<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/NCT02227082</url>
  </required_header>
  <id_info>
    <org_study_id>N13ORB</org_study_id>
    <secondary_id>2011-001586-40</secondary_id>
    <nct_id>NCT02227082</nct_id>
  </id_info>
  <brief_title>Olaparib and Radiotherapy in Inoperable Breast Cancer</brief_title>
  <official_title>Olaparib Dose Escalation in Combination With High Dose Radiotherapy to the Breast Andregional Lymph Nodes in Patients With Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Netherlands Cancer Institute</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 majority of breast cancer patients receive radiotherapy as part of their treatment.&#xD;
      Radiotherapy improves both locoregional control and overall survival. In most patients with&#xD;
      breast cancer the locoregional recurrence rate (LRR) is low, however still high LRRs are&#xD;
      found in certain patient groups, especially in locally advanced, inflammatory and triple&#xD;
      negative breast cancer. Olaparib is a potent PARP inhibitor developed as an anti-cancer drug&#xD;
      for homologous recombination (HR) defected tumors and as a dose intensifier for chemo- and&#xD;
      radiotherapy. The combination of olaparib and radiotherapy is expected to improve&#xD;
      locoregional control and thereby overall survival in both breast cancer patients with a high&#xD;
      probability of locoregional recurrence and patients with HR deficient tumors. However, this&#xD;
      combination treatment has never been tested in humans before. The purpose of this study is to&#xD;
      determine the safety and tolerability of radiotherapy to the breast and regional lymph nodes&#xD;
      with concurrent olaparib.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 21, 2013</start_date>
  <completion_date type="Actual">August 2020</completion_date>
  <primary_completion_date type="Actual">September 2019</primary_completion_date>
  <phase>Phase 1</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>The incidence of dose limiting toxicities.</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Acute toxicity</measure>
    <time_frame>3 months after treatment</time_frame>
    <description>severity, duration and relation with treatment of all adverse events according to CTCAE version 4.03 occurring from start of treatment until 3 months after end of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Late toxicity</measure>
    <time_frame>3 months until 2 years after end of treatment</time_frame>
    <description>severity, duration and relation with treatment of all adverse events that are possibly, probably or definitely related to the combination treatment according to CTCAE version 4.03</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Locally Advanced Malignant Neoplasm</condition>
  <condition>Inflammatory Breast Carcinoma</condition>
  <condition>Triple-Negative Invasive Breast Carcinoma</condition>
  <arm_group>
    <arm_group_label>radiotherapy and olaparib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>radiotherapy: 61.18 Gy olaparib: dose escalating</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>radiotherapy</intervention_name>
    <description>The whole breast and regional lymph nodes will receive 23 x 2.03 Gy per fraction (total 46.69 Gy) At the macroscopic tumor a added SIB will be given of 23 x 0.63Gy . Total dose: 61.18 Gy</description>
    <arm_group_label>radiotherapy and olaparib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>olaparib</intervention_name>
    <description>The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, 300 and 400 mg BID</description>
    <arm_group_label>radiotherapy and olaparib</arm_group_label>
    <other_name>AZD2281</other_name>
    <other_name>KU-0059436</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  ≥18 years of age&#xD;
&#xD;
          -  Histological proven breast cancer or local recurrence of breast cancer which is&#xD;
             inoperable or/and metastatic, including inflammatory breast cancer&#xD;
&#xD;
          -  No participation in trial with neoadjuvant systemic treatment, except for previous&#xD;
             contralateral breast cancer&#xD;
&#xD;
          -  Tumor in breast accessible for biopsy&#xD;
&#xD;
          -  WHO performance 0-2&#xD;
&#xD;
          -  Life expectancy of at least 6 months&#xD;
&#xD;
          -  Adequate hematological, renal and hepatic functions&#xD;
&#xD;
          -  Hemoglobin 6.2 mmol/l&#xD;
&#xD;
          -  Leucocytes 3.0 x 10E9/l&#xD;
&#xD;
               -  Absolute neutrophil count 1.5x10E9/l&#xD;
&#xD;
               -  Platelet count 100 x 10E9/l&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x ULN&#xD;
&#xD;
               -  ASAT/ALAT ≤ 2.5 x ULN; or in the presence of liver metastases ≤ 5 x ULN&#xD;
&#xD;
               -  Creatinine clearance 50 ml/min; measured or calculated&#xD;
&#xD;
          -  Evidence of non-childbearing status for women of childbearing potential: negative&#xD;
             urine or serum pregnancy test within 21 days of study treatment. Non-childbearing&#xD;
             potential or postmenopausal is defined as:&#xD;
&#xD;
               -  Amenorrheic for 1 year or more following cessation of exogenous hormonal&#xD;
                  treatments&#xD;
&#xD;
               -  LH and FSH levels in post menopausal range for women under 50 years of age&#xD;
&#xD;
               -  Radiation-induced oophorectomy with last menses &gt; 1 year ago&#xD;
&#xD;
               -  Chemotherapy-induced menopause with &gt; 1 year interval since last menses&#xD;
&#xD;
               -  Surgical sterilisation (bilateral oophorectomy or hysterectomy)&#xD;
&#xD;
          -  Patients of reproductive potential must agree to practice two effective medically&#xD;
             approved contraceptive method during the trial and 3 months afterwards&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy,&#xD;
             immunotherapy or use of other investigational agents within 3 weeks prior to start of&#xD;
             therapy (or a longer period depending on the defined characteristics of the agents&#xD;
             used e.g. 6 weeks for mitomycin ornitrosourea). Patient may continue the use of&#xD;
             tamoxifen, aromatase inhibitor and LHRH agonists for cancer; bisphosphonates for bone&#xD;
             disease and corticosteroids. The use of denosumab for bone disease is not allowed.&#xD;
&#xD;
          -  Major surgery within two weeks of starting study treatment.&#xD;
&#xD;
          -  Participation in other trial with investigational drug or treatment modality&#xD;
&#xD;
          -  Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence&#xD;
             of brain metastases is not required.&#xD;
&#xD;
          -  Prior ipsilateral radiotherapy to the chest or breast.&#xD;
&#xD;
          -  Blood transfusion in the four weeks prior to study entry&#xD;
&#xD;
          -  Persistent toxicities (CTC ≥ grade 2) with the exception of alopecia, caused by&#xD;
             previous cancer therapy&#xD;
&#xD;
          -  QT-interval &gt; 470 msec&#xD;
&#xD;
          -  Significant cardiovascular disease as defined by&#xD;
&#xD;
               -  History of congestive heart failure defined as NYHA class III&#xD;
&#xD;
               -  History of unstable angina pectoris or myocardial infarction up to 3 months prior&#xD;
                  to trial entry;&#xD;
&#xD;
               -  Presence of severe valvular heart disease&#xD;
&#xD;
               -  Presence of a ventricular arrhythmia requiring treatment;&#xD;
&#xD;
               -  Uncontrolled hypertension&#xD;
&#xD;
          -  Patients considered a poor medical risk due to:&#xD;
&#xD;
               -  non-malignant systemic disease&#xD;
&#xD;
               -  active, uncontrolled infection requiring parenteral antibiotics&#xD;
&#xD;
               -  a serious, uncontrolled medical disorder; examples include, but are not limited&#xD;
                  to:&#xD;
&#xD;
                    -  uncontrolled major seizure disorder&#xD;
&#xD;
                    -  unstable spinal cord compression&#xD;
&#xD;
                    -  superior vena cava syndrome&#xD;
&#xD;
                    -  extensive bilateral lung disease on HRCT scan&#xD;
&#xD;
                    -  any psychiatric disorder that prohibits obtaining informed consent.&#xD;
&#xD;
          -  Any psychological, familial, sociological or geographical condition potentially&#xD;
             hampering compliance with the study protocol and follow-up schedule.&#xD;
&#xD;
          -  Patients who are known to be serologically positive for human immunodeficiency virus&#xD;
             (HIV) and are receiving antiviral therapy.&#xD;
&#xD;
          -  Patients with known active hepatic disease (i.e. Hepatitis B or C)&#xD;
&#xD;
          -  Patients with myelodysplastic syndrome/acute myeloid leukaemia or features suggestive&#xD;
             of MDS/AML on peripheral blood smear.&#xD;
&#xD;
          -  Gastrointestinal disorders that may interfere with absorption of the study drug or&#xD;
             patients who are not able to take oral medication&#xD;
&#xD;
          -  Concomitant medications:&#xD;
&#xD;
               -  Any previous treatment with a PARP inhibitor, including Olaparib&#xD;
&#xD;
               -  Patients receiving the following classes of inhibitors of CYP3A4 (see Section&#xD;
                  6.4.2 for guidelines and wash out periods)&#xD;
&#xD;
                    -  Azole antifungals&#xD;
&#xD;
                    -  Macrolide antibiotics&#xD;
&#xD;
                    -  Protease inhibitors&#xD;
&#xD;
          -  Patients with a known hypersensitivity to olaparib or any of the excipients of the&#xD;
             product&#xD;
&#xD;
          -  Breast-feeding women&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gabe Sonke, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Netherlands Cancer Institute</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Marcel verheij, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Netherlands Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Netherlands Cancer Institute</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>August 26, 2014</study_first_submitted>
  <study_first_submitted_qc>August 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2014</study_first_posted>
  <last_update_submitted>August 3, 2021</last_update_submitted>
  <last_update_submitted_qc>August 3, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 4, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>radiotherapy</keyword>
  <keyword>olaparib</keyword>
  <keyword>breast cancer</keyword>
  <keyword>locally advanced breast cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Inflammatory Breast Neoplasms</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/NCT02227082
org study id: N13ORB
secondary id: 2011-001586-40
nct id: NCT02227082
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The majority of breast cancer patients receive radiotherapy as part of their treatment.
      Radiotherapy improves both locoregional control and overall survival. In most patients with
      breast cancer the locoregional recurrence rate (LRR) is low, however still high LRRs are
      found in certain patient groups, especially in locally advanced, inflammatory and triple
      negative breast cancer. Olaparib is a potent PARP inhibitor developed as an anti-cancer drug
      for homologous recombination (HR) defected tumors and as a dose intensifier for chemo- and
      radiotherapy. The combination of olaparib and radiotherapy is expected to improve
      locoregional control and thereby overall survival in both breast cancer patients with a high
      probability of locoregional recurrence and patients with HR deficient tumors. However, this
      combination treatment has never been tested in humans before. The purpose of this study is to
      determine the safety and tolerability of radiotherapy to the breast and regional lymph nodes
      with concurrent olaparib.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The incidence of dose limiting toxicities.
time frame: 1 year
measure: Acute toxicity
time frame: 3 months after treatment
description: severity, duration and relation with treatment of all adverse events according to CTCAE version 4.03 occurring from start of treatment until 3 months after end of treatment
measure: Late toxicity
time frame: 3 months until 2 years after end of treatment
description: severity, duration and relation with treatment of all adverse events that are possibly, probably or definitely related to the combination treatment according to CTCAE version 4.03
arm group label: radiotherapy and olaparib
arm group type: Experimental
description: radiotherapy: 61.18 Gy olaparib: dose escalating
intervention type: Radiation
intervention name: radiotherapy
description: The whole breast and regional lymph nodes will receive 23 x 2.03 Gy per fraction (total 46.69 Gy) At the macroscopic tumor a added SIB will be given of 23 x 0.63Gy . Total dose: 61.18 Gy
arm group label: radiotherapy and olaparib
intervention type: Drug
intervention name: olaparib
description: The pre-defined dose levels of olaparib are 25mg QD, 25, 50, 100, 200, 300 and 400 mg BID
arm group label: radiotherapy and olaparib
other name: AZD2281
other name: KU-0059436
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gabe Sonke, MD, PhD
role: Principal Investigator
affiliation: The Netherlands Cancer Institute
last name: Marcel verheij, MD, PhD
role: Principal Investigator
affiliation: The Netherlands Cancer Institute
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Breast Neoplasms
mesh term: Neoplasms
mesh term: Inflammatory Breast Neoplasms
mesh term: Olaparib