performed through:
Facial skeleton and neck MRI with and without contrast or CT with and without contrast if MRI is unfeasible.
arm group label: Arm 1
arm group type: Experimental
description: Radiotherapy treatment associated with concurrent Cetuximab administration.
Patients candidate to curative concurrent Cetuximab and Radiotherapy are eligible for this study. After expressing written informed consent, patients will perform CT simulation. Then an IMRT-SIB (Simultaneous Integrated Boost) treatment plan will be elaborated and deliver the following Cetuximab pharmacokinetic:
Length: 6 weeks; 1 fraction daily (From Monday to Friday) 30 Total Fractions (5 per week, 6 weeks of treatment). Cetuximab will be administered weekly from a week before starting radiotherapy until the end of treatment for 7 subsequent administration accordingly to the standard schedule (1 before and 6 during radiotherapy).
intervention type: Drug
intervention name: Cetuximab plus Radiotherapy
description: Standard dose of a curative radiotherapy treatment is 70Gy given with conventional fractionation (2G daily) in an overall length of 7 weeks. In this study, the fractionation has been modified accordingly Cetuximab pharmacokinetics. Cetuximab will be administered with standard schedule: charge dose of 400mg/mq a week before the beginning of concurrent treatment, then weekly doses of 250mg/mq intravenous for 7 administration. This schedule to obtain the same biological efficacy on tumour with lower toxicity on healthy tissues.
arm group label: Arm 1
other name: Radiotherapy, IMRT
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Roberto Orecchia, Prof
role: Study Director
affiliation: European Institute of Oncology
last name: Roberto Orecchia, Prof.
email: roberto.orecchia@ieo.it
last name: Daniela Alterio, MD
email: daniela.alterio@ieo.it
facility: 
status: Recruiting
contact: 
country: Italy
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Cetuximab
sharing ipd: No