<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/NCT04447612</url>
  </required_header>
  <id_info>
    <org_study_id>UW 19-534</org_study_id>
    <nct_id>NCT04447612</nct_id>
  </id_info>
  <brief_title>Concurrent Chemoradiation and Durvalumab for Locoregionally Advanced Nasopharyngeal Carcinoma</brief_title>
  <official_title>A Multi-centre Phase II Randomized-controlled Study on Addition of Durvalumab (MEDI4736) to Induction Chemotherapy and Concurrent Chemoradiation and Followed by Maintenance Durvalumab for Locoregionally Advanced Nasopharyngeal Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The University of Hong Kong</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The University of Hong Kong</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <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>
      The investigators propose a phase II randomized-controlled study on using durvalumab in&#xD;
      combination with induction chemotherapy followed by concurrent chemoradiation and adjuvant&#xD;
      durvalumab, compared to induction chemotherapy followed by concurrent chemoradiation for&#xD;
      previously untreated locoregionally advanced stage III to IVA NPC. In parallel, the&#xD;
      investigators will also perform collateral tumor and serum biomarker studies which will be&#xD;
      correlated with the treatment response. The investigators will collect fresh tumour biopsies&#xD;
      at pretreatment, then serially after induction chemotherapy and after concurrent&#xD;
      chemoradiation to investigate the change in microenvironment of the tumour and the&#xD;
      surrounding inflammatory cells before and after durvalumab. In addition, the investigators&#xD;
      will also measure the change in number and intensity of PD-L1-positive circulating tumour&#xD;
      cells (CTC) before and after durvalumab and evaluate their correlation with treatment&#xD;
      response.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Nasopharyngeal carcinoma (NPC) of the undifferentiated histology is endemic in southern China&#xD;
      and southeast Asia including Hong Kong, Taiwan, Singapore and Malaysia, with a peak annual&#xD;
      incidence of up to 30 per 100,000 persons. According to global cancer registry, NPC ranked&#xD;
      11th most common among all malignancies in China in 2008 with an incidence of 2.8/100,000&#xD;
      person-years in men and 1.9/100,000 person-years in females. It is highly associated with&#xD;
      prior infection with Epstein-Barr virus and thus it is a highly immune-related malignancy.&#xD;
      Treatment strategy is mainly based on the disease stage according to the American Joint&#xD;
      Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. In&#xD;
      general, stage I-II diseases are treated with radiation therapy alone while stage III-IV&#xD;
      diseases are treated with concurrent chemoradiation with or without adjunct chemotherapy&#xD;
      (induction or adjuvant). Intensive pretreatment workup including blood hematology and&#xD;
      biochemistry, dedicated head and neck imaging with computed tomography and magnetic resonance&#xD;
      imaging and positron-emission tomography with integrated computed tomography (PET-CT) and&#xD;
      plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) are essential in high-risk&#xD;
      locoregionally advanced diseases to confirm non-metastatic diseases, since the treatment&#xD;
      protocol and overall prognosis between locoregionally advanced (stage III-IVA) disease differ&#xD;
      significantly from metastatic disease.&#xD;
&#xD;
      Despite intensive radical treatment in the contemporary radiotherapy era with concurrent&#xD;
      chemoradiation with or without adjunct chemotherapy, between 15% and 30% of these patients&#xD;
      with stage III-IVA disease develop metastatic diseases at distant sites. Further systemic&#xD;
      chemotherapy following radical concurrent chemoradiation may not bring survival benefits,&#xD;
      attributed by the compromised physique following intensive radical concurrent chemoradiation&#xD;
      and the prolonged treatment-related toxicities brought by adjuvant chemotherapy. The recent&#xD;
      Hong Kong NPC Study Group NPC-0502 study failed to show survival benefit in patients with&#xD;
      post-treatment detectable plasma EBV DNA after a further 6 cycles of adjuvant chemotherapy&#xD;
      compared to those who just observed after radical concurrent chemoradiation. On the other&#xD;
      hand, induction chemotherapy followed by concurrent chemoradiation may be the more preferred&#xD;
      regimen due to the perceived efficacy of eradication of tumor micro-metastasis and early&#xD;
      shrinkage of primary tumor and bulky neck nodes, which allow a more radical radiotherapy dose&#xD;
      and better coverage of both the primary tumor and neck nodes. Very recently, a China&#xD;
      multi-centre phase III randomised-controlled trial demonstrated an improvement in&#xD;
      recurrence-free survival and overall survival (OS) with induction chemotherapy gemcitabine&#xD;
      plus cisplatin followed by concurrent chemoradiation versus concurrent chemoradiation alone.&#xD;
      Nevertheless, new treatment strategies must be developed to improve treatment outcomes of&#xD;
      these high-risk patients with stage III-IVA disease, which has become the major research&#xD;
      focus in the past decade. A recent meta-analysis demonstrated that induction chemotherapy&#xD;
      followed by concurrent chemoradiation improved overall survival compared to concurrent&#xD;
      chemoradiation in the era of modern radiotherapy with intensity-modulated radiation therapy&#xD;
      (IMRT).&#xD;
&#xD;
      Immune checkpoint inhibitors are now comprehensively and extensively tested in combination&#xD;
      with radiotherapy (RT) as well (NCT01935921, NCT01860430). It has been recently known that RT&#xD;
      increases the expression of the major histocompatibility complex (MHC). In turn, the MHC&#xD;
      class-I restricted tumor antigen-specific cells elicited by RT will upregulate interferons in&#xD;
      the tumors. This radiation-induced local inflammation and tumor-specific effector T cells&#xD;
      will provide an additional mechanism for tumor control by modification of the tumor&#xD;
      vasculature. In addition, RT will increase dendritic cell surface antigen presentation to T&#xD;
      cells and production of cytokines leading to recruitment and activation of leucocytes from&#xD;
      peripheral blood and extravasation to tumor parenchyma. These are part of the mechanisms of&#xD;
      abscopal effect, a phenomenon where the tumors at the sites far away from the irradiated&#xD;
      sites also regress after localized radiotherapy. Having learnt from the pivotal PACIFIC trial&#xD;
      on the use of consolidation therapy with durvalumab (anti-PD-L1 monoclonal antibody) which&#xD;
      confirmed the efficacy and safety of combination of chemoradiation and immunotherapy for&#xD;
      stage III non-small-cell lung cancer, it is prime time to consider incorporation of immune&#xD;
      checkpoint inhibitors into concurrent chemoradiation for other solid tumors like head and&#xD;
      neck squamous cell carcinoma and NPC. In concurrent +/- adjuvant setting for locoregionally&#xD;
      advanced NPC, there are at least two clinical trials on immune checkpoint inhibitors for&#xD;
      locoregionally advanced disease. The first one is a phase II single-arm study using nivolumab&#xD;
      in combination with concurrent chemoradiation with or without by adjuvant nivolumab for up to&#xD;
      3 months at different dose schedules (NCT03267498). A phase III multi-center&#xD;
      randomized-controlled trial (RCT) in China on the use of a locally-manufactured PD-1&#xD;
      monoclonal antibody (SHR-1210) every 4 weeks for 12 cycles starting at 4-6 weeks after&#xD;
      concurrent chemoradiation for stage III-IVA NPC versus no adjuvant therapy is currently under&#xD;
      way (NCT03427827). It is highly expected and eagerly awaited that immunotherapy with immune&#xD;
      checkpoint inhibitors will bring a new insight on the adjuvant treatment for NPC.&#xD;
&#xD;
      In view of the above with promising synergy between radiation therapy and immune checkpoint&#xD;
      inhibitors, the investigators propose a phase II RCT on adding durvalumab in combination with&#xD;
      induction chemotherapy followed by concurrent chemoradiation and adjuvant durvalumab for&#xD;
      previously untreated locoregionally advanced NPC. In parallel, the investigators will also&#xD;
      perform collateral tumor and serum biomarker studies which will be correlated with the&#xD;
      treatment response. The investigators will collect fresh tumour biopsies at pretreatment,&#xD;
      then serially after induction chemotherapy and after concurrent chemoradiation to investigate&#xD;
      the change in microenvironment of the tumour and the surrounding inflammatory cells before&#xD;
      and after durvalumab. In addition, the investigators will also measure the change in number&#xD;
      and intensity of PD-L1-positive circulating tumour cells before and after durvalumab and&#xD;
      evaluate their correlation with treatment response.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</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>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomized-controlled trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>No masking.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>36 months</time_frame>
    <description>Progression-free survival</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Best objective response</measure>
    <time_frame>36 months</time_frame>
    <description>Best objective response</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>36 months</time_frame>
    <description>Overall survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity profile</measure>
    <time_frame>36 months</time_frame>
    <description>Toxicity profile as assessed by Common Terminology Criteria for Adverse Events version 5.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the number of PD-L1 positive circulating tumor cells before and after induction chemotherapy and concurrent chemoradiation</measure>
    <time_frame>36 months</time_frame>
    <description>Changes in the number of PD-L1 positive circulating tumor cells before and after induction chemotherapy and concurrent chemoradiation</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">118</enrollment>
  <condition>Nasopharyngeal Carcinoma</condition>
  <arm_group>
    <arm_group_label>Durvalumab arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Induction phase: Durvalumab 1500mg via intravenous infusion every 4 weeks, with chemotherapy gemcitabine 1000mg/m2 on day 1 and day 8 and cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles.&#xD;
Concurrent phase: Durvalumab 1500mg via intravenous infusion every 4 weeks for 2 cycles, with cisplatin 100mg/m2 via intravenous infusion every 3 weeks for 3 cycles.&#xD;
Maintenance phase: Durvalumab 1500mg daily via intravenous infusion every 4 weeks for 8 cycles.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Induction phase: Chemotherapy with gemcitabine 1000mg/m2 on day 1 and day 8 and cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles.&#xD;
Concurrent phase: Cisplatin 100mg/m2 on day 1 of radiation therapy via intravenous infusion every 3 weeks for 3 cycles.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Intravenous infusion of durvalumab 1500mg every 4 weeks for 13 cycles (1 year), starting 1 week before start of induction chemotherapy</description>
    <arm_group_label>Durvalumab arm</arm_group_label>
    <other_name>MEDI4736</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Induction phase: cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles Concurrent phase: cisplatin 100mg/m2 starting on day 1 of radiation therapy via intravenous infusion every 3 weeks for 3 cycles</description>
    <arm_group_label>Durvalumab arm</arm_group_label>
    <arm_group_label>Standard of care arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Induction phase: gemcitabine 1000mg/m2 on day 1 and day 8 via intravenous infusion every 3 weeks for 3 cycles</description>
    <arm_group_label>Durvalumab arm</arm_group_label>
    <arm_group_label>Standard of care arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients must have pathologically confirmed, previously untreated stage III-IVA&#xD;
             nasopharyngeal carcinoma (staged by American Joint Committee on Cancer/Union&#xD;
             International for Cancer Control 8th edition staging classification) who plan to&#xD;
             receive radical chemoradiation +/- durvalumab.&#xD;
&#xD;
          2. Fresh frozen tumour and archived formalin-fixed paraffin-embedded (FFPE)&#xD;
             nasopharyngeal tumour specimens must be available for PD-L1 expression and/other&#xD;
             biomarker correlation studies.&#xD;
&#xD;
          3. Age between 18-75 years. (The age limit set at 75 years because a previous Hong Kong&#xD;
             study showed that elderly patient &gt;70 years had poor tolerance to radiotherapy and&#xD;
             worse survival for their NPC. Please refer to Sze et al. Radical radiotherapy for&#xD;
             nasopharyngeal carcinoma in elderly patients: The importance of co-morbidity&#xD;
             assessment Oral Oncology 2012;48:162-167.)&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group Performance Status of 0 or 1&#xD;
&#xD;
          5. All eligible patients must be magnetic resonance imaging of T1, T2 and T1-contrast&#xD;
             enhanced sequences of the head and neck region and PET-CT scan within 60 days of study&#xD;
             entry&#xD;
&#xD;
          6. Modified Charlson Comorbidity Score &lt;2&#xD;
&#xD;
          7. Adult Comorbidity Evaluation (ACE)-27 Index &lt;2&#xD;
&#xD;
          8. Pre-existing peripheral neuropathy ≤1&#xD;
&#xD;
          9. Baseline creatinine clearance &gt;60ml/min, calculated by Cockcroft-Gault Formula or&#xD;
             derived by collection of 24-hour urine.&#xD;
&#xD;
             Males:&#xD;
&#xD;
             Creatinine Clearance (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine&#xD;
             (mg/dL)&#xD;
&#xD;
             Females:&#xD;
&#xD;
             Creatinine Clearance (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine&#xD;
             (mg/dL)&#xD;
&#xD;
         10. Adequate serum hematological function defined as:&#xD;
&#xD;
               -  Absolute neutrophil count ≥1.5 × 109/l&#xD;
&#xD;
               -  Hemoglobin ≥9.0 g/dl&#xD;
&#xD;
               -  Platelet ≥100 × 109/l&#xD;
&#xD;
         11. Adequate serum biochemical functions defined as:&#xD;
&#xD;
               -  Alanine transferase ≤3 × upper limit of normal range (ULT)&#xD;
&#xD;
               -  Aspartate transferase ≤3 × ULT&#xD;
&#xD;
               -  Total bilirubin ≤2 x ULT&#xD;
&#xD;
               -  Albumin ≥2.8 g/dl&#xD;
&#xD;
         12. For women of childbearing potential, a negative serum or urine pregnancy test within&#xD;
             14 days prior to the start of treatment for their NPC. Women will be considered&#xD;
             postmenopausal if they are amenorrheic for 12 months without an alternative medical&#xD;
             cause. The following age-specific requirements apply:&#xD;
&#xD;
               -  Women &lt;50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of exogenous hormonal&#xD;
                  treatments and if they have luteinizing hormone and follicle-stimulating hormone&#xD;
                  levels in the post-menopausal range for the institution or underwent surgical&#xD;
                  sterilization (bilateral oophorectomy or hysterectomy).&#xD;
&#xD;
               -  Women ≥50 years of age would be considered post-menopausal if they have been&#xD;
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal&#xD;
                  treatments, had radiation-induced menopause with last menses &gt;1 year ago, had&#xD;
                  chemotherapy-induced menopause with last menses &gt;1 year ago, or underwent&#xD;
                  surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or&#xD;
                  hysterectomy).&#xD;
&#xD;
         13. Capable of giving signed informed consent which includes compliance with the&#xD;
             requirements and restrictions listed in the informed consent form (ICF) and in this&#xD;
             protocol. Written informed consent and any locally required authorization (eg, Health&#xD;
             Insurance Portability and Accountability Act in the US, European Union [EU] Data&#xD;
             Privacy Directive in the EU) obtained from the patient/legal representative prior to&#xD;
             performing any protocol-related procedures, including screening evaluations.&#xD;
&#xD;
         14. Body Weight &gt;30kg&#xD;
&#xD;
         15. Patient is willing and able to comply with the protocol for the duration of the study&#xD;
             including undergoing treatment and scheduled visits and examinations including follow&#xD;
             up.&#xD;
&#xD;
         16. Must have a life expectancy of at least 12 weeks.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Is currently participating in or has participated in a study of an investigational&#xD;
             agent or using an investigational device within 4 weeks of the first dose of treatment&#xD;
             or 5 half-lives, whichever is shorter.&#xD;
&#xD;
          2. Has a diagnosis of severe active scleroderma, lupus, other rheumatologic or autoimmune&#xD;
             disease within the past 3 months before study recruitment. Patients with a documented&#xD;
             history of clinically severe autoimmune disease or a syndrome requiring systemic&#xD;
             steroids or immunosuppressive agents will not be allowed on this study. Subjects with&#xD;
             vitiligo or resolved childhood asthma/atopy are an exception to this rule. Subjects&#xD;
             that require intermittent use of bronchodilators or local steroid injections are not&#xD;
             excluded from the study. Subjects with hypothyroidism stable on hormone replacement&#xD;
             are not excluded from this study.&#xD;
&#xD;
          3. Has had a prior monoclonal antibody within 4 weeks or 5 half-lives, whichever is&#xD;
             shorter, prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at&#xD;
             baseline) from adverse events due to agents administered more than 4 weeks earlier.&#xD;
&#xD;
          4. Has had prior chemotherapy or targeted small molecule therapy (including sorafenib or&#xD;
             other anti-vascular endothelial growth factor inhibitor) within 3 weeks prior to&#xD;
             administration of the study drug or who has not recovered (i.e., ≤Grade 1 or at&#xD;
             baseline) from adverse events due to a previously administered agent. *Note: Subjects&#xD;
             with permanent ≤Grade 2 toxicities (e.g. neuropathy) or toxicities corrected through&#xD;
             routine medical management (e.g. thyroid replacement for hypothyroidism), are an&#xD;
             exception to this criterion and may qualify for the study. *Note: If subject received&#xD;
             major surgery, they must have recovered adequately from the toxicity and/or&#xD;
             complications from the intervention prior to starting therapy. *Note: Subjects with&#xD;
             ≤Grade 2 amylase or lipase elevations abnormalities that have no corresponding&#xD;
             clinical manifestations (e.g. manifestation of pancreatitis), are an exception to this&#xD;
             criterion and may qualify for the study.&#xD;
&#xD;
          5. Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the&#xD;
             skin, indolent lymphomas, or in situ cervical cancer that has undergone potentially&#xD;
             curative therapy&#xD;
&#xD;
          6. Has known carcinomatous meningitis (also known as leptomeningeal carcinomatosis).&#xD;
&#xD;
          7. Has an active infection requiring intravenous systemic therapy or hospital admission.&#xD;
&#xD;
          8. Has a history or current evidence of any condition, therapy, or laboratory&#xD;
             abnormality, including psychiatric or substance abuse disorder, that might confound&#xD;
             the results of the trial, interfere with the subject's participation for the full&#xD;
             duration of the trial, or is not in the best interest of the subject to participate,&#xD;
             in the opinion of the treating investigator.&#xD;
&#xD;
          9. Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the screening visit through 31 weeks&#xD;
             after the last dose of trial treatment.&#xD;
&#xD;
         10. Has a known history of Human Immunodeficiency Virus (HIV) (HIV type 1/2 antibodies).&#xD;
             Routine checking for Anti-HIV type 1 or Anti-HIV type 2 is not mandatory.&#xD;
&#xD;
         11. Untreated hepatitis B infection. Patients with chronic hepatitis B infection (defined&#xD;
             as HBsAg positive) are eligible if they have started anti-viral therapy for at least 1&#xD;
             month and is continuing anti-viral treatment throughout the whole duration of this&#xD;
             study.&#xD;
&#xD;
         12. Has received a live vaccine 30 days prior to the first dose of trial treatment.&#xD;
&#xD;
         13. Has experienced Grade 4 toxicity on treatment with prior radiation.&#xD;
&#xD;
         14. Has experienced Grade 3-4 intracranial toxicity (hypophysitis or central nervous&#xD;
             system toxicity) with either prior intracranial radiation, anti programmed cell&#xD;
             death-1 (PD-1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor&#xD;
             therapy.&#xD;
&#xD;
         15. Is taking &gt; 4mg/day of dexamethasone or its equivalent at the start of immunotherapy&#xD;
             or has required &gt; 4mg/day of dexamethasone or its equivalent for 3 consecutive days&#xD;
             within 1 week of starting treatment.&#xD;
&#xD;
         16. Allergies and adverse drug reaction to the following: History of allergy to study drug&#xD;
             components; History of severe hypersensitivity reaction to any monoclonal antibody.&#xD;
&#xD;
         17. Prior systemic therapy utilizing an anti CTLA-4 or PD-1/PD-L1 agent or other forms of&#xD;
             immunotherapy.&#xD;
&#xD;
         18. Has had prior radiation therapy&#xD;
&#xD;
         19. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the&#xD;
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion&#xD;
             criteria&#xD;
&#xD;
               1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after&#xD;
                  consultation with the Study Physician.&#xD;
&#xD;
               2. Patients with irreversible toxicity not reasonably expected to be exacerbated by&#xD;
                  treatment with durvalumab may be included only after consultation with the Study&#xD;
                  Physician&#xD;
&#xD;
         20. Major surgical procedure (as defined by the Investigator within 28 days prior to the&#xD;
             first dose of IP. Local surgery of isolated lesions for palliative intent is&#xD;
             acceptable.&#xD;
&#xD;
         21. History of allogenic organ transplantation.&#xD;
&#xD;
         22. History of leptomeningeal carcinomatosis&#xD;
&#xD;
         23. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470ms&#xD;
             calculated from 3 ECGs (within 15 minutes at 5 minutes apart).&#xD;
&#xD;
         24. Current or prior use of immunosuppressive medication within 14 days before the first&#xD;
             dose of durvalumab. The following are exceptions to this criterion:&#xD;
&#xD;
               1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra&#xD;
                  articular injection)&#xD;
&#xD;
               2. Systemic corticosteroids at physiologic doses not to exceed &lt;&lt;10 mg/day&gt;&gt; of&#xD;
                  prednisone or its equivalent&#xD;
&#xD;
               3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan&#xD;
                  premedication)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Victor Lee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The University of Hong Kong</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Victor Lee, MD</last_name>
    <phone>852-2255-4352</phone>
    <email>vhflee@hku.hk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sandy Cheung, MSc</last_name>
    <phone>852-2255-4216</phone>
    <email>sandy718@hku.hk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Department of Clinical Oncology, Queen Mary Hospital</name>
      <address>
        <city>Hong Kong</city>
        <country>Hong Kong</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Victor Lee, MD</last_name>
      <phone>852-2255-4352</phone>
      <email>vhflee@hku.hk</email>
    </contact>
    <contact_backup>
      <last_name>Ka-On Lam, FRCR</last_name>
      <phone>852-2255-4352</phone>
      <email>lamkaon@hku.hk</email>
    </contact_backup>
    <investigator>
      <last_name>Ka On Lam, FRCR</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Hong Kong</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 21, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>June 23, 2020</last_update_submitted>
  <last_update_submitted_qc>June 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The University of Hong Kong</investigator_affiliation>
    <investigator_full_name>Dr. Victor H.F. Lee</investigator_full_name>
    <investigator_title>Clinical Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Nasopharyngeal carcinoma</keyword>
  <keyword>Immune checkpoint inhibitors</keyword>
  <keyword>Chemotherapy</keyword>
  <keyword>Radiation therapy</keyword>
  <keyword>Locoregionally advanced</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Nasopharyngeal Carcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Durvalumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to make individual participant data (IPD) available to other researchers.</ipd_description>
  </patient_data>
  <!-- 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/NCT04447612
org study id: UW 19-534
nct id: NCT04447612
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The investigators propose a phase II randomized-controlled study on using durvalumab in
      combination with induction chemotherapy followed by concurrent chemoradiation and adjuvant
      durvalumab, compared to induction chemotherapy followed by concurrent chemoradiation for
      previously untreated locoregionally advanced stage III to IVA NPC. In parallel, the
      investigators will also perform collateral tumor and serum biomarker studies which will be
      correlated with the treatment response. The investigators will collect fresh tumour biopsies
      at pretreatment, then serially after induction chemotherapy and after concurrent
      chemoradiation to investigate the change in microenvironment of the tumour and the
      surrounding inflammatory cells before and after durvalumab. In addition, the investigators
      will also measure the change in number and intensity of PD-L1-positive circulating tumour
      cells (CTC) before and after durvalumab and evaluate their correlation with treatment
      response.
Nasopharyngeal carcinoma (NPC) of the undifferentiated histology is endemic in southern China
      and southeast Asia including Hong Kong, Taiwan, Singapore and Malaysia, with a peak annual
      incidence of up to 30 per 100,000 persons. According to global cancer registry, NPC ranked
      11th most common among all malignancies in China in 2008 with an incidence of 2.8/100,000
      person-years in men and 1.9/100,000 person-years in females. It is highly associated with
      prior infection with Epstein-Barr virus and thus it is a highly immune-related malignancy.
      Treatment strategy is mainly based on the disease stage according to the American Joint
      Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system. In
      general, stage I-II diseases are treated with radiation therapy alone while stage III-IV
      diseases are treated with concurrent chemoradiation with or without adjunct chemotherapy
      (induction or adjuvant). Intensive pretreatment workup including blood hematology and
      biochemistry, dedicated head and neck imaging with computed tomography and magnetic resonance
      imaging and positron-emission tomography with integrated computed tomography (PET-CT) and
      plasma Epstein-Barr virus (EBV) deoxyribonucleic acid (DNA) are essential in high-risk
      locoregionally advanced diseases to confirm non-metastatic diseases, since the treatment
      protocol and overall prognosis between locoregionally advanced (stage III-IVA) disease differ
      significantly from metastatic disease.

      Despite intensive radical treatment in the contemporary radiotherapy era with concurrent
      chemoradiation with or without adjunct chemotherapy, between 15% and 30% of these patients
      with stage III-IVA disease develop metastatic diseases at distant sites. Further systemic
      chemotherapy following radical concurrent chemoradiation may not bring survival benefits,
      attributed by the compromised physique following intensive radical concurrent chemoradiation
      and the prolonged treatment-related toxicities brought by adjuvant chemotherapy. The recent
      Hong Kong NPC Study Group NPC-0502 study failed to show survival benefit in patients with
      post-treatment detectable plasma EBV DNA after a further 6 cycles of adjuvant chemotherapy
      compared to those who just observed after radical concurrent chemoradiation. On the other
      hand, induction chemotherapy followed by concurrent chemoradiation may be the more preferred
      regimen due to the perceived efficacy of eradication of tumor micro-metastasis and early
      shrinkage of primary tumor and bulky neck nodes, which allow a more radical radiotherapy dose
      and better coverage of both the primary tumor and neck nodes. Very recently, a China
      multi-centre phase III randomised-controlled trial demonstrated an improvement in
      recurrence-free survival and overall survival (OS) with induction chemotherapy gemcitabine
      plus cisplatin followed by concurrent chemoradiation versus concurrent chemoradiation alone.
      Nevertheless, new treatment strategies must be developed to improve treatment outcomes of
      these high-risk patients with stage III-IVA disease, which has become the major research
      focus in the past decade. A recent meta-analysis demonstrated that induction chemotherapy
      followed by concurrent chemoradiation improved overall survival compared to concurrent
      chemoradiation in the era of modern radiotherapy with intensity-modulated radiation therapy
      (IMRT).

      Immune checkpoint inhibitors are now comprehensively and extensively tested in combination
      with radiotherapy (RT) as well (NCT01935921, NCT01860430). It has been recently known that RT
      increases the expression of the major histocompatibility complex (MHC). In turn, the MHC
      class-I restricted tumor antigen-specific cells elicited by RT will upregulate interferons in
      the tumors. This radiation-induced local inflammation and tumor-specific effector T cells
      will provide an additional mechanism for tumor control by modification of the tumor
      vasculature. In addition, RT will increase dendritic cell surface antigen presentation to T
      cells and production of cytokines leading to recruitment and activation of leucocytes from
      peripheral blood and extravasation to tumor parenchyma. These are part of the mechanisms of
      abscopal effect, a phenomenon where the tumors at the sites far away from the irradiated
      sites also regress after localized radiotherapy. Having learnt from the pivotal PACIFIC trial
      on the use of consolidation therapy with durvalumab (anti-PD-L1 monoclonal antibody) which
      confirmed the efficacy and safety of combination of chemoradiation and immunotherapy for
      stage III non-small-cell lung cancer, it is prime time to consider incorporation of immune
      checkpoint inhibitors into concurrent chemoradiation for other solid tumors like head and
      neck squamous cell carcinoma and NPC. In concurrent +/- adjuvant setting for locoregionally
      advanced NPC, there are at least two clinical trials on immune checkpoint inhibitors for
      locoregionally advanced disease. The first one is a phase II single-arm study using nivolumab
      in combination with concurrent chemoradiation with or without by adjuvant nivolumab for up to
      3 months at different dose schedules (NCT03267498). A phase III multi-center
      randomized-controlled trial (RCT) in China on the use of a locally-manufactured PD-1
      monoclonal antibody (SHR-1210) every 4 weeks for 12 cycles starting at 4-6 weeks after
      concurrent chemoradiation for stage III-IVA NPC versus no adjuvant therapy is currently under
      way (NCT03427827). It is highly expected and eagerly awaited that immunotherapy with immune
      checkpoint inhibitors will bring a new insight on the adjuvant treatment for NPC.

      In view of the above with promising synergy between radiation therapy and immune checkpoint
      inhibitors, the investigators propose a phase II RCT on adding durvalumab in combination with
      induction chemotherapy followed by concurrent chemoradiation and adjuvant durvalumab for
      previously untreated locoregionally advanced NPC. In parallel, the investigators will also
      perform collateral tumor and serum biomarker studies which will be correlated with the
      treatment response. The investigators will collect fresh tumour biopsies at pretreatment,
      then serially after induction chemotherapy and after concurrent chemoradiation to investigate
      the change in microenvironment of the tumour and the surrounding inflammatory cells before
      and after durvalumab. In addition, the investigators will also measure the change in number
      and intensity of PD-L1-positive circulating tumour cells before and after durvalumab and
      evaluate their correlation with treatment response.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized-controlled trial
primary purpose: Treatment
masking: None (Open Label)
masking description: No masking.
measure: Progression-free survival
time frame: 36 months
description: Progression-free survival
measure: Best objective response
time frame: 36 months
description: Best objective response
measure: Overall survival
time frame: 36 months
description: Overall survival
measure: Toxicity profile
time frame: 36 months
description: Toxicity profile as assessed by Common Terminology Criteria for Adverse Events version 5.0
measure: Changes in the number of PD-L1 positive circulating tumor cells before and after induction chemotherapy and concurrent chemoradiation
time frame: 36 months
description: Changes in the number of PD-L1 positive circulating tumor cells before and after induction chemotherapy and concurrent chemoradiation
arm group label: Durvalumab arm
arm group type: Experimental
description: Induction phase: Durvalumab 1500mg via intravenous infusion every 4 weeks, with chemotherapy gemcitabine 1000mg/m2 on day 1 and day 8 and cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles.
Concurrent phase: Durvalumab 1500mg via intravenous infusion every 4 weeks for 2 cycles, with cisplatin 100mg/m2 via intravenous infusion every 3 weeks for 3 cycles.
Maintenance phase: Durvalumab 1500mg daily via intravenous infusion every 4 weeks for 8 cycles.
arm group label: Standard of care arm
arm group type: Active Comparator
description: Induction phase: Chemotherapy with gemcitabine 1000mg/m2 on day 1 and day 8 and cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles.
Concurrent phase: Cisplatin 100mg/m2 on day 1 of radiation therapy via intravenous infusion every 3 weeks for 3 cycles.
intervention type: Drug
intervention name: Durvalumab
description: Intravenous infusion of durvalumab 1500mg every 4 weeks for 13 cycles (1 year), starting 1 week before start of induction chemotherapy
arm group label: Durvalumab arm
other name: MEDI4736
intervention type: Drug
intervention name: Cisplatin
description: Induction phase: cisplatin 100mg/m2 on day 1 via intravenous infusion every 3 weeks for 3 cycles Concurrent phase: cisplatin 100mg/m2 starting on day 1 of radiation therapy via intravenous infusion every 3 weeks for 3 cycles
arm group label: Durvalumab arm
arm group label: Standard of care arm
intervention type: Drug
intervention name: Gemcitabine
description: Induction phase: gemcitabine 1000mg/m2 on day 1 and day 8 via intravenous infusion every 3 weeks for 3 cycles
arm group label: Durvalumab arm
arm group label: Standard of care arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Victor Lee, MD
role: Principal Investigator
affiliation: The University of Hong Kong
last name: Victor Lee, MD
phone: 852-2255-4352
email: vhflee@hku.hk
last name: Sandy Cheung, MSc
phone: 852-2255-4216
email: sandy718@hku.hk
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: Hong Kong
responsible party type: Principal Investigator
investigator affiliation: The University of Hong Kong
investigator full name: Dr. Victor H.F. Lee
investigator title: Clinical Associate Professor
mesh term: Carcinoma
mesh term: Nasopharyngeal Carcinoma
mesh term: Gemcitabine
mesh term: Durvalumab
sharing ipd: No
ipd description: There is no plan to make individual participant data (IPD) available to other researchers.