<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/NCT02229656</url>
  </required_header>
  <id_info>
    <org_study_id>N13ORH</org_study_id>
    <secondary_id>2011-002963-79</secondary_id>
    <nct_id>NCT02229656</nct_id>
  </id_info>
  <brief_title>Olaparib and Radiotherapy in Head and Neck Cancer</brief_title>
  <official_title>Olaparib Dose Escalation Trial in Patients Treated With Radiotherapy for Stage II-III Laryngeal and Stage II-III HPV-negative Oropharyngeal Squamous Cell Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </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>
      Accelerated, normofractionated radiotherapy is the treatment of choice in stage II-III&#xD;
      laryngeal and oropharyngeal squamous cell carcinoma (SCC). However, twenty to thirty percent&#xD;
      of patients with stage II-III laryngeal and HPV negative oropharyngeal SCC develop disease&#xD;
      progression, mainly due to lack of locoregional control. Radiosensitizers such as cisplatin&#xD;
      and cetuximab are added to radiotherapy in more advanced stage of head and neck (H&amp;N) cancer.&#xD;
      These radiosensitizers improve loco-regional control and overall survival. Unfortunately, as&#xD;
      these radiosensitizers, notably cisplatin, also dose intensify the radiation dose in normal&#xD;
      tissues, they also significantly increase toxicity. Adding a more tumor-specific&#xD;
      radiosensitizing agent could improve loco-regional control and overall survival without&#xD;
      significantly increasing toxicity.&#xD;
&#xD;
      Radiotherapy kills tumor cells by inducing DNA damage. The efficacy of radiotherapy is&#xD;
      limited by the ability of tumor cells to repair this DNA damage. Poly(ADP-ribose)polymerase&#xD;
      (PARP) is an essential enzyme in base excision repair and single strand break DNA repair, DNA&#xD;
      lesions arising from radiation treatment. PARP inhibition and consequently the inhibition of&#xD;
      PARP-facilitated DNA repair enhances the anti-tumor activity of radiotherapy, as shown in&#xD;
      preclinical studies including head and neck xenograft studies. This radiosensitization is&#xD;
      thought to be proliferation dependent and is more pronounced in homologous recombination (HR)&#xD;
      deficient cells, providing an opportunity for tumor specific targeting. Genetic analyses&#xD;
      suggest that HR deficiency is commonly found in H&amp;N SCC: ATM loss has been reported in 60% of&#xD;
      human H&amp;N SCC biopsies and FANC-F defects were reported in 15-21% of human H&amp;N SCC biopsies&#xD;
      and cell lines.&#xD;
&#xD;
      The efficacy of radiotherapy is also limited by tumor hypoxia, as tumor hypoxia results in&#xD;
      radioresistance. Some PARP inhibiting compounds increase tumor perfusion in xenograft models,&#xD;
      thereby reducing hypoxia and specifically sensitizing tumor cells to radiotherapy. Hypoxia is&#xD;
      commonly found in H&amp;N SCC and a high pre-treatment hypoxic fraction in H&amp;N SCC tumors is&#xD;
      associated with worse outcome. The high prevalence of both hypoxia and HR deficiencies in H&amp;N&#xD;
      SCC support the concept of tumor-specific radiosensitization by PARP inhibition in head and&#xD;
      neck cancer patients.&#xD;
&#xD;
      Olaparib is a potent PARP inhibitor developed as an anti-cancer drug for HR defected tumors&#xD;
      and as a dose intensifier for chemo- and radiotherapy. In humans, olaparib has a low toxicity&#xD;
      profile as a single agent, with increasing bone marrow toxicity when combined with&#xD;
      chemotherapy. The combination of olaparib and radiotherapy for H&amp;N SCC is expected to improve&#xD;
      locoregional control and thereby overall survival. However, this combination treatment has&#xD;
      never been tested in humans before. The purpose of this study is to determine the safety and&#xD;
      tolerability of radiotherapy for stage II-III laryngeal and stage II-III HPV-negative&#xD;
      oropharyngeal SCC with concurrent olaparib.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 24, 2014</start_date>
  <completion_date type="Anticipated">January 2024</completion_date>
  <primary_completion_date type="Actual">January 14, 2020</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>
    <description>Blood transfusion dependency as judged by the PI, unless the patient has progressive disease&#xD;
Development of MDS/AML&#xD;
Grade ≥ 4 dysphagia&#xD;
Grade ≥ 3 hemorrhage, aspiration, skin atrophy, trismus, osteoradionecrosis, radiation dermatitis, pneumonitis&#xD;
Grade ≥ 2 fistula, myelitis&#xD;
Grade ≥ 2 mucosal ulcer present ≥ 6 months after end of treatment&#xD;
Fibrosis limiting joint or orifice movement (e.g. mouth) and/or limiting self care ADL&#xD;
Only in patients with oropharynx SCC: grade ≥ 3 larynx stenosis&#xD;
Any other (non-)hematological toxicity, which in the judgment of the Investigator is viewed as DLT; excluding fatigue</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>acute toxicity</measure>
    <time_frame>until 3 months after treatment</time_frame>
    <description>severity, duration and relation with treatment of all adverse events according to CTCAE version 4.03</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>late toxicity</measure>
    <time_frame>3 months until 2 year after treatment</time_frame>
    <description>severity, duration and relation with treatment of possibly, probably or definitely related adverse events according to CTCAE version 4.03</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Laryngeal Cancer Stage II</condition>
  <condition>Laryngeal Cancer Stage III</condition>
  <condition>Carcinoma, Squamous Cell</condition>
  <condition>Head and Neck Neoplasms</condition>
  <arm_group>
    <arm_group_label>radiotherapy and olaparib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Radiotherapy will be given with accelerated fractionation following the DAHANCA schedule Olaparib: dose escalation</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>radiotherapy</intervention_name>
    <description>Primary tumor and lymph nodes will receive 35 fractions of 2 Gy resulting in a total dose of 70 Gy. Elective fields will receive 35 fractions of 1.55 Gy resulting in a total dose of 54.25 Gy in case a SIB technique is used, or 23 fractions of 2 Gy resulting in a total dose of 46 Gy in case a sequential boost technique is used. The higher total prescribed physical dose to the elective fields in a SIB technique based RT plan compensates for the lower dose per fraction and results in an equal biological effective dose when compared with a sequential boost technique.</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, and 300 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;
          -  Histologically confirmed squamous cell carcinoma of the larynx stage II-III (T2N0M0 or&#xD;
             T1-2N1M0 or T3N0-1M0) or histologically confirmed squamous cell carcinoma of the&#xD;
             oropharynx stage II-III (T1-2N1M0 or T3N0-1M0)&#xD;
&#xD;
          -  In case of oropharyngeal carcinoma: tumor HPV status negative&#xD;
&#xD;
          -  WHO performance 0-1&#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 UNL&#xD;
&#xD;
               -  ASAT/ALAT ≤ 2.5 x UNL&#xD;
&#xD;
               -  Creatinine clearance 50 ml/min; measured using a 24-hours urine sample or&#xD;
                  calculated using the Cockcroft-Gault formula&#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;
          -  Patients eligible for concurrent chemoradiotherapy rather than radiotherapy alone&#xD;
&#xD;
          -  Concurrent active malignancy other than localized, non-melanoma skin cancer or&#xD;
             carcinoma-in-situ of the cervix (unless definitive treatment was completed 3 years or&#xD;
             more before study entry and the patient has remained disease free)&#xD;
&#xD;
          -  Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy,&#xD;
             immunotherapy or use of other investigational agents within the 3 weeks prior to start&#xD;
             of therapy (or a longer period depending on the defined characteristics of the agents&#xD;
             used e.g. 6 weeks for mitomycin or nitrosourea). Patients may continue the use of LHRH&#xD;
             agonists for cancer; bisphosphonates for bone disease and corticosteroids.&#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;
          -  Gastrointestinal disorders that may interfere with absorption of the study drug or&#xD;
             patients who are not able to take oral medication.&#xD;
&#xD;
          -  Tube feeding before the start of treatment.&#xD;
&#xD;
          -  Prior radiotherapy to head &amp; neck region.&#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;
          -  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 paragraph&#xD;
                  6.4.2 for guidelines and wash out periods)&#xD;
&#xD;
                    -  Azole antifungals&#xD;
&#xD;
                    -  Macrolide antibiotics&#xD;
&#xD;
                    -  Protease inhibitors&#xD;
&#xD;
          -  Breast-feeding women&#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>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>September 2022</verification_date>
  <study_first_submitted>August 28, 2014</study_first_submitted>
  <study_first_submitted_qc>August 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 1, 2014</study_first_posted>
  <last_update_submitted>September 27, 2022</last_update_submitted>
  <last_update_submitted_qc>September 27, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>olaparib</keyword>
  <keyword>radiotherapy</keyword>
  <keyword>Laryngeal SCC</keyword>
  <keyword>oropharyngeal SCC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Head and Neck Neoplasms</mesh_term>
    <mesh_term>Laryngeal Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</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/NCT02229656
org study id: N13ORH
secondary id: 2011-002963-79
nct id: NCT02229656
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Accelerated, normofractionated radiotherapy is the treatment of choice in stage II-III
      laryngeal and oropharyngeal squamous cell carcinoma (SCC). However, twenty to thirty percent
      of patients with stage II-III laryngeal and HPV negative oropharyngeal SCC develop disease
      progression, mainly due to lack of locoregional control. Radiosensitizers such as cisplatin
      and cetuximab are added to radiotherapy in more advanced stage of head and neck (H&N) cancer.
      These radiosensitizers improve loco-regional control and overall survival. Unfortunately, as
      these radiosensitizers, notably cisplatin, also dose intensify the radiation dose in normal
      tissues, they also significantly increase toxicity. Adding a more tumor-specific
      radiosensitizing agent could improve loco-regional control and overall survival without
      significantly increasing toxicity.

      Radiotherapy kills tumor cells by inducing DNA damage. The efficacy of radiotherapy is
      limited by the ability of tumor cells to repair this DNA damage. Poly(ADP-ribose)polymerase
      (PARP) is an essential enzyme in base excision repair and single strand break DNA repair, DNA
      lesions arising from radiation treatment. PARP inhibition and consequently the inhibition of
      PARP-facilitated DNA repair enhances the anti-tumor activity of radiotherapy, as shown in
      preclinical studies including head and neck xenograft studies. This radiosensitization is
      thought to be proliferation dependent and is more pronounced in homologous recombination (HR)
      deficient cells, providing an opportunity for tumor specific targeting. Genetic analyses
      suggest that HR deficiency is commonly found in H&N SCC: ATM loss has been reported in 60% of
      human H&N SCC biopsies and FANC-F defects were reported in 15-21% of human H&N SCC biopsies
      and cell lines.

      The efficacy of radiotherapy is also limited by tumor hypoxia, as tumor hypoxia results in
      radioresistance. Some PARP inhibiting compounds increase tumor perfusion in xenograft models,
      thereby reducing hypoxia and specifically sensitizing tumor cells to radiotherapy. Hypoxia is
      commonly found in H&N SCC and a high pre-treatment hypoxic fraction in H&N SCC tumors is
      associated with worse outcome. The high prevalence of both hypoxia and HR deficiencies in H&N
      SCC support the concept of tumor-specific radiosensitization by PARP inhibition in head and
      neck cancer patients.

      Olaparib is a potent PARP inhibitor developed as an anti-cancer drug for HR defected tumors
      and as a dose intensifier for chemo- and radiotherapy. In humans, olaparib has a low toxicity
      profile as a single agent, with increasing bone marrow toxicity when combined with
      chemotherapy. The combination of olaparib and radiotherapy for H&N SCC is expected to improve
      locoregional control and thereby overall survival. 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 for stage II-III laryngeal and stage II-III HPV-negative
      oropharyngeal SCC 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
description: Blood transfusion dependency as judged by the PI, unless the patient has progressive disease
Development of MDS/AML
Grade ≥ 4 dysphagia
Grade ≥ 3 hemorrhage, aspiration, skin atrophy, trismus, osteoradionecrosis, radiation dermatitis, pneumonitis
Grade ≥ 2 fistula, myelitis
Grade ≥ 2 mucosal ulcer present ≥ 6 months after end of treatment
Fibrosis limiting joint or orifice movement (e.g. mouth) and/or limiting self care ADL
Only in patients with oropharynx SCC: grade ≥ 3 larynx stenosis
Any other (non-)hematological toxicity, which in the judgment of the Investigator is viewed as DLT; excluding fatigue
measure: acute toxicity
time frame: until 3 months after treatment
description: severity, duration and relation with treatment of all adverse events according to CTCAE version 4.03
measure: late toxicity
time frame: 3 months until 2 year after treatment
description: severity, duration and relation with treatment of possibly, probably or definitely related adverse events according to CTCAE version 4.03
arm group label: radiotherapy and olaparib
arm group type: Experimental
description: Radiotherapy will be given with accelerated fractionation following the DAHANCA schedule Olaparib: dose escalation
intervention type: Radiation
intervention name: radiotherapy
description: Primary tumor and lymph nodes will receive 35 fractions of 2 Gy resulting in a total dose of 70 Gy. Elective fields will receive 35 fractions of 1.55 Gy resulting in a total dose of 54.25 Gy in case a SIB technique is used, or 23 fractions of 2 Gy resulting in a total dose of 46 Gy in case a sequential boost technique is used. The higher total prescribed physical dose to the elective fields in a SIB technique based RT plan compensates for the lower dose per fraction and results in an equal biological effective dose when compared with a sequential boost technique.
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, and 300 mg BID
arm group label: radiotherapy and olaparib
other name: AZD2281
other name: KU-0059436
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
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: Head and Neck Neoplasms
mesh term: Laryngeal Neoplasms
mesh term: Carcinoma, Squamous Cell
mesh term: Olaparib