<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/NCT04477759</url>
  </required_header>
  <id_info>
    <org_study_id>PRO00038841</org_study_id>
    <secondary_id>R21CA256144</secondary_id>
    <nct_id>NCT04477759</nct_id>
  </id_info>
  <brief_title>Dose-Escalated Hypofractionated Adaptive Radiotherapy for Head and Neck Cancer</brief_title>
  <acronym>DEHART</acronym>
  <official_title>A Phase I Trial of MR-Guided Dose-Escalated Hypofractionated Adaptive Radiation Therapy and Immunotherapy in Primary Metastatic or Very Locally Advanced Patients With Head and Neck Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical College of Wisconsin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Medical College of Wisconsin</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Locoregional failure remains the principal mode of mortality in head and neck squamous cell&#xD;
      carcinoma (HNSCC) treated with conventional chemoradiation therapy. Magnetic resonance-guided&#xD;
      radiation therapy (MRgRT) allows for adaptive radiation dose escalation based on tumor&#xD;
      response and may improve therapeutic outcomes while limiting toxicities.&#xD;
&#xD;
      This protocol evaluates a novel framework for radiation delivery with concurrent atezolizumab&#xD;
      in patients with advanced HNSCC. Dose-Escalated Hypofractionated Adaptive Radiotherapy&#xD;
      (DEHART) modifies radiation dose using MRgRT by escalating radiation dose to residual tumor&#xD;
      while deescalating radiation dose to areas of tumor regression.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Locoregional failure remains the principal mode of mortality in head and neck squamous cell&#xD;
      carcinoma (HNSCC) treated with conventional chemoradiation therapy. Radiation dose escalation&#xD;
      with hypofractionation has shown unparalleled local control in other malignancies, such as&#xD;
      non-small cell lung cancer, but has been limited in HNSCC due to toxicity concerns. Magnetic&#xD;
      resonance-guided radiation therapy (MRgRT) allows for adaptive radiation dose escalation&#xD;
      based on tumor response and may improve therapeutic outcomes while limiting toxicities.&#xD;
&#xD;
      This protocol evaluates a novel framework for radiation delivery using MRgRT with concurrent&#xD;
      atezolizumab in patients with advanced HNSCC. Unlike conventional radiotherapy,&#xD;
      Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART) modifies radiation dose using&#xD;
      MRgRT by adapting the radiation plan during the course of treatment, escalating radiation&#xD;
      dose to residual tumor while deescalating radiation dose to areas of tumor regression. The&#xD;
      hypothesis is that DEHART will safely deliver ablative radiation doses in 15 fractions over 3&#xD;
      weeks while limiting both toxicity and the effect of tumor repopulation by resistant&#xD;
      clonogens, thus resulting in an improved therapeutic ratio.&#xD;
&#xD;
      This Phase I clinical trial will encompass the following specific aims: (1) determine the&#xD;
      maximum tolerated dose (MTD) of the DEHART regimen delivered using MRgRT with concurrent&#xD;
      atezolizumab in a population of patients who are not candidates or unsuitable for definitive&#xD;
      chemoradiation therapy; (2) evaluate the toxicity and functional outcomes of the DEHART&#xD;
      regimen; and (3) assess the efficacy of DEHART and obtain volumetric and functional imaging&#xD;
      correlates of efficacy using MRgRT to serve as hypothesis-generating data for future trials&#xD;
      of radiation dose adaptation. A modified Time-to Event Continual Reassessment (TITE-CRM)&#xD;
      Phase I Design with three radiation dose levels delivered to regressing disease will be used&#xD;
      to determine the MTD: 50 Gy in 15 fractions, 55 Gy in 15 fractions and 60 Gy in 15 fractions.&#xD;
&#xD;
      If DEHART is found to be safe and shows a signal of efficacy in this study, a future Phase II&#xD;
      trial will be conducted to compare this novel treatment strategy to standard-of care&#xD;
      conventionally fractionated chemoradiation in patients with locally advanced HNSCC.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 26, 2021</start_date>
  <completion_date type="Anticipated">December 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This study will use a time-to-event continual reassessment method (TITE-CRM) for assigning subjects to the radiation therapy dosages.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Dose-Limiting Toxicities at 50 Gy</measure>
    <time_frame>12 months</time_frame>
    <description>This measure is the number of subjects experiencing a dose-limiting toxicity. A dose-limiting toxicity is defined as an inability to complete radiation treatment within 30 days of the start of radiotherapy that is not deemed to be related to disease progression; OR an unacceptable toxicity within one year of treatment (Grade 4+ toxicity) that is probably or definitely related to radiation treatment as determined by the treating physician or a death within one year of treatment that is probably or definitely related to treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of Dose-Limiting Toxicities at 55 Gy</measure>
    <time_frame>12 months</time_frame>
    <description>This measure is the number of subjects experiencing a dose-limiting toxicity. A dose-limiting toxicity is defined as an inability to complete radiation treatment within 30 days of the start of radiotherapy that is not deemed to be related to disease progression; OR an unacceptable toxicity within one year of treatment (Grade 4+ toxicity) that is probably or definitely related to radiation treatment as determined by the treating physician or a death within one year of treatment that is probably or definitely related to treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of Dose-Limiting Toxicities at 60 Gy</measure>
    <time_frame>12 months</time_frame>
    <description>This measure is the number of subjects experiencing a dose-limiting toxicity. A dose-limiting toxicity is defined as an inability to complete radiation treatment within 30 days of the start of radiotherapy that is not deemed to be related to disease progression; OR an unacceptable toxicity within one year of treatment (Grade 4+ toxicity) that is probably or definitely related to radiation treatment as determined by the treating physician or a death within one year of treatment that is probably or definitely related to treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Radiation Dose</measure>
    <time_frame>12 months</time_frame>
    <description>This measure is the highest radiation dose at which there is a 30% or more rate of dose-limiting toxicity up to 12 months after completion of radiation treatment using the TITE-CRM design.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>1 year</time_frame>
    <description>This measure is the number of subjects alive at 1 year following the conclusion of scheduled radiation therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Locoregional progression</measure>
    <time_frame>1 year</time_frame>
    <description>This measure is the number of subjects showing disease progression in the head and neck by RECIST criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gross Tumor Volume at Radiation Fraction 6 (Change from Baseline)</measure>
    <time_frame>6th Radiation Fraction (approximately 1 week)</time_frame>
    <description>This measure is the change in gross tumor volume for each subject as contoured on pre-treatment (baseline) and treatment 6 imaging scans. This will be measured in cubic centimeters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gross Tumor Volume at Radiation Fraction 11 (Change from Baseline)</measure>
    <time_frame>11th Radiation Fraction (approximately 2 weeks)</time_frame>
    <description>This measure is the change in gross tumor volume for each subject as contoured on pre-treatment (baseline) and treatment 11 imaging scans. This will be measured in cubic centimeters.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Head and Neck Neoplasm</condition>
  <arm_group>
    <arm_group_label>50 Gray (Gy) Radiation Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>50 Gy of ionizing radiation therapy will be administered in 15 fractions.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>55 Gray (Gy) Radiation Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>55 Gy of ionizing radiation therapy will be administered in 15 fractions.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>60 Gray (Gy) Radiation Therapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>60 Gy of ionizing radiation therapy will be administered in 15 fractions.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>50 Gy Radiation Therapy</intervention_name>
    <description>Ionizing radiation</description>
    <arm_group_label>50 Gray (Gy) Radiation Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>55 Gy Radiation Therapy</intervention_name>
    <description>Ionizing radiation</description>
    <arm_group_label>55 Gray (Gy) Radiation Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>60 Gy Radiation Therapy</intervention_name>
    <description>Ionizing radiation</description>
    <arm_group_label>60 Gray (Gy) Radiation Therapy</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Atezolizumab (1,680 mg) will be given to all subjects by intravenous injection every 4 weeks following the initiation of radiation treatment up to 1 year from radiation fraction 1.</description>
    <arm_group_label>50 Gray (Gy) Radiation Therapy</arm_group_label>
    <arm_group_label>55 Gray (Gy) Radiation Therapy</arm_group_label>
    <arm_group_label>60 Gray (Gy) Radiation Therapy</arm_group_label>
    <other_name>Tecentriq</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 years&#xD;
&#xD;
          -  Diagnosis of T3-T4 N0-N3 M0 or T0-T4 N1-N3 M0 squamous cell carcinoma of the head and&#xD;
             neck squamous cell carcinoma of the larynx, hypopharynx, oropharynx, oral cavity, or&#xD;
             carcinoma of unknown head/neck primary) based on American Joint Committee on Cancer&#xD;
             guideline (AJCC; 8th edition) with measurable disease who meet at least 1 one of the&#xD;
             following 3 criteria:&#xD;
&#xD;
             1. Not a candidates for concurrent, bolus, cisplatin-based chemoradiation therapy&#xD;
             based on one of the following criteria (a-e)&#xD;
&#xD;
               1. Age ≥ 70 with moderate to severe comorbidity or vulnerability to cisplatin,&#xD;
                  defined as having one or more of the following conditions within 4 week of&#xD;
                  registration:&#xD;
&#xD;
                    1. Modified Charlson Comorbidity Index ≥ 1&#xD;
&#xD;
                    2. Adult Comorbidity Evaluation-27 (ACE-27) Index ≥ 1&#xD;
&#xD;
                    3. ω score &lt; 0.80&#xD;
&#xD;
                    4. Geriatric 8 (G-8) score ≤ 14&#xD;
&#xD;
                    5. Cancer and Aging Research Group (CARG) Toxicity Score ≥ 30%&#xD;
&#xD;
                    6. Cumulative Illness Rating Scale-Geriatric (CIRS-G) Score ≥ 4&#xD;
&#xD;
               2. Age &lt; 70 with severe comorbidity or vulnerability to cisplatin, defined as having&#xD;
                  two or more of the following conditions within 4 weeks prior to registration:&#xD;
&#xD;
                    1. Modified Charlson Comorbidity Index ≥ 1&#xD;
&#xD;
                    2. ACE-27 Index ≥ 1&#xD;
&#xD;
                    3. ω score &lt; 0.80&#xD;
&#xD;
                    4. G-8 score ≤ 14&#xD;
&#xD;
                    5. CARG Toxicity Score ≥ 30%&#xD;
&#xD;
                    6. CIRS-G Score ≥ 4&#xD;
&#xD;
               3. Creatinine clearance &lt; 60 cc/min by the Cockroft-Gault formula&#xD;
&#xD;
               4. Pre-existing peripheral neuropathy&#xD;
&#xD;
               5. Clinical need for a hearing aid or 25+ decibel shift over 2 contiguous&#xD;
                  frequencies on a pre-treatment hearing test&#xD;
&#xD;
                  2. Patient refuses concurrent cisplatin-based chemoradiation therapy&#xD;
&#xD;
                  3. Patient has recurrent disease after definitive surgical resection&#xD;
&#xD;
          -  Any patient 18 years or older with primary metastatic (AJCC 8th edition T1-T4 N0-N3&#xD;
             M1) squamous cell carcinoma of the head and neck&#xD;
&#xD;
          -  Zubrod performance status 0-3&#xD;
&#xD;
          -  Measurable primary and/or nodal tumor in the head and neck region at the time of&#xD;
             radiotherapy&#xD;
&#xD;
          -  Patients must have the psychological ability and general health that permits&#xD;
             completion of the study requirements and required follow up.&#xD;
&#xD;
          -  Ability to tolerate multiple MRIs&#xD;
&#xD;
          -  Adequate hematologic function within 14 days prior to registration defined as follows:&#xD;
             Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3, platelets ≥ 100,000 cells/mm^3,&#xD;
             hemoglobin ≥ 9.0 g/dl, lymphocyte count ≥500/mL. (Note: The use of transfusion or&#xD;
             other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable).&#xD;
&#xD;
          -  Adequate hepatic function within 14 days prior to registration defined as follows:&#xD;
             aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 times&#xD;
             institutional upper limit of normal, serum bilirubin ≤ 1.5 x institutional upper limit&#xD;
             of normal.&#xD;
&#xD;
          -  For patients not receiving therapeutic anticoagulation: international normalized ratio&#xD;
             (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.&#xD;
&#xD;
          -  For patients receiving therapeutic anticoagulation: stable anticoagulant regimen.&#xD;
&#xD;
          -  Negative HIV test at screening{, with the following exception: patients with a&#xD;
             positive HIV test at screening are eligible provided they are stable on&#xD;
             anti-retroviral therapy, have a CD4 count ≥ 200/μL, and have an undetectable viral&#xD;
             load}.&#xD;
&#xD;
          -  Negative hepatitis B surface antigen (HBsAg) test at screening.&#xD;
&#xD;
          -  Inclusion of Covid-19 positive patients will be based on standard institutional&#xD;
             protocol.&#xD;
&#xD;
          -  Female patients must meet one of the following:&#xD;
&#xD;
               -  Postmenopausal for at least one year before the screening visit, or&#xD;
&#xD;
               -  Surgically sterile (i.e., undergone a hysterectomy or bilateral oophorectomy), or&#xD;
&#xD;
               -  If subject is of childbearing potential (defined as not satisfying either of the&#xD;
                  above two criteria), agree to practice two acceptable methods of contraception&#xD;
                  (combination methods require use of two of the following: diaphragm with&#xD;
                  spermicide, cervical cap with spermicide, contraceptive sponge, male or female&#xD;
                  condom, hormonal contraceptive) from the time of signing of the informed consent&#xD;
                  form through 90 150 days after the last dose of study agent, AND o Agree to&#xD;
                  practice true abstinence when this is in line with the preferred and usual&#xD;
                  lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation,&#xD;
                  symptom-thermal, post ovulation methods] and withdrawal are not acceptable&#xD;
                  contraception methods).&#xD;
&#xD;
          -  Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree&#xD;
             to one of the following:&#xD;
&#xD;
               -  Practice effective barrier contraception during the entire study period and&#xD;
                  through 150 calendar days after the last dose of study agent, OR&#xD;
&#xD;
               -  Must also adhere to the guidelines of any study-specific pregnancy prevention&#xD;
                  program, if applicable, OR o Agree to practice true abstinence when this is in&#xD;
                  line with the preferred and usual lifestyle of the subject. (Periodic abstinence&#xD;
                  [e.g., calendar, ovulation, symptom-thermal, postovulation methods] and&#xD;
                  withdrawal are not acceptable methods of contraception.)&#xD;
&#xD;
          -  Ability to understand a written informed consent document, and the willingness to sign&#xD;
             it.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior invasive malignancy within the past 3 years (except for non-melanomatous skin&#xD;
             cancer, and early stage treated prostate cancer);&#xD;
&#xD;
          -  Life expectancy less than 12 months&#xD;
&#xD;
          -  Performance status Zubrod &gt;3&#xD;
&#xD;
          -  Inability to encompass all gross disease in 19 cm superior to inferior planning target&#xD;
             volume to be treated on the MR LINAC&#xD;
&#xD;
          -  MRI-incompatible foreign body&#xD;
&#xD;
          -  Claustrophobia precluding ability to tolerate multiple MRIs&#xD;
&#xD;
          -  MRI-incompatible pacemaker or implantable cardioverter defibrillator (ICD) placement&#xD;
&#xD;
          -  Patients with Cochlear implant&#xD;
&#xD;
          -  Patients with prior radiation therapy to the head and neck Note: Prior external beam&#xD;
             radiotherapy is excluded, but Iodine 131 is allowed.&#xD;
&#xD;
          -  Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted therapy,&#xD;
             or immune therapy for the study cancer&#xD;
&#xD;
          -  Major surgery within 28 days prior to registration&#xD;
&#xD;
          -  Body weight ≤ 30 kg&#xD;
&#xD;
          -  Any of the following severe laboratory abnormalities within 14 days of registration,&#xD;
             unless corrected prior to it: Sodium &lt; 130 mmol/L or &gt; 155 mmol/L; Potassium &lt; 3.5&#xD;
             mmol/L or &gt; 6 mmol/L ;Fasting glucose &lt; 40 mg/dl or &gt; 400 mg/dl;Serum calcium (ionized&#xD;
             or adjusted for albumin) &lt; 7 mg/dl or &gt; 12.5 mg/dl; Magnesium &lt; 0.9 mg/dl or &gt; 3 mg/dl&#xD;
&#xD;
          -  Unstable angina and/or congestive heart failure requiring hospitalization within 3&#xD;
             months prior to Step 1 registration&#xD;
&#xD;
          -  Transmural myocardial infarction within 3 months prior to Step 1 registration&#xD;
&#xD;
          -  Respiratory illness requiring hospitalization at the time of Step 1 registration&#xD;
&#xD;
          -  Note: If the respiratory illness is resolved and the patient meets the eligibility&#xD;
             status above, then the patient can be considered for the trial.&#xD;
&#xD;
          -  Idiopathic pulmonary fibrosis or other severe interstitial lung disease that requires&#xD;
             oxygen therapy or is thought to require oxygen therapy within 1 year prior to Step 1&#xD;
             registration&#xD;
&#xD;
          -  History of (non-infectious) pneumonitis that required steroids or current pneumonitis&#xD;
&#xD;
          -  Clinically apparent jaundice and/or known coagulation defects&#xD;
&#xD;
          -  Active or prior documented autoimmune or inflammatory disorders (including&#xD;
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with&#xD;
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,&#xD;
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid&#xD;
             arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this&#xD;
             criterion: Patients with vitiligo or alopecia; Patients with hypothyroidism (e.g.,&#xD;
             following Hashimoto syndrome) stable on hormone replacement; Any chronic skin&#xD;
             condition that does not require systemic therapy; Patients without active disease in&#xD;
             the last 5 years may be included but only after consultation with the medical oncology&#xD;
             study chair; Patients with celiac disease controlled by diet alone.&#xD;
&#xD;
          -  History of active primary immunodeficiency including, but not limited to Acquired&#xD;
             Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control (CDC)&#xD;
             definition. The need to exclude patients with AIDS from this protocol is necessary&#xD;
             because the treatment involved in this protocol may be immunosuppressive. Patients&#xD;
             with known HIV, cluster of differentiation 4 (CD4) cell counts ≥ 200/μL, and&#xD;
             undetectable viral loads who are stable on an antiretroviral regimen may be included.&#xD;
&#xD;
          -  Current or prior use of immunosuppressive medication within 14 days before&#xD;
             registration, with the exceptions of intranasal and inhaled corticosteroids or&#xD;
             systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of&#xD;
             prednisone, or an equivalent corticosteroid. Treatment with systemic immunosuppressive&#xD;
             medication (including, but not limited to, corticosteroids, cyclophosphamide,&#xD;
             azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior&#xD;
             to initiation of study treatment, or anticipation of need for systemic&#xD;
             immunosuppressive medication during study treatment, with the following exceptions:&#xD;
             Patients who received acute, low-dose systemic immunosuppressant medication or a&#xD;
             one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of&#xD;
             corticosteroids for a contrast allergy) are eligible for the study after Principal&#xD;
             Investigator confirmation has been obtained. Patients who received mineralocorticoids&#xD;
             (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease&#xD;
             (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal&#xD;
             insufficiency are eligible for the study.&#xD;
&#xD;
          -  Receipt of live attenuated vaccination within 30 days prior to registration&#xD;
&#xD;
          -  Medical or psychiatric illness which would compromise the patient's ability to&#xD;
             tolerate treatment or limit compliance with study requirements&#xD;
&#xD;
          -  Pregnancy or women of childbearing potential and men who are sexually active and not&#xD;
             willing/able to use medically acceptable forms of contraception during treatment and&#xD;
             for 6 months after the last dose of atezolizumab, this exclusion is necessary because&#xD;
             the treatment involved in this study may be significantly teratogenic. Women who are&#xD;
             breastfeeding are also excluded.&#xD;
&#xD;
          -  Prior allergic reaction or hypersensitivity to atezolizumab or any of study drug&#xD;
             excipients.&#xD;
&#xD;
          -  History of allogenic stem cell or organ transplantation&#xD;
&#xD;
          -  Uncontrolled hypertension&#xD;
&#xD;
          -  Uncontrolled cardiac arrhythmia&#xD;
&#xD;
          -  Uncontrolled serious chronic gastrointestinal condition associated with diarrhea&#xD;
&#xD;
          -  Active infection including tuberculosis (clinical evaluation that includes clinical&#xD;
             history, physical examination and radiographic findings, and tuberculosis (TB) testing&#xD;
             in line with local practice), hepatitis B (known positive hepatitis B viral (HBV)&#xD;
             surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV&#xD;
             infection (defined as the presence of hepatitis B core antibody (anti-HBc) and absence&#xD;
             of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible&#xD;
             only if polymerase chain reaction is negative for HCV RNA.&#xD;
&#xD;
          -  History of leptomeningeal disease.&#xD;
&#xD;
          -  Asymptomatic metastatic lesions that would likely cause functional deficits or&#xD;
             intractable pain with further growth (e.g., epidural metastasis that is not currently&#xD;
             associated with spinal cord compression) should be considered for loco-regional&#xD;
             therapy if appropriate prior to enrollment.&#xD;
&#xD;
          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent&#xD;
             drainage procedures (once monthly or more frequently) Patients with indwelling&#xD;
             catheters (e.g., PleurXâ) are allowed.&#xD;
&#xD;
          -  Uncontrolled or symptomatic hypercalcemia (ionized calcium &gt; 1.5 mmol/L, calcium &gt; 12&#xD;
             mg/dL or corrected serum calcium &gt; ULN)&#xD;
&#xD;
          -  Active or history of autoimmune disease or immune deficiency, including, but not&#xD;
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus&#xD;
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid&#xD;
             antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,&#xD;
             or multiple sclerosis&#xD;
&#xD;
               -  Patients with a history of autoimmune-related hypothyroidism who are on&#xD;
                  thyroid-replacement hormone are eligible for the study.&#xD;
&#xD;
               -  Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen&#xD;
                  are eligible for the study.&#xD;
&#xD;
               -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with&#xD;
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis are&#xD;
                  excluded) are eligible for the study provided all of following conditions are&#xD;
                  met:&#xD;
&#xD;
                    -  Rash must cover &lt; 10% of body surface area&#xD;
&#xD;
                    -  Disease is well controlled at baseline and requires only low-potency topical&#xD;
                       corticosteroids&#xD;
&#xD;
                    -  No occurrence of acute exacerbations of the underlying condition requiring&#xD;
                       psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic&#xD;
                       agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids&#xD;
                       within the previous 12 months&#xD;
&#xD;
          -  Significant cardiovascular disease (such as New York Heart Association Class II or&#xD;
             greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3&#xD;
             months prior to initiation of study treatment, unstable arrhythmia, or unstable angina&#xD;
&#xD;
          -  Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation&#xD;
             of study treatment, or anticipation of need for a major surgical procedure during the&#xD;
             study&#xD;
&#xD;
          -  Severe infection within 4 weeks prior to initiation of study treatment, including, but&#xD;
             not limited to, hospitalization for complications of infection, bacteremia, or severe&#xD;
             pneumonia&#xD;
&#xD;
             o Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation&#xD;
             of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a&#xD;
             urinary tract infection or chronic obstructive pulmonary disease exacerbation) are&#xD;
             eligible for the study.&#xD;
&#xD;
          -  Any other disease, metabolic dysfunction, physical examination finding, or clinical&#xD;
             laboratory finding that contraindicates the use of an investigational drug, may affect&#xD;
             the interpretation of the results, or may render the patient at high risk from&#xD;
             treatment complications&#xD;
&#xD;
          -  Live, attenuated vaccines (e.g., FluMistâ) are prohibited within 4 weeks prior to&#xD;
             initiation of study treatment, during treatment with atezolizumab, and for 5 months&#xD;
             after the last dose of atezolizumab.&#xD;
&#xD;
          -  Current treatment with anti-viral therapy for HBV&#xD;
&#xD;
          -  Treatment with investigational therapy within 28 days prior to initiation of study&#xD;
             treatment&#xD;
&#xD;
          -  Prior treatment with cluster of differentiation 137 (CD137) agonists or immune&#xD;
             checkpoint blockade therapies, including anti-Cytotoxic T lymphocyte-associated&#xD;
             antigen (anti-CTLA-4), anti-PD-1, and anti-PD-L1 therapeutic antibodies.&#xD;
&#xD;
          -  Treatment with systemic immunostimulatory agents (including, but not limited to,&#xD;
             interferon and interleukin 2 (IL-2) within 4 weeks or 5 half-lives of the drug&#xD;
             (whichever is longer) prior to initiation of study treatment&#xD;
&#xD;
          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies&#xD;
             or fusion proteins&#xD;
&#xD;
          -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of&#xD;
             the atezolizumab formulation&#xD;
&#xD;
          -  Known allergy or hypersensitivity to any component of the chemotherapy formulation&#xD;
&#xD;
          -  Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment&#xD;
             or within 5 months after the final dose of study treatment&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test result&#xD;
             within 14 days prior to initiation of study treatment.&#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>Musaddiq Awan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical College of Wisconsin</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Medical College of Wisconsin Clinical Trials Office</last_name>
    <phone>414-805-8900</phone>
    <email>cccto@mcw.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Froedtert &amp; Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 15, 2020</study_first_submitted>
  <study_first_submitted_qc>July 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 20, 2020</study_first_posted>
  <last_update_submitted>August 9, 2023</last_update_submitted>
  <last_update_submitted_qc>August 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Musaddiq Awan</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Radiotherapy</keyword>
  <keyword>Atezolizumab</keyword>
  <keyword>Targeted Radiation Therapy</keyword>
  <keyword>Head and Neck Cancer</keyword>
  <keyword>Cancer</keyword>
  <keyword>Magnetic Resonance Guided Radiation Therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Head and Neck Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atezolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04477759
org study id: PRO00038841
secondary id: R21CA256144
nct id: NCT04477759
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: Yes
is us export: No
Locoregional failure remains the principal mode of mortality in head and neck squamous cell
      carcinoma (HNSCC) treated with conventional chemoradiation therapy. Magnetic resonance-guided
      radiation therapy (MRgRT) allows for adaptive radiation dose escalation based on tumor
      response and may improve therapeutic outcomes while limiting toxicities.

      This protocol evaluates a novel framework for radiation delivery with concurrent atezolizumab
      in patients with advanced HNSCC. Dose-Escalated Hypofractionated Adaptive Radiotherapy
      (DEHART) modifies radiation dose using MRgRT by escalating radiation dose to residual tumor
      while deescalating radiation dose to areas of tumor regression.
Locoregional failure remains the principal mode of mortality in head and neck squamous cell
      carcinoma (HNSCC) treated with conventional chemoradiation therapy. Radiation dose escalation
      with hypofractionation has shown unparalleled local control in other malignancies, such as
      non-small cell lung cancer, but has been limited in HNSCC due to toxicity concerns. Magnetic
      resonance-guided radiation therapy (MRgRT) allows for adaptive radiation dose escalation
      based on tumor response and may improve therapeutic outcomes while limiting toxicities.

      This protocol evaluates a novel framework for radiation delivery using MRgRT with concurrent
      atezolizumab in patients with advanced HNSCC. Unlike conventional radiotherapy,
      Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART) modifies radiation dose using
      MRgRT by adapting the radiation plan during the course of treatment, escalating radiation
      dose to residual tumor while deescalating radiation dose to areas of tumor regression. The
      hypothesis is that DEHART will safely deliver ablative radiation doses in 15 fractions over 3
      weeks while limiting both toxicity and the effect of tumor repopulation by resistant
      clonogens, thus resulting in an improved therapeutic ratio.

      This Phase I clinical trial will encompass the following specific aims: (1) determine the
      maximum tolerated dose (MTD) of the DEHART regimen delivered using MRgRT with concurrent
      atezolizumab in a population of patients who are not candidates or unsuitable for definitive
      chemoradiation therapy; (2) evaluate the toxicity and functional outcomes of the DEHART
      regimen; and (3) assess the efficacy of DEHART and obtain volumetric and functional imaging
      correlates of efficacy using MRgRT to serve as hypothesis-generating data for future trials
      of radiation dose adaptation. A modified Time-to Event Continual Reassessment (TITE-CRM)
      Phase I Design with three radiation dose levels delivered to regressing disease will be used
      to determine the MTD: 50 Gy in 15 fractions, 55 Gy in 15 fractions and 60 Gy in 15 fractions.

      If DEHART is found to be safe and shows a signal of efficacy in this study, a future Phase II
      trial will be conducted to compare this novel treatment strategy to standard-of care
      conventionally fractionated chemoradiation in patients with locally advanced HNSCC.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: This study will use a time-to-event continual reassessment method (TITE-CRM) for assigning subjects to the radiation therapy dosages.
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of Dose-Limiting Toxicities at 50 Gy
time frame: 12 months
description: This measure is the number of subjects experiencing a dose-limiting toxicity. A dose-limiting toxicity is defined as an inability to complete radiation treatment within 30 days of the start of radiotherapy that is not deemed to be related to disease progression; OR an unacceptable toxicity within one year of treatment (Grade 4+ toxicity) that is probably or definitely related to radiation treatment as determined by the treating physician or a death within one year of treatment that is probably or definitely related to treatment.
measure: Incidence of Dose-Limiting Toxicities at 55 Gy
time frame: 12 months
description: This measure is the number of subjects experiencing a dose-limiting toxicity. A dose-limiting toxicity is defined as an inability to complete radiation treatment within 30 days of the start of radiotherapy that is not deemed to be related to disease progression; OR an unacceptable toxicity within one year of treatment (Grade 4+ toxicity) that is probably or definitely related to radiation treatment as determined by the treating physician or a death within one year of treatment that is probably or definitely related to treatment.
measure: Incidence of Dose-Limiting Toxicities at 60 Gy
time frame: 12 months
description: This measure is the number of subjects experiencing a dose-limiting toxicity. A dose-limiting toxicity is defined as an inability to complete radiation treatment within 30 days of the start of radiotherapy that is not deemed to be related to disease progression; OR an unacceptable toxicity within one year of treatment (Grade 4+ toxicity) that is probably or definitely related to radiation treatment as determined by the treating physician or a death within one year of treatment that is probably or definitely related to treatment.
measure: Maximum Tolerated Radiation Dose
time frame: 12 months
description: This measure is the highest radiation dose at which there is a 30% or more rate of dose-limiting toxicity up to 12 months after completion of radiation treatment using the TITE-CRM design.
measure: Overall Survival
time frame: 1 year
description: This measure is the number of subjects alive at 1 year following the conclusion of scheduled radiation therapy.
measure: Locoregional progression
time frame: 1 year
description: This measure is the number of subjects showing disease progression in the head and neck by RECIST criteria.
measure: Gross Tumor Volume at Radiation Fraction 6 (Change from Baseline)
time frame: 6th Radiation Fraction (approximately 1 week)
description: This measure is the change in gross tumor volume for each subject as contoured on pre-treatment (baseline) and treatment 6 imaging scans. This will be measured in cubic centimeters.
measure: Gross Tumor Volume at Radiation Fraction 11 (Change from Baseline)
time frame: 11th Radiation Fraction (approximately 2 weeks)
description: This measure is the change in gross tumor volume for each subject as contoured on pre-treatment (baseline) and treatment 11 imaging scans. This will be measured in cubic centimeters.
arm group label: 50 Gray (Gy) Radiation Therapy
arm group type: Experimental
description: 50 Gy of ionizing radiation therapy will be administered in 15 fractions.
arm group label: 55 Gray (Gy) Radiation Therapy
arm group type: Experimental
description: 55 Gy of ionizing radiation therapy will be administered in 15 fractions.
arm group label: 60 Gray (Gy) Radiation Therapy
arm group type: Experimental
description: 60 Gy of ionizing radiation therapy will be administered in 15 fractions.
intervention type: Radiation
intervention name: 50 Gy Radiation Therapy
description: Ionizing radiation
arm group label: 50 Gray (Gy) Radiation Therapy
intervention type: Radiation
intervention name: 55 Gy Radiation Therapy
description: Ionizing radiation
arm group label: 55 Gray (Gy) Radiation Therapy
intervention type: Radiation
intervention name: 60 Gy Radiation Therapy
description: Ionizing radiation
arm group label: 60 Gray (Gy) Radiation Therapy
intervention type: Drug
intervention name: Atezolizumab
description: Atezolizumab (1,680 mg) will be given to all subjects by intravenous injection every 4 weeks following the initiation of radiation treatment up to 1 year from radiation fraction 1.
arm group label: 50 Gray (Gy) Radiation Therapy
arm group label: 55 Gray (Gy) Radiation Therapy
arm group label: 60 Gray (Gy) Radiation Therapy
other name: Tecentriq
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Musaddiq Awan, MD
role: Principal Investigator
affiliation: Medical College of Wisconsin
last name: Medical College of Wisconsin Clinical Trials Office
phone: 414-805-8900
email: cccto@mcw.edu
facility: 
status: Recruiting
country: United States
responsible party type: Principal Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Musaddiq Awan
investigator title: Principal Investigator
mesh term: Head and Neck Neoplasms
mesh term: Atezolizumab
sharing ipd: No