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/NCT05974774</url>
    </required_header>
    <id_info>
      <org_study_id>EORTC 2238</org_study_id>
      <nct_id>NCT05974774</nct_id>
    </id_info>
    <brief_title>Intermittent Androgen Deprivation Therapy in the Era of AR Pathway Inhibitors</brief_title>
    <official_title>Intermittent Androgen Deprivation Therapy in the Era of AR Pathway Inhibitors; a Phase 3 Pragmatic Randomized Trial.</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>European Organisation for Research and Treatment of Cancer - EORTC</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Cancer Trials Ireland</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>UNICANCER</agency>
        <agency_class>Other</agency_class>
      </collaborator>
      <collaborator>
        <agency>Spanish Oncology Genito-Urinary Group</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>European Organisation for Research and Treatment of Cancer - EORTC</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        This study addresses the global topic of treatment optimization, i.e. achieving similar&#xD;
        benefit while reducing the duration of treatment, hence hoping to decrease the burden of&#xD;
        side-effects, improve quality-of life and reduce resource utilization.&#xD;
  &#xD;
        The primary goal of de-escalation is to investigate whether using an intermittent regime&#xD;
        results in a similar OS to continuous treatment.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Prostate cancer is known to be dependent on testicular and adrenal androgens and the earliest&#xD;
        identified treatments were the suppression of the body's production of testosterone. Then&#xD;
        came the development of drugs able to block the androgen receptors that multiplied on the&#xD;
        cancer cell membranes. The combination of these drugs presently approved by the EMA for first&#xD;
        line treatment of mHNPC are understood to be given maximum androgen blockage and to be used&#xD;
        until progression. All have been shown to positively impact overall survival. For patients,&#xD;
        however, the consequences of continuous intensified MAB, and thereby testosterone&#xD;
        suppression, have impacted their quality of life, especially in the form of fatigue,&#xD;
        emotional distress, decrease of libido and loss of sexual function. This is in addition to&#xD;
        toxicities linked to the mechanisms of these drugs which include cardiovascular diseases,&#xD;
        cognitive effects and loss of bone mineral density.&#xD;
  &#xD;
        Treatment optimization is rarely addressed by clinical trials run for registration purposes.&#xD;
        Toxicity is subsumed under efficacy and keeping the cancer at bay or controlled at any cost.&#xD;
        Overall patient experience is not taken into account when determining what is an acceptable&#xD;
        trade-off. Intermittent treatment or drug holiday are options to manage drug toxicities but&#xD;
        longer off-treatment periods remain rare due to the fear of losing efficacy.&#xD;
  &#xD;
        Prostate cancer is an ideal setting to study the benefits of intermittent treatment as PSA&#xD;
        levels have been shown to be a good indicator of cancer status. By holding androgen blockade&#xD;
        after good PSA response, patients get the opportunity of seeing an improvement in their&#xD;
        quality of life as testosterone levels slowly recover. The longer a patient stays off&#xD;
        treatment, the more improvements to his overall wellbeing can be felt. Monitoring PSA levels&#xD;
        provides an early signal to cancer regrowth and allows for the restart of MAB when it becomes&#xD;
        necessary.&#xD;
  &#xD;
        While improving the patient's quality of life, there is as yet no indication as to the&#xD;
        possible impact of this approach on overall survival. Alternating off/on treatment could&#xD;
        delay both the start of the next line of treatment and the development of castration&#xD;
        resistance but the absence of constant androgen suppression could also have the opposite&#xD;
        effect and precipitate new alternatives to cancer cells testosterone dependence.&#xD;
  &#xD;
        This trial will randomize patients to either continue with their treatment as prescribed or&#xD;
        to stop treatment until PSA levels indicate the necessity of restarting suppression. The&#xD;
        latter group can stop treatment again when PSA levels reaches 0.2 ng/mL or lower. There is a&#xD;
        need to investigate whether the benefit to patient's lives of holding long-term treatment&#xD;
        will outweigh the risks of shortening overall survival. This trial is being done to allow&#xD;
        both patients and their treating teams to have the data needed to make an informed decision&#xD;
        on the best treatment approach.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">December 15, 2023</start_date>
    <completion_date type="Anticipated">December 15, 2030</completion_date>
    <primary_completion_date type="Anticipated">September 15, 2029</primary_completion_date>
    <phase>Phase 3</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>overall survival</measure>
      <time_frame>3 years from randomisation</time_frame>
      <description>the overall survival (OS) at 3 years using an iMAB regimen is non-inferior to continuous treatment.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>proportion of patients who do not restart their hormonal therapy within 1 year of interrupting their MAB therapy (given as part of the induction phase)</measure>
      <time_frame>1 year from stopping the MAB therapy</time_frame>
      <description>proportion of patients who do not restart within 1 year of interrupting their MAB therapy (given as part of the induction phase) is not less than 70%</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>occurrence of adverse events</measure>
      <time_frame>5 years from randomisation</time_frame>
      <description>Safety according to the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time spent on MAB treatment</measure>
      <time_frame>5 years from randomisation</time_frame>
      <description>the overall time in months that the patient was on MAB treatment</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Time to next systemic prostate cancer therapy</measure>
      <time_frame>5 years from randomisation</time_frame>
      <description>the overall time in months until the patient began the next systemic prostate cancer therapy</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The magnitude of change in HRQoL</measure>
      <time_frame>60 months from randomisation</time_frame>
      <description>The magnitude of change in HRQoL in terms of physical functioning from EORTC QLQ-C30</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The magnitude of change in HRQoL</measure>
      <time_frame>60 months from randomisation</time_frame>
      <description>The magnitude of change in HRQoL in terms of sexual activity scale of EORTC QLQ PR25</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The magnitude of change in HRQoL</measure>
      <time_frame>60 months from randomisation</time_frame>
      <description>The magnitude of change in HRQoL in terms of pain characteristics from the IL249 item list; To cover all important HRQoL domains and to have more granularity on some of the selected domains, additional HRQoL concepts are searched in the EORTC item library. This resulted in the inclusion of an additional scale that measures the pain characteristics.&#xD;
  The selected scale and corresponding items address the pain characteristics (the nature of the pain: constant versus intermittent and whether the pain can be relieved by pain medications)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>The magnitude of change in HRQoL</measure>
      <time_frame>60 months from randomisation</time_frame>
      <description>The magnitude of change in HRQoL in terms of physical fatigue from the IL249 item list; To cover all important HRQoL domains and to have more granularity on some of the selected domains, additional HRQoL concepts are searched in the EORTC item library. This resulted in the inclusion of an additional scale that measures the physical fatigue.&#xD;
  The selected scale and corresponding items address the energy levels, exhaustion, sleepiness.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>health utility derived from the QLQ-C30 questionnaires data</measure>
      <time_frame>5 years from randomisation</time_frame>
      <description>Health utility derived from patient reported QLQ-C30 data and patient demographics;Health utilities summarize a patient's overall health status, and this parameter can be applied in cost-effectiveness analyses. Published mapping algorithms can be used to calculate health utility based on the collected QLQ-C30 data, either directly or indirectly. The indirect algorithms first maps QLQ-C30 scores to European Quality-of-Life-5 Dimensions (EQ-5D) scores and then to health utility scores. The collected HRQoL data using QLQ-C30 will be mapped first to EQ-5D scores using an established mapping approach from the literature, and then further translated to health utility values for each study subject and at each assessment of HRQoL, taking into account published national value sets for this conversion.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">1600</enrollment>
    <condition>Prostate Cancer</condition>
    <arm_group>
      <arm_group_label>Arm A - continuous treatment</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Arm A (cMAB): ADT (LHRH agonist or antagonist) + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide) continuously until start of a new anti-cancer therapy.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Arm B - intermittent treatment</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Arm B (iMAB): no further treatment, including ADT and ARPI; decision to restart ADT (LHRH agonist or antagonist) and the initial ARPI (abiraterone, enzalutamide, apalutamide or darolutamide) is left at Investigator discretion.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>iMAB</intervention_name>
      <description>no treatment until significant PSA increase as per treating physician at which point patient restarts ADT (LHRH agonist or antagonist) + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide). Once PSA &lt; 0.2 ng/mL, treatment stops again.</description>
      <arm_group_label>Arm B - intermittent treatment</arm_group_label>
      <other_name>intermittent maximum androgen blockade</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>cMAB</intervention_name>
      <description>LHRH agonist or antagonist + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide)</description>
      <arm_group_label>Arm A - continuous treatment</arm_group_label>
      <other_name>continuous maximum androgen blockade</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patient treated with ADT and an ARPI for mHNPC for 6-12 months and presenting with a&#xD;
               PSA ≤ 0.2 ng/mL Note: Patient may have received docetaxel and radiotherapy of the&#xD;
               prostate and metastases&#xD;
  &#xD;
            -  Before patient 's enrolment, written informed consent must be given according to&#xD;
               ICH/GCP, and national/local regulations&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients with M1a on modern imaging technique (PET-Choline or -PSMA or Whole Body MRI)&#xD;
               only for whom radiation therapy and 2 years of hormone therapy is recommended&#xD;
  &#xD;
            -  Patients with a prior or concurrent malignancy whose natural history or treatment has&#xD;
               the potential to interfere with the safety or efficacy assessment for this trial&#xD;
  &#xD;
            -  Patients who have received an investigational treatment as early intensification,&#xD;
               which includes radical prostatectomy&#xD;
  &#xD;
            -  Any psychological, familial, sociological or geographical condition potentially&#xD;
               hampering compliance with the study protocol and follow-up schedule; those conditions&#xD;
               should be assessed and discussed with the patient before the enrolment in the trial&#xD;
        </textblock>
      </criteria>
      <gender>Male</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>100 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Bertrand Tombal, Prof</last_name>
      <role>Study Chair</role>
      <affiliation>Cliniques Universitaires de Saint Luc</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Silke Gillessen, Prof</last_name>
      <role>Study Chair</role>
      <affiliation>Oncology Institute of Southern Switzerland - Ospedale San Giovanni</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>EORTC</last_name>
      <phone>+3227741611</phone>
      <email>eortc@eortc.org</email>
    </overall_contact>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>June 26, 2023</study_first_submitted>
    <study_first_submitted_qc>July 26, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 3, 2023</study_first_posted>
    <last_update_submitted>July 26, 2023</last_update_submitted>
    <last_update_submitted_qc>July 26, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 3, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>Metastatic hormone-naïve prostate cancer</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Prostatic Neoplasms</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Ascorbic Acid</mesh_term>
      <mesh_term>Methyltestosterone</mesh_term>
      <mesh_term>Androgens</mesh_term>
      <mesh_term>Estrogens, Conjugated (USP)</mesh_term>
    </intervention_browse>
    <!-- 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/NCT05974774
  org study id: EORTC 2238
  nct id: NCT05974774
  lead sponsor: 
  collaborator: 
  collaborator: 
  collaborator: 
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  This study addresses the global topic of treatment optimization, i.e. achieving similar
        benefit while reducing the duration of treatment, hence hoping to decrease the burden of
        side-effects, improve quality-of life and reduce resource utilization.
  
        The primary goal of de-escalation is to investigate whether using an intermittent regime
        results in a similar OS to continuous treatment.
  Prostate cancer is known to be dependent on testicular and adrenal androgens and the earliest
        identified treatments were the suppression of the body's production of testosterone. Then
        came the development of drugs able to block the androgen receptors that multiplied on the
        cancer cell membranes. The combination of these drugs presently approved by the EMA for first
        line treatment of mHNPC are understood to be given maximum androgen blockage and to be used
        until progression. All have been shown to positively impact overall survival. For patients,
        however, the consequences of continuous intensified MAB, and thereby testosterone
        suppression, have impacted their quality of life, especially in the form of fatigue,
        emotional distress, decrease of libido and loss of sexual function. This is in addition to
        toxicities linked to the mechanisms of these drugs which include cardiovascular diseases,
        cognitive effects and loss of bone mineral density.
  
        Treatment optimization is rarely addressed by clinical trials run for registration purposes.
        Toxicity is subsumed under efficacy and keeping the cancer at bay or controlled at any cost.
        Overall patient experience is not taken into account when determining what is an acceptable
        trade-off. Intermittent treatment or drug holiday are options to manage drug toxicities but
        longer off-treatment periods remain rare due to the fear of losing efficacy.
  
        Prostate cancer is an ideal setting to study the benefits of intermittent treatment as PSA
        levels have been shown to be a good indicator of cancer status. By holding androgen blockade
        after good PSA response, patients get the opportunity of seeing an improvement in their
        quality of life as testosterone levels slowly recover. The longer a patient stays off
        treatment, the more improvements to his overall wellbeing can be felt. Monitoring PSA levels
        provides an early signal to cancer regrowth and allows for the restart of MAB when it becomes
        necessary.
  
        While improving the patient's quality of life, there is as yet no indication as to the
        possible impact of this approach on overall survival. Alternating off/on treatment could
        delay both the start of the next line of treatment and the development of castration
        resistance but the absence of constant androgen suppression could also have the opposite
        effect and precipitate new alternatives to cancer cells testosterone dependence.
  
        This trial will randomize patients to either continue with their treatment as prescribed or
        to stop treatment until PSA levels indicate the necessity of restarting suppression. The
        latter group can stop treatment again when PSA levels reaches 0.2 ng/mL or lower. There is a
        need to investigate whether the benefit to patient's lives of holding long-term treatment
        will outweigh the risks of shortening overall survival. This trial is being done to allow
        both patients and their treating teams to have the data needed to make an informed decision
        on the best treatment approach.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: overall survival
  time frame: 3 years from randomisation
  description: the overall survival (OS) at 3 years using an iMAB regimen is non-inferior to continuous treatment.
  measure: proportion of patients who do not restart their hormonal therapy within 1 year of interrupting their MAB therapy (given as part of the induction phase)
  time frame: 1 year from stopping the MAB therapy
  description: proportion of patients who do not restart within 1 year of interrupting their MAB therapy (given as part of the induction phase) is not less than 70%
  measure: occurrence of adverse events
  time frame: 5 years from randomisation
  description: Safety according to the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0 for toxicity and Serious Adverse Event reporting.
  measure: Time spent on MAB treatment
  time frame: 5 years from randomisation
  description: the overall time in months that the patient was on MAB treatment
  measure: Time to next systemic prostate cancer therapy
  time frame: 5 years from randomisation
  description: the overall time in months until the patient began the next systemic prostate cancer therapy
  measure: The magnitude of change in HRQoL
  time frame: 60 months from randomisation
  description: The magnitude of change in HRQoL in terms of physical functioning from EORTC QLQ-C30
  measure: The magnitude of change in HRQoL
  time frame: 60 months from randomisation
  description: The magnitude of change in HRQoL in terms of sexual activity scale of EORTC QLQ PR25
  measure: The magnitude of change in HRQoL
  time frame: 60 months from randomisation
  description: The magnitude of change in HRQoL in terms of pain characteristics from the IL249 item list; To cover all important HRQoL domains and to have more granularity on some of the selected domains, additional HRQoL concepts are searched in the EORTC item library. This resulted in the inclusion of an additional scale that measures the pain characteristics.
  The selected scale and corresponding items address the pain characteristics (the nature of the pain: constant versus intermittent and whether the pain can be relieved by pain medications)
  measure: The magnitude of change in HRQoL
  time frame: 60 months from randomisation
  description: The magnitude of change in HRQoL in terms of physical fatigue from the IL249 item list; To cover all important HRQoL domains and to have more granularity on some of the selected domains, additional HRQoL concepts are searched in the EORTC item library. This resulted in the inclusion of an additional scale that measures the physical fatigue.
  The selected scale and corresponding items address the energy levels, exhaustion, sleepiness.
  measure: health utility derived from the QLQ-C30 questionnaires data
  time frame: 5 years from randomisation
  description: Health utility derived from patient reported QLQ-C30 data and patient demographics;Health utilities summarize a patient's overall health status, and this parameter can be applied in cost-effectiveness analyses. Published mapping algorithms can be used to calculate health utility based on the collected QLQ-C30 data, either directly or indirectly. The indirect algorithms first maps QLQ-C30 scores to European Quality-of-Life-5 Dimensions (EQ-5D) scores and then to health utility scores. The collected HRQoL data using QLQ-C30 will be mapped first to EQ-5D scores using an established mapping approach from the literature, and then further translated to health utility values for each study subject and at each assessment of HRQoL, taking into account published national value sets for this conversion.
  arm group label: Arm A - continuous treatment
  arm group type: Active Comparator
  description: Arm A (cMAB): ADT (LHRH agonist or antagonist) + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide) continuously until start of a new anti-cancer therapy.
  arm group label: Arm B - intermittent treatment
  arm group type: Experimental
  description: Arm B (iMAB): no further treatment, including ADT and ARPI; decision to restart ADT (LHRH agonist or antagonist) and the initial ARPI (abiraterone, enzalutamide, apalutamide or darolutamide) is left at Investigator discretion.
  intervention type: Drug
  intervention name: iMAB
  description: no treatment until significant PSA increase as per treating physician at which point patient restarts ADT (LHRH agonist or antagonist) + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide). Once PSA < 0.2 ng/mL, treatment stops again.
  arm group label: Arm B - intermittent treatment
  other name: intermittent maximum androgen blockade
  intervention type: Drug
  intervention name: cMAB
  description: LHRH agonist or antagonist + ARPI (abiraterone or enzalutamide or apalutamide or darolutamide)
  arm group label: Arm A - continuous treatment
  other name: continuous maximum androgen blockade
  criteria: 
  gender: Male
  minimum age: 18 Years
  maximum age: 100 Years
  healthy volunteers: No
  last name: Bertrand Tombal, Prof
  role: Study Chair
  affiliation: Cliniques Universitaires de Saint Luc
  last name: Silke Gillessen, Prof
  role: Study Chair
  affiliation: Oncology Institute of Southern Switzerland - Ospedale San Giovanni
  last name: EORTC
  phone: +3227741611
  email: eortc@eortc.org
  responsible party type: Sponsor
  mesh term: Prostatic Neoplasms
  mesh term: Ascorbic Acid
  mesh term: Methyltestosterone
  mesh term: Androgens
  mesh term: Estrogens, Conjugated (USP)