<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/NCT01682772</url>
  </required_header>
  <id_info>
    <org_study_id>ICR-CTSU/2011/10030</org_study_id>
    <secondary_id>2011-000601-49</secondary_id>
    <secondary_id>CRUK/C12540/A12354</secondary_id>
    <secondary_id>ISRCTN15124653</secondary_id>
    <secondary_id>ISS22810018</secondary_id>
    <nct_id>NCT01682772</nct_id>
  </id_info>
  <brief_title>TOPARP: A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer</brief_title>
  <acronym>TOPARP</acronym>
  <official_title>A Phase II Trial of Olaparib in Patients With Advanced Castration Resistant Prostate Cancer (TOPARP)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institute of Cancer Research, United Kingdom</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Royal Marsden NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Institute of Cancer Research, United Kingdom</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open-label, single arm, two part adaptive design phase II trial of Olaparib in&#xD;
      patients with advanced castration resistant prostate cancer.&#xD;
&#xD;
      The trial aims to evaluate the the anti-tumour activity of Olaparib in metastatic castration&#xD;
      resistant prostate cancer, identify molecular signatures of tumour cells in responding and&#xD;
      non-responding patients, and to identify predictive biomarkers of Olaparib response.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with advanced castration resistant prostate cancer will receive single agent&#xD;
      Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle. Olaparib will be&#xD;
      administered until objective disease progression or unacceptable toxicity or patient&#xD;
      withdrawal for whatever reason&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">July 2012</start_date>
  <completion_date type="Anticipated">February 2020</completion_date>
  <primary_completion_date type="Actual">March 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>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>Response rate to Olaparib</measure>
    <time_frame>Response will be evaluated 6 months post trial entry</time_frame>
    <description>Response will be defined on the basis of the following outcomes, if any of these occur patients will be considered to have responded:&#xD;
Objective response by modified RECIST&#xD;
PSA decline of ≥50% according to the Prostate Cancer Working Group 2&#xD;
Conversion of circulating tumour cell count from ≥5 cells/7.5ml blood at baseline to &lt;5 cells/7.5ml blood confirmed by at least two readings 4 weeks apart</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Radiographic progression free survival</measure>
    <time_frame>Radiographic progression free survival will be evaluated 6 months post trial entry</time_frame>
    <description>rPFS will be defined by either RECIST progression and/or progression on bone scan. It will be measured from the date of trial entry to the first occurence of radiographic progression or death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression free survival</measure>
    <time_frame>Progression free survival will be evaluated 6 months post trial entry</time_frame>
    <description>PFS will be measured from date of trial entry until radiographic progression, unequivocal clinical progression or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to PSA Progression</measure>
    <time_frame>Time to PSA progression will be evaluated 6 months post trial entry</time_frame>
    <description>For patients who have achieved ≥50% decrease from the cycle 1 day 1 (baseline), the PSA progression date is defined as the date that a ≥25% increase and an absolute increase of ≥2ng.mL above the nadir is documented. This must be confirmed by a second consecutive value. For patients without a PSA decrease of this magnitude or no decrease at all, PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline is documented. This must also be confirmed by a second consecutive value.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CTC count conversion rate</measure>
    <time_frame>CTC count conversion rate will be evaluated 6 months post trial entry</time_frame>
    <description>Proportion of patients with conversion of CTC count from ≥5/7.5ml blood at baseline to &lt;5/7.5ml blood nadir</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of PSA response</measure>
    <time_frame>Duration of PSA response will be evaluated 6 months post trial entry</time_frame>
    <description>Duration of PSA response is calculated from the time the PSA value first declines by at least 50% of the cycle 1 day 1 (baseline) value (must be confirmed by a second value) until the time there is an increase of 25% of PSA nadir, provided the absolute increase is at least 2 ng/mL. The increase must be confirmed by a second consecutive measurement.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with grade 3 or 4 adverse events as a measure of safety and tolerability.</measure>
    <time_frame>Will be evaluated 1) when the first 5 and 10 participants have completed the 1st cycle of treatment and, 2) at 6 months post trial entry.</time_frame>
    <description>The proportion of patients with grade 3/4 adverse events will be described along with other descriptive measures of safety and tolerability and evaluated by the IDMC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to radiographic progression</measure>
    <time_frame>Will be evaluated 6 months post trial entry</time_frame>
    <description>Time to radiographic progression (progression defined by either RECIST progression and /or progression on bone scan) will be measured from the date of trial entry to the first occurrence of radiographic progression. Death from prostate cancer or any other cause without prior radiographic evidence of progression will not count as an event.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Will be evaluated 6 months post trial entry</time_frame>
    <description>OS will be measured from the date of trial entry to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow-up</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PSA objective response</measure>
    <time_frame>Will be evaluated 6 months post trial entry</time_frame>
    <description>PSA response and PSA progression are defined according to the consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">148</enrollment>
  <condition>Adenocarcinoma of the Prostate</condition>
  <arm_group>
    <arm_group_label>Olaparib 400mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Olaparib 300mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral Olaparib at a dose of 300mg twice daily, continuously on a 28 day cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Olaparib</intervention_name>
    <description>Until objective disease progression, unacceptable toxicity or patient withdrawal for whatever reason</description>
    <arm_group_label>Olaparib 300mg</arm_group_label>
    <arm_group_label>Olaparib 400mg</arm_group_label>
    <other_name>AZD2281</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subject capable of understanding &amp; complying with protocol requirements &amp; signed the&#xD;
             informed consent form&#xD;
&#xD;
          2. Minimum age 18 years&#xD;
&#xD;
          3. Histologically confirmed adenocarcinoma of the prostate with tumour tissue available&#xD;
             for molecular analyses&#xD;
&#xD;
          4. At least one but no more than two previous taxane-based chemotherapy regimens. If&#xD;
             docetaxel chemotherapy is used more than once, this will be considered as one regime.&#xD;
             Patients may have had prior exposure to cabazitaxel treatment&#xD;
&#xD;
          5. At least 28 days since the completion of prior therapy, including major surgery,&#xD;
             chemotherapy &amp; other investigational agents. Clinically relevant sequelae should have&#xD;
             resolved to grade 1 or less prior to recommencing treatment. For hormonal treatment &amp;&#xD;
             radiotherapy refer to the protocol guidelines&#xD;
&#xD;
          6. Documented prostate cancer progression as described in the protocol.&#xD;
&#xD;
          7. Surgically or medically castrated, with testosterone levels of &lt; 50 ng/dL (&lt; 2.0 nM).&#xD;
             If the patient is being treated with LHRH agonists this must have been initiated at&#xD;
             least 4 weeks prior to Cycle 1 Day 1 &amp; must be continued throughout the study.&#xD;
&#xD;
          8. Eastern Cooperative Oncology Group Performance Status of 0, 1, 2&#xD;
&#xD;
          9. Life expectancy &gt; 12 weeks&#xD;
&#xD;
         10. Able to swallow a whole tablet&#xD;
&#xD;
         11. Patient &amp; the patient's partner of childbearing potential, must agree to use medically&#xD;
             accepted methods of contraception during the course of the study &amp; for 3 months after&#xD;
             the last dose of study drug&#xD;
&#xD;
         12. Agreeable to have all the biomarker studies including the paired fresh tumour&#xD;
             biopsies.&#xD;
&#xD;
         13. CTC count of 5 cells/7.5mls blood or more at screening. Note: For Part B, CTC count &gt;5&#xD;
             cells/7.5mls blood is not mandatory if patient has measurable disease by modified&#xD;
             RECIST and a lesion &gt;2cm and PSA greater than or equal to 2ng/ml at screening.&#xD;
&#xD;
         14. Adequate bone marrow, hepatic &amp; renal function as defined in the protocol&#xD;
&#xD;
         15. For Part B only, patients must have genomic defects associated with olaparib&#xD;
             sensitivity identified by NGS by the central lab.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Surgery, or local prostatic intervention (excluding a prostatic biopsy) less than 28&#xD;
             days of Cycle 1 Day 1&#xD;
&#xD;
          2. Less than 28 days from any active anticancer therapy or investigational agents. For&#xD;
             hormonal treatment &amp; radiotherapy refer to the guidelines outlined in the inclusion&#xD;
             criteria&#xD;
&#xD;
          3. Prior treatment with a PARP inhibitor, platinum, cyclophosphamide or mitoxantrone&#xD;
             chemotherapy&#xD;
&#xD;
          4. Uncontrolled intercurrent illness including, but not limited to, active infection,&#xD;
             symptomatic congestive heart failure (New York Heart Association Class III or IV heart&#xD;
             disease), unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension or&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements&#xD;
&#xD;
          5. Any acute toxicities due to prior chemotherapy &amp; / or radiotherapy that have not&#xD;
             resolved to a NCI-CTCAE v4.02 grade 0 or 1 with the exception of chemotherapy induced&#xD;
             alopecia &amp; grade 2 peripheral neuropathy&#xD;
&#xD;
          6. Malignancy within the previous 2-years with a &gt; 30% probability of recurrence within&#xD;
             12 months with the exception of non-melanoma skin cancer, in-situ or superficial&#xD;
             bladder cancer&#xD;
&#xD;
          7. Patients with myelodysplastic syndrome/acute myeloid leukaemia&#xD;
&#xD;
          8. Patients with known symptomatic brain metastasis are not suitable for enrollment.&#xD;
             Patients with asymptomatic, stable, treated brain metastases are eligible for study&#xD;
             entry&#xD;
&#xD;
          9. Patients with symptomatic or impending cord compression unless appropriately treated&#xD;
             beforehand &amp; clinically stable &amp; asymptomatic&#xD;
&#xD;
         10. Patients who have experienced a seizure or seizures within 6 months of study treatment&#xD;
             or who are currently being treated with cytochrome P450 enzyme inducing anti-epileptic&#xD;
             drugs for seizures&#xD;
&#xD;
         11. Patients receiving any of the following classes of inhibitors of CYP3A4 (see protocol&#xD;
             for guidelines &amp; wash out periods)&#xD;
&#xD;
         12. Patients with gastrointestinal disorders likely to interfere with absorption of the&#xD;
             study medication&#xD;
&#xD;
         13. Initiating bisphosphonate therapy or adjusting bisphosphonate dose/regimen within 30&#xD;
             days prior to Cycle 1 Day 1. Patients on a stable bisphosphonate regimen are eligible&#xD;
             &amp; may continue&#xD;
&#xD;
         14. Presence of a condition or situation, which, may put the patient at significant risk,&#xD;
             confound the study results, or interfere significantly with participation in the study&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Johann de Bono</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institute of Cancer Research, United Kingdom</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Royal Marsden NHS Foundation Trust</name>
      <address>
        <city>Sutton</city>
        <state>Surrey</state>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University College Hospital London</name>
      <address>
        <city>London</city>
        <zip>NW1 2BU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>July 27, 2012</study_first_submitted>
  <study_first_submitted_qc>September 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2012</study_first_posted>
  <last_update_submitted>August 13, 2019</last_update_submitted>
  <last_update_submitted_qc>August 13, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Olaparib</keyword>
  <keyword>Adenocarcinoma</keyword>
  <keyword>Prostate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenocarcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Olaparib</mesh_term>
  </intervention_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/NCT01682772
org study id: ICR-CTSU/2011/10030
secondary id: 2011-000601-49
secondary id: CRUK/C12540/A12354
secondary id: ISRCTN15124653
secondary id: ISS22810018
nct id: NCT01682772
lead sponsor: 
collaborator: 
has dmc: Yes
This is an open-label, single arm, two part adaptive design phase II trial of Olaparib in
      patients with advanced castration resistant prostate cancer.

      The trial aims to evaluate the the anti-tumour activity of Olaparib in metastatic castration
      resistant prostate cancer, identify molecular signatures of tumour cells in responding and
      non-responding patients, and to identify predictive biomarkers of Olaparib response.
Patients with advanced castration resistant prostate cancer will receive single agent
      Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle. Olaparib will be
      administered until objective disease progression or unacceptable toxicity or patient
      withdrawal for whatever reason
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Response rate to Olaparib
time frame: Response will be evaluated 6 months post trial entry
description: Response will be defined on the basis of the following outcomes, if any of these occur patients will be considered to have responded:
Objective response by modified RECIST
PSA decline of ≥50% according to the Prostate Cancer Working Group 2
Conversion of circulating tumour cell count from ≥5 cells/7.5ml blood at baseline to <5 cells/7.5ml blood confirmed by at least two readings 4 weeks apart
measure: Radiographic progression free survival
time frame: Radiographic progression free survival will be evaluated 6 months post trial entry
description: rPFS will be defined by either RECIST progression and/or progression on bone scan. It will be measured from the date of trial entry to the first occurence of radiographic progression or death from any cause
measure: Progression free survival
time frame: Progression free survival will be evaluated 6 months post trial entry
description: PFS will be measured from date of trial entry until radiographic progression, unequivocal clinical progression or death
measure: Time to PSA Progression
time frame: Time to PSA progression will be evaluated 6 months post trial entry
description: For patients who have achieved ≥50% decrease from the cycle 1 day 1 (baseline), the PSA progression date is defined as the date that a ≥25% increase and an absolute increase of ≥2ng.mL above the nadir is documented. This must be confirmed by a second consecutive value. For patients without a PSA decrease of this magnitude or no decrease at all, PSA progression date is defined as the date that a ≥ 25% increase and an absolute increase of ≥ 2 ng/mL above the baseline is documented. This must also be confirmed by a second consecutive value.
measure: CTC count conversion rate
time frame: CTC count conversion rate will be evaluated 6 months post trial entry
description: Proportion of patients with conversion of CTC count from ≥5/7.5ml blood at baseline to <5/7.5ml blood nadir
measure: Duration of PSA response
time frame: Duration of PSA response will be evaluated 6 months post trial entry
description: Duration of PSA response is calculated from the time the PSA value first declines by at least 50% of the cycle 1 day 1 (baseline) value (must be confirmed by a second value) until the time there is an increase of 25% of PSA nadir, provided the absolute increase is at least 2 ng/mL. The increase must be confirmed by a second consecutive measurement.
measure: Number of participants with grade 3 or 4 adverse events as a measure of safety and tolerability.
time frame: Will be evaluated 1) when the first 5 and 10 participants have completed the 1st cycle of treatment and, 2) at 6 months post trial entry.
description: The proportion of patients with grade 3/4 adverse events will be described along with other descriptive measures of safety and tolerability and evaluated by the IDMC
measure: Time to radiographic progression
time frame: Will be evaluated 6 months post trial entry
description: Time to radiographic progression (progression defined by either RECIST progression and /or progression on bone scan) will be measured from the date of trial entry to the first occurrence of radiographic progression. Death from prostate cancer or any other cause without prior radiographic evidence of progression will not count as an event.
measure: Overall survival
time frame: Will be evaluated 6 months post trial entry
description: OS will be measured from the date of trial entry to the date of death (whatever the cause). Survival time of living patients will be censored on the last date a patient is known to be alive or lost to follow-up
measure: PSA objective response
time frame: Will be evaluated 6 months post trial entry
description: PSA response and PSA progression are defined according to the consensus guidelines of the Prostate Cancer Clinical Trials Working Group 2.
arm group label: Olaparib 400mg
arm group type: Experimental
description: Oral Olaparib at a dose of 400mg twice daily, continuously on a 28 day cycle
arm group label: Olaparib 300mg
arm group type: Experimental
description: Oral Olaparib at a dose of 300mg twice daily, continuously on a 28 day cycle
intervention type: Drug
intervention name: Olaparib
description: Until objective disease progression, unacceptable toxicity or patient withdrawal for whatever reason
arm group label: Olaparib 300mg
arm group label: Olaparib 400mg
other name: AZD2281
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Johann de Bono
role: Principal Investigator
affiliation: Institute of Cancer Research, United Kingdom
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Olaparib