<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/NCT02223923</url>
  </required_header>
  <id_info>
    <org_study_id>CCR4087</org_study_id>
    <nct_id>NCT02223923</nct_id>
  </id_info>
  <brief_title>Phase I Study to Assess Safety of AZD6738 Alone and in Combination With Radiotherapy in Patients With Solid Tumours</brief_title>
  <acronym>Patriot</acronym>
  <official_title>A Phase I Study to Assess the Tolerability, Safety and Biological Effects of ATR Inhibitor (AZD6738) as a Single Agent and in Combination With Palliative Radiation Therapy in Patients With Solid Tumours</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Royal Marsden NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cancer Research UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>RM/ICR Biomedical Research Centre</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Royal Marsden NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will investigate the use of a new drug targeting the DNA repair pathway AZD6738,&#xD;
      an ATR inhibitor). Many tumours have lost important DNA repair functions and rely more&#xD;
      heavily on a few remaining repair pathways to survive. Preclinical studies indicate that, in&#xD;
      these tumours, preventing the function of the remaining pathways will lead to tumour cell&#xD;
      death, while sparing normal cells. This study aims to investigate the safety and tolerability&#xD;
      of the new drug in patients with advanced cancer, as well as in combination with palliative&#xD;
      radiotherapy, where the drug may increase the effectiveness of radiotherapy by preventing&#xD;
      repair of the radiationinduced DNA damage. As the drug has only been given to a small number&#xD;
      of patients, the study will focus on safety and finding the correct dose to proceed to&#xD;
      further studies, although preliminary signs of drug activity will also be examined.&#xD;
&#xD;
      The initial part of the study will administer increasing doses of the drug to groups of&#xD;
      patients with advanced cancer who have no standard anticancer treatment options available.&#xD;
      Testing will establish whether the drug levels in the body and tumour are adequate for the&#xD;
      drug to have an effect, and any toxicity will be assessed. After the recommended dose is&#xD;
      established, the recommended dose schedule will be stablished by trialing different&#xD;
      schedules. Participants will be tested to see if their tumours lack the main DNA repair&#xD;
      pathway (those who are predicted to have a better response to this drug). Finally, the drug&#xD;
      will be given to patients with advanced cancer who require a course of radiotherapy for&#xD;
      symptom control - the drug will be tested at different doses and with different doses of&#xD;
      radiotherapy.&#xD;
&#xD;
      Side effects will be monitored and tests will establish whether the drug is enhancing the&#xD;
      radiotherapy effect in the tumours or normal tissues.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>July 2014</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Identifying the maximum tolerated dose (MTD) of AZD6738 as a single-agent; and in combination with palliative radiation schedules.</measure>
    <time_frame>4 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Determining causality of each adverse event in relation to AZD6738 and grading severity according to CTCAE version 4;</measure>
    <time_frame>4 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Single and multiple dose pharmacokinetics: measurement of plasma levels of AZD6738 at pre-defined intervals in the dose-escalation part of the study in order to establish pharmacokinetic parameters;</measure>
    <time_frame>Day 0 and Day 1</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Any response (stable disease, partial response or complete response) in any of the patients by physical, tumour marker and/or radiographic assessments of tumours as determined by RECIST 1.1.</measure>
    <time_frame>8 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Solid Tumour Refractory to Conventional Treatment</condition>
  <arm_group>
    <arm_group_label>Dose Escalation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AZD6738 PO 20 to 380mg BD increasing</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AZD6738 - Expansion Phase</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AZD6738 starting dose and regimen to be determined in dose escalation phase</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AZD6738 + Radiotherapy (Head and Neck)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>AZD6738 + Radiotherapy (Abdomen / Pelvis)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD6738</intervention_name>
    <arm_group_label>AZD6738 + Radiotherapy (Abdomen / Pelvis)</arm_group_label>
    <arm_group_label>AZD6738 + Radiotherapy (Head and Neck)</arm_group_label>
    <arm_group_label>AZD6738 - Expansion Phase</arm_group_label>
    <arm_group_label>Dose Escalation</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Palliative radiotherapy</intervention_name>
    <arm_group_label>AZD6738 + Radiotherapy (Abdomen / Pelvis)</arm_group_label>
    <arm_group_label>AZD6738 + Radiotherapy (Head and Neck)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically documented solid tumour refractory to conventional&#xD;
             treatment&#xD;
&#xD;
          -  Evidence of measurable or evaluable disease by RECIST 1.1&#xD;
&#xD;
          -  Age must be 18 years or over.&#xD;
&#xD;
          -  ECOG performance status 0-1 (part A); 0-2 (parts B and C)&#xD;
&#xD;
          -  Life expectancy of at least 3 months.&#xD;
&#xD;
          -  Patients must have normal organ and bone marrow function measured within 7 days prior&#xD;
             to administration of study treatment as defined below:&#xD;
&#xD;
          -  Signed informed consent indicating that the subject is aware of the neoplastic nature&#xD;
             of their disease and have been informed of the procedures to be followed, the&#xD;
             experimental nature of the therapy, alternatives, potential benefits, side effects,&#xD;
             risks, and discomforts.&#xD;
&#xD;
          -  Willing and able to comply with scheduled visits, tissue sampling, treatment plan, and&#xD;
             laboratory tests.&#xD;
&#xD;
          -  Able to swallow, absorb and retain oral medication.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Therapy with any other investigational medical product (IMP) concurrently or within 28&#xD;
             days prior to signing of consent.&#xD;
&#xD;
          -  Pregnant or breast-feeding women.&#xD;
&#xD;
          -  Ability to become pregnant (or already pregnant or lactating).&#xD;
&#xD;
          -  Clinically significant cardiac disease including:&#xD;
&#xD;
          -  Known HIV positive or active hepatitis B or C infection&#xD;
&#xD;
          -  Uncontrolled active infection&#xD;
&#xD;
          -  Symptomatic and progressive or steroid-requiring brain metastases or leptomeningeal&#xD;
             disease involvement.&#xD;
&#xD;
          -  Uncontrolled hypertension requiring clinical intervention, hypertension requiring 2 or&#xD;
             more antihypertensive agents&#xD;
&#xD;
          -  Dementia or altered mental status that would prohibit informed consent.&#xD;
&#xD;
          -  Other severe, acute, or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration or may interfere with the interpretation of study results and, in&#xD;
             the judgment of the Principal Investigator, would make the subject inappropriate for&#xD;
             this study.&#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>Kevin Harrington, MBBS MRCP FRCR</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institute of Cancer Research, United Kingdom</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Martin Forster</last_name>
    <role>Principal Investigator</role>
    <affiliation>University College London Hospitals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University College Hospital</name>
      <address>
        <city>London</city>
        <zip>NW1 2BU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Guys and St Thomas' NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SE1 9RT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Marsden Hospital</name>
      <address>
        <city>London</city>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>August 21, 2014</study_first_submitted>
  <study_first_submitted_qc>August 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2014</study_first_posted>
  <last_update_submitted>April 7, 2020</last_update_submitted>
  <last_update_submitted_qc>April 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Phase 1</keyword>
  <keyword>Maximimum tolerated dose</keyword>
  <keyword>ATR Inhibitor</keyword>
  <keyword>Radiotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <!-- 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/NCT02223923
org study id: CCR4087
nct id: NCT02223923
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
This study will investigate the use of a new drug targeting the DNA repair pathway AZD6738,
      an ATR inhibitor). Many tumours have lost important DNA repair functions and rely more
      heavily on a few remaining repair pathways to survive. Preclinical studies indicate that, in
      these tumours, preventing the function of the remaining pathways will lead to tumour cell
      death, while sparing normal cells. This study aims to investigate the safety and tolerability
      of the new drug in patients with advanced cancer, as well as in combination with palliative
      radiotherapy, where the drug may increase the effectiveness of radiotherapy by preventing
      repair of the radiationinduced DNA damage. As the drug has only been given to a small number
      of patients, the study will focus on safety and finding the correct dose to proceed to
      further studies, although preliminary signs of drug activity will also be examined.

      The initial part of the study will administer increasing doses of the drug to groups of
      patients with advanced cancer who have no standard anticancer treatment options available.
      Testing will establish whether the drug levels in the body and tumour are adequate for the
      drug to have an effect, and any toxicity will be assessed. After the recommended dose is
      established, the recommended dose schedule will be stablished by trialing different
      schedules. Participants will be tested to see if their tumours lack the main DNA repair
      pathway (those who are predicted to have a better response to this drug). Finally, the drug
      will be given to patients with advanced cancer who require a course of radiotherapy for
      symptom control - the drug will be tested at different doses and with different doses of
      radiotherapy.

      Side effects will be monitored and tests will establish whether the drug is enhancing the
      radiotherapy effect in the tumours or normal tissues.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Identifying the maximum tolerated dose (MTD) of AZD6738 as a single-agent; and in combination with palliative radiation schedules.
time frame: 4 weeks
measure: Determining causality of each adverse event in relation to AZD6738 and grading severity according to CTCAE version 4;
time frame: 4 weeks
measure: Single and multiple dose pharmacokinetics: measurement of plasma levels of AZD6738 at pre-defined intervals in the dose-escalation part of the study in order to establish pharmacokinetic parameters;
time frame: Day 0 and Day 1
measure: Any response (stable disease, partial response or complete response) in any of the patients by physical, tumour marker and/or radiographic assessments of tumours as determined by RECIST 1.1.
time frame: 8 weeks
arm group label: Dose Escalation
arm group type: Experimental
description: AZD6738 PO 20 to 380mg BD increasing
arm group label: AZD6738 - Expansion Phase
arm group type: Experimental
description: AZD6738 starting dose and regimen to be determined in dose escalation phase
arm group label: AZD6738 + Radiotherapy (Head and Neck)
arm group type: Experimental
description: AZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)
arm group label: AZD6738 + Radiotherapy (Abdomen / Pelvis)
arm group type: Experimental
description: AZD6738 starting dose to be determined in dose escalation phase + increasing doses of radiotherapy (20 or 30Gy)
intervention type: Drug
intervention name: AZD6738
arm group label: AZD6738 + Radiotherapy (Abdomen / Pelvis)
arm group label: AZD6738 + Radiotherapy (Head and Neck)
arm group label: AZD6738 - Expansion Phase
arm group label: Dose Escalation
intervention type: Radiation
intervention name: Palliative radiotherapy
arm group label: AZD6738 + Radiotherapy (Abdomen / Pelvis)
arm group label: AZD6738 + Radiotherapy (Head and Neck)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kevin Harrington, MBBS MRCP FRCR
role: Principal Investigator
affiliation: Institute of Cancer Research, United Kingdom
last name: Martin Forster
role: Principal Investigator
affiliation: University College London Hospitals
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Neoplasms