<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/NCT04430452</url>
  </required_header>
  <id_info>
    <org_study_id>194522</org_study_id>
    <secondary_id>NCI-2020-03671</secondary_id>
    <nct_id>NCT04430452</nct_id>
  </id_info>
  <brief_title>Hypofractionated Radiotherapy Followed by Durvalumab With or Without Tremelimumab for Liver Cancer After Progression on PD-1 Inhibition</brief_title>
  <official_title>Phase II Trial of Palliative Hypofractionated Radiotherapy Followed by Durvalumab (MEDI4736) With/Without Tremelimumab for Advanced Hepatocellular Carcinoma After Progression on Prior PD-1 Inhibition</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mary Feng, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</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>
      This phase II trial studies how well standard of care hypofractionated radiation therapy&#xD;
      followed by durvalumab with or without tremelimumab works in treating patients with&#xD;
      hepatocellular cancer (liver cancer) that has spread to other places in the body (advanced)&#xD;
      and that is growing, spreading, or getting worse (progressing) after treatment with PD-1&#xD;
      inhibitor immunotherapy. In some patients, cancer cells and immune cells start to express&#xD;
      signals that stop the body's immune system from killing the cancer. New drugs being&#xD;
      developed, such as durvalumab and tremelimumab, are designed to target and block these&#xD;
      signals and may help increase the immune response to prevent or slow down cancer growth.&#xD;
      Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter&#xD;
      period of time and may help the immune system work even better. Giving durvalumab with or&#xD;
      without tremelimumab after radiation therapy may work better than radiation therapy alone in&#xD;
      treating patients with liver cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. Determine objective response rate (ORR) of durvalumab (D) and D + tremelimumab (T) after&#xD;
      radiation therapy (RT) in advanced hepatocellular carcinoma (HCC) patients with progression&#xD;
      on prior PD-1 immune checkpoint inhibitor.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine the safety of D and D + T in advanced HCC patients with progression on prior&#xD;
      PD-1 immune checkpoint inhibitor.&#xD;
&#xD;
      II. Determine the efficacy of D and D + T in advanced HCC patients with progression on prior&#xD;
      PD-1 immune checkpoint inhibitor.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. Profile peripheral blood mononuclear cell (PBMC) immune cells and plasma samples before&#xD;
      RT, after RT, and during D or D + T immunotherapy.&#xD;
&#xD;
      II. Explore relationship between plasma biomarkers and PBMC immune profiles, the proportion&#xD;
      of participants with adverse events (AEs), (safety endpoint), and clinical outcomes (ORR),&#xD;
      progression-free survival (PFS), duration of response (DOR), overall survival (OS).&#xD;
&#xD;
      III. Profile immune cells in archival pre-treatment tumor tissue for all patients and&#xD;
      on-/post-treatment tumor samples and/or non-tumor liver tissue samples when available, and&#xD;
      explore for relationship with safety/tolerability and clinical outcomes.&#xD;
&#xD;
      IV. Determine incidence of tumor PD-L1 expression by immunohistochemistry (IHC) in&#xD;
      pre-treatment archival tumor samples in all patients, and in on-/post-treatment tumor samples&#xD;
      if repeat tumor sampling is obtained for clinical indications.&#xD;
&#xD;
      V. Explore relationship between tumor PD-L1 status and clinical outcomes. VI. Explore&#xD;
      relationship between viral hepatitis status, viral load, safety/tolerability, and clinical&#xD;
      outcomes.&#xD;
&#xD;
      VII. Measure tumor marker alpha-fetoprotein (AFP) response to immunotherapy plus RT and&#xD;
      explore for relationship with clinical outcomes.&#xD;
&#xD;
      VIII. Explore relationship between site of RT (liver, bone, other soft tissue), number of RT&#xD;
      sites (1 or &gt; 1), safety/tolerability, clinical outcomes, and changes in immune cell profiles&#xD;
      on treatment.&#xD;
&#xD;
      OUTLINE: Patients are assigned to 1 of 2 arms.&#xD;
&#xD;
      ARM I: Patients undergo standard of care hypofractionated RT over 5 fractions once daily (QD)&#xD;
      for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days&#xD;
      after completion of RT, patients receive durvalumab intravenously (IV) over 1 hour on day 1.&#xD;
      Treatment repeats every 28 days for up to 2 years in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      This arm will close after the 6th participant is enrolled.&#xD;
&#xD;
      ARM II: Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days&#xD;
      in the absence of disease progression or unacceptable toxicity. Within 3-10 days after&#xD;
      completion of RT, patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour&#xD;
      on day 1. Treatment with durvalumab repeats every 28 days for up to 2 years in the absence of&#xD;
      disease progression or unacceptable toxicity. Patients who complete the first dose of&#xD;
      tremelimumab and demonstrate clinical benefit based upon radiographic tumor regression and/or&#xD;
      other clinical response without progression for at least 6 cycles or 6 months on treatment,&#xD;
      whichever is shorter, and subsequently have evidence of progressive disease during the&#xD;
      durvalumab monotherapy portion may receive a repeat dose of tremelimumab at the next&#xD;
      scheduled cycle of treatment with durvalumab per physician discretion.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 2 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 4, 2022</start_date>
  <completion_date type="Anticipated">February 28, 2027</completion_date>
  <primary_completion_date type="Anticipated">February 28, 2027</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Defined per Response Evaluation Criteria in Solid Tumors 1.1, excluding radiation therapy-treated lesions. assessed from initiation of study treatment until discontinuation of treatment. Proportion of response and corresponding exact confidence intervals will be reported for objective response rate in each Arm. Patients with unevaluable or unknown response status will be considered non-responders.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of of treatment-related adverse events</measure>
    <time_frame>up to 24 months</time_frame>
    <description>Summary tables for AEs will include only AEs that started or worsened during the on-treatment period, the treatment-emergent AEs graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Progression will be calculated in months from date of first dose of protocol therapy to date of first documented radiographic and/or clinical disease progression or death from any cause. For cases without progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within a short period of time following the date last known progression-free, in which case the death will be counted as a failure. The 'short period of time' will generally be no more than 3 months. For patients discontinued from study for other reasons than progression or death, progression-free survival will be censored at the date last known to be progression-free</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of overall response (DOR)</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>The period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented, taking as reference the smallest measurements recorded since treatment started</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 24 months</time_frame>
    <description>Survival will be measured from the date of entry on study and from first dose of protocol therapy to the date of death due to any cause. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">21</enrollment>
  <condition>Advanced Hepatocellular Carcinoma</condition>
  <condition>Stage III Hepatocellular Carcinoma AJCC v8</condition>
  <condition>Stage IIIA Hepatocellular Carcinoma AJCC v8</condition>
  <condition>Stage IIIB Hepatocellular Carcinoma AJCC v8</condition>
  <condition>Stage IV Hepatocellular Carcinoma AJCC v8</condition>
  <condition>Stage IVA Hepatocellular Carcinoma AJCC v8</condition>
  <condition>Stage IVB Hepatocellular Carcinoma AJCC v8</condition>
  <arm_group>
    <arm_group_label>Arm I (hypofractionated RT, durvalumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive durvalumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm II (hypofractionated RT, durvalumab, tremelimumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with durvalumab repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who complete the first dose of tremelimumab and demonstrate clinical benefit based upon radiographic tumor regression and/or other clinical response without progression for at least 6 cycles or 6 months on treatment, whichever is shorter, and subsequently have evidence of progressive disease during the durvalumab monotherapy portion may receive a repeat dose of tremelimumab at the next scheduled cycle of treatment with durvalumab per physician discretion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm I (hypofractionated RT, durvalumab)</arm_group_label>
    <arm_group_label>Arm II (hypofractionated RT, durvalumab, tremelimumab)</arm_group_label>
    <other_name>Imfinzi</other_name>
    <other_name>Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer</other_name>
    <other_name>MEDI-4736</other_name>
    <other_name>MEDI4736</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Hypofractionated Radiation Therapy</intervention_name>
    <description>Undergo hypofractionated RT</description>
    <arm_group_label>Arm I (hypofractionated RT, durvalumab)</arm_group_label>
    <arm_group_label>Arm II (hypofractionated RT, durvalumab, tremelimumab)</arm_group_label>
    <other_name>Hypofractionated Radiotherapy</other_name>
    <other_name>hypofractionation</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Tremelimumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm II (hypofractionated RT, durvalumab, tremelimumab)</arm_group_label>
    <other_name>Anti-CTLA4 Human Monoclonal Antibody CP-675,206</other_name>
    <other_name>CP-675</other_name>
    <other_name>CP-675,206</other_name>
    <other_name>CP-675206</other_name>
    <other_name>Ticilimumab</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologically-diagnosed HCC with progression during or after prior PD-(L)1 checkpoint&#xD;
             inhibitor immunotherapy (e.g., nivolumab and/or pembrolizumab or atezolizumab; prior&#xD;
             durvalumab excluded.&#xD;
&#xD;
             a. For patients without prior histologic or cytologic diagnosis, radiographic&#xD;
             diagnosis is allowed provided patients meet American Association for the Study of&#xD;
             Liver Diseases (AASLD) criteria for radiographic diagnosis.&#xD;
&#xD;
          2. At least 1 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1-measurable tumor&#xD;
             present which has not received RT or other local therapy prior to enrollment.&#xD;
&#xD;
          3. Clinical indication for RT to any site (e.g. painful primary or metastatic tumor,&#xD;
             local complication risk such as impending biliary or vascular obstruction).&#xD;
&#xD;
          4. Child Pugh score of A, B7, or B8 provided other liver function criteria are met.&#xD;
&#xD;
          5. Eastern Cooperative Oncology Group (ECOG) 0 or 1&#xD;
&#xD;
          6. Appropriate antiviral therapy for hepatitis B virus (HBV) according to institutional&#xD;
             standard of care with HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR)&#xD;
             &lt; 2000 IU/mL.&#xD;
&#xD;
          7. Adequate organ function as defined below:&#xD;
&#xD;
               -  Hemoglobin &gt;= 9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count &gt;= 1,500/microliter (mcL)&#xD;
&#xD;
               -  Platelet count &gt;= 75,000/mcL&#xD;
&#xD;
               -  Serum bilirubin =&lt; 1.5 x institutional upper limit of normal. This will not apply&#xD;
                  to patients with confirmed Gilbert's syndrome (persistent or recurrent&#xD;
                  hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis&#xD;
                  or hepatic pathology), who will be allowed only in consultation with their&#xD;
                  physician&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) =&lt; 2.5 x institutional upper limit of normal&#xD;
                  unless liver metastases are present in which case it can be =&lt; 5 x upper limit of&#xD;
                  normal (ULN)&#xD;
&#xD;
               -  International normalized ratio (INR) &lt; 1.5&#xD;
&#xD;
               -  Creatinine clearance &gt; 40 mL/min by Cockcroft Gault formula.&#xD;
&#xD;
          8. No contraindication to immune checkpoint inhibitor immunotherapy.&#xD;
&#xD;
          9. No contraindication to RT.&#xD;
&#xD;
         10. Age &gt;=18 years at time of study entry.&#xD;
&#xD;
         11. Life expectancy of &gt;= 12 weeks.&#xD;
&#xD;
         12. Body weight &gt; 30 kg (66.1 pounds).&#xD;
&#xD;
         13. Evidence of post-menopausal status or negative urinary or serum pregnancy test for&#xD;
             female pre-menopausal patients. Women will be considered post-menopausal if they have&#xD;
             been amenorrheic for 12 months without an alternative medical cause. The following&#xD;
             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 &gt;= 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;
         14. Women of childbearing potential and men must agree to use adequate contraception from&#xD;
             the time of screening through the duration of study participation and for at least 6&#xD;
             months after receiving combination of durvalumab plus tremelimumab and 3 months after&#xD;
             last dose of durvalumab.&#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. 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 (e.g.,&#xD;
             Health Insurance Portability and Accountability Act in the United States (US) obtained&#xD;
             from the patient/legal representative prior to performing any protocol-related&#xD;
             procedures, including screening evaluations.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior radiotherapy to tumor sites requiring RT which could compromise safety of&#xD;
             additional treatments.&#xD;
&#xD;
          2. Prior radiotherapy to more than 30% of bone marrow or to a wide field within 4 weeks&#xD;
             of the first study treatment.&#xD;
&#xD;
          3. Prior treatment with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or PD-L1&#xD;
             inhibitor.&#xD;
&#xD;
          4. History of allogenic organ transplantation.&#xD;
&#xD;
          5. On prior PD-1 inhibitor immunotherapy:&#xD;
&#xD;
               -  Any immune-related adverse events with National Cancer Institute (NCI) Common&#xD;
                  Terminology Criteria for Adverse Events (CTCAE) version (v) 5 grade &gt;= 3 on any&#xD;
                  prior immunotherapy or toxicity that led to permanent discontinuation of prior&#xD;
                  immunotherapy.&#xD;
&#xD;
               -  Any AEs while receiving prior immunotherapy not resolved to grade =&lt; 1 or&#xD;
                  resolved to baseline, with the exception of patients with endocrine AE of grade&#xD;
                  =&lt; 2, who are permitted to enroll if they are stably maintained on appropriate&#xD;
                  replacement therapy and are asymptomatic&#xD;
&#xD;
               -  Required the use of additional immunosuppression other than corticosteroids for&#xD;
                  the management of an AE, experienced recurrence of a grade &gt;= 3 AE if previously&#xD;
                  re-challenged, and currently require maintenance doses of &gt; 10 mg prednisone or&#xD;
                  equivalent per day&#xD;
&#xD;
          6. Major surgery, liver-directed therapy, or any other anticancer therapy (e.g.&#xD;
             chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy,&#xD;
             tumor embolization, monoclonal antibodies) less than 4 weeks prior to enrollment&#xD;
&#xD;
          7. Any other unresolved toxicity NCI CTCAE grade &gt;= 2 from previous anticancer therapy&#xD;
             with the exception of alopecia, vitiligo, and the laboratory values defined in the&#xD;
             inclusion criteria.&#xD;
&#xD;
               -  Patients with grade &gt;= 2 neuropathy will be evaluated on a case-by-case basis&#xD;
                  after consultation with the study physician&#xD;
&#xD;
               -  Patients with irreversible toxicity not reasonably expected to be exacerbated by&#xD;
                  treatment with durvalumab or tremelimumab may be included only after consultation&#xD;
                  with the study physician&#xD;
&#xD;
          8. Concurrent enrollment in another interventional clinical study, except only in the&#xD;
             follow-up period of that study.&#xD;
&#xD;
          9. Participation in another interventional clinical study with an investigational product&#xD;
             during the past 4 weeks except only in the follow-up period of that study.&#xD;
&#xD;
         10. 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:&#xD;
&#xD;
               -  Patients with vitiligo or alopecia&#xD;
&#xD;
               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on&#xD;
                  hormone replacement&#xD;
&#xD;
               -  Any chronic skin condition that does not require systemic therapy&#xD;
&#xD;
               -  Patients with celiac disease controlled by diet alone&#xD;
&#xD;
               -  Patients without active disease in the last 5 years may be included but only&#xD;
                  after consultation with the study physician&#xD;
&#xD;
         11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable&#xD;
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic&#xD;
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirement, substantially increase&#xD;
             risk of incurring AEs or compromise the ability of the patient to give written&#xD;
             informed consent&#xD;
&#xD;
         12. History of another primary malignancy except for:&#xD;
&#xD;
               -  Malignancy treated with curative intent and with no known active disease &gt;= 2&#xD;
                  years before the first dose of investigational product (IP) and of low potential&#xD;
                  risk for recurrence&#xD;
&#xD;
               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence&#xD;
                  of disease&#xD;
&#xD;
               -  Adequately treated carcinoma in situ without evidence of disease&#xD;
&#xD;
         13. History of leptomeningeal carcinomatosis.&#xD;
&#xD;
         14. History of active primary immunodeficiency.&#xD;
&#xD;
         15. 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).&#xD;
&#xD;
         16. Known human immunodeficiency virus (HIV) infection.&#xD;
&#xD;
         17. Current or prior use of immunosuppressive medication within 14 days before the first&#xD;
             dose of durvalumab/tremelimumab. The following are exceptions to this criterion:&#xD;
&#xD;
               -  Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra&#xD;
                  articular injection)&#xD;
&#xD;
               -  Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of&#xD;
                  prednisone or its equivalent&#xD;
&#xD;
               -  Steroids as premedication for hypersensitivity reactions (e.g., computed&#xD;
                  tomography [CT] scan premedication)&#xD;
&#xD;
         18. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:&#xD;
             Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to&#xD;
             30 days after the last dose of IP.&#xD;
&#xD;
         19. Female patients who are pregnant or breastfeeding or male or female patients of&#xD;
             reproductive potential who are not willing to employ effective birth control from&#xD;
             screening through the duration of study participation and for at least 6 months after&#xD;
             receiving combination of durvalumab plus tremelimumab and 3 months after last dose of&#xD;
             durvalumab.&#xD;
&#xD;
         20. Known allergy or hypersensitivity to IP, any of the study drugs, or any of the study&#xD;
             drug excipients.&#xD;
&#xD;
         21. Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical&#xD;
             study regardless of treatment arm assignment.&#xD;
&#xD;
         22. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca&#xD;
             staff and/or staff at the study site).&#xD;
&#xD;
         23. Any condition which, in the investigator's opinion, makes the subject unsuitable for&#xD;
             trial participation.&#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>Mary Feng, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Hewitt Chang</last_name>
    <phone>(415) 514-1571</phone>
    <email>Hewitt.Chang@ucsf.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hewitt Chang</last_name>
      <phone>415-514-1571</phone>
      <email>Hewitt.Chang@ucsf.edu</email>
    </contact>
    <contact_backup>
      <phone>877-827-3222</phone>
      <email>cancertrials@ucsf.edu</email>
    </contact_backup>
    <investigator>
      <last_name>Mary Feng, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>June 10, 2020</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>July 31, 2023</last_update_submitted>
  <last_update_submitted_qc>July 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 2, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of California, San Francisco</investigator_affiliation>
    <investigator_full_name>Mary Feng, MD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Tremelimumab</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Antibodies, Monoclonal</mesh_term>
    <mesh_term>Immunoglobulin G</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/NCT04430452
org study id: 194522
secondary id: NCI-2020-03671
nct id: NCT04430452
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This phase II trial studies how well standard of care hypofractionated radiation therapy
      followed by durvalumab with or without tremelimumab works in treating patients with
      hepatocellular cancer (liver cancer) that has spread to other places in the body (advanced)
      and that is growing, spreading, or getting worse (progressing) after treatment with PD-1
      inhibitor immunotherapy. In some patients, cancer cells and immune cells start to express
      signals that stop the body's immune system from killing the cancer. New drugs being
      developed, such as durvalumab and tremelimumab, are designed to target and block these
      signals and may help increase the immune response to prevent or slow down cancer growth.
      Hypofractionated radiation therapy delivers higher doses of radiation therapy over a shorter
      period of time and may help the immune system work even better. Giving durvalumab with or
      without tremelimumab after radiation therapy may work better than radiation therapy alone in
      treating patients with liver cancer.
PRIMARY OBJECTIVE:

      I. Determine objective response rate (ORR) of durvalumab (D) and D + tremelimumab (T) after
      radiation therapy (RT) in advanced hepatocellular carcinoma (HCC) patients with progression
      on prior PD-1 immune checkpoint inhibitor.

      SECONDARY OBJECTIVES:

      I. To determine the safety of D and D + T in advanced HCC patients with progression on prior
      PD-1 immune checkpoint inhibitor.

      II. Determine the efficacy of D and D + T in advanced HCC patients with progression on prior
      PD-1 immune checkpoint inhibitor.

      EXPLORATORY OBJECTIVES:

      I. Profile peripheral blood mononuclear cell (PBMC) immune cells and plasma samples before
      RT, after RT, and during D or D + T immunotherapy.

      II. Explore relationship between plasma biomarkers and PBMC immune profiles, the proportion
      of participants with adverse events (AEs), (safety endpoint), and clinical outcomes (ORR),
      progression-free survival (PFS), duration of response (DOR), overall survival (OS).

      III. Profile immune cells in archival pre-treatment tumor tissue for all patients and
      on-/post-treatment tumor samples and/or non-tumor liver tissue samples when available, and
      explore for relationship with safety/tolerability and clinical outcomes.

      IV. Determine incidence of tumor PD-L1 expression by immunohistochemistry (IHC) in
      pre-treatment archival tumor samples in all patients, and in on-/post-treatment tumor samples
      if repeat tumor sampling is obtained for clinical indications.

      V. Explore relationship between tumor PD-L1 status and clinical outcomes. VI. Explore
      relationship between viral hepatitis status, viral load, safety/tolerability, and clinical
      outcomes.

      VII. Measure tumor marker alpha-fetoprotein (AFP) response to immunotherapy plus RT and
      explore for relationship with clinical outcomes.

      VIII. Explore relationship between site of RT (liver, bone, other soft tissue), number of RT
      sites (1 or > 1), safety/tolerability, clinical outcomes, and changes in immune cell profiles
      on treatment.

      OUTLINE: Patients are assigned to 1 of 2 arms.

      ARM I: Patients undergo standard of care hypofractionated RT over 5 fractions once daily (QD)
      for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days
      after completion of RT, patients receive durvalumab intravenously (IV) over 1 hour on day 1.
      Treatment repeats every 28 days for up to 2 years in the absence of disease progression or
      unacceptable toxicity.

      This arm will close after the 6th participant is enrolled.

      ARM II: Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days
      in the absence of disease progression or unacceptable toxicity. Within 3-10 days after
      completion of RT, patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour
      on day 1. Treatment with durvalumab repeats every 28 days for up to 2 years in the absence of
      disease progression or unacceptable toxicity. Patients who complete the first dose of
      tremelimumab and demonstrate clinical benefit based upon radiographic tumor regression and/or
      other clinical response without progression for at least 6 cycles or 6 months on treatment,
      whichever is shorter, and subsequently have evidence of progressive disease during the
      durvalumab monotherapy portion may receive a repeat dose of tremelimumab at the next
      scheduled cycle of treatment with durvalumab per physician discretion.

      After completion of study treatment, patients are followed up every 2 months.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate (ORR)
time frame: up to 24 months
description: Defined per Response Evaluation Criteria in Solid Tumors 1.1, excluding radiation therapy-treated lesions. assessed from initiation of study treatment until discontinuation of treatment. Proportion of response and corresponding exact confidence intervals will be reported for objective response rate in each Arm. Patients with unevaluable or unknown response status will be considered non-responders.
measure: Number of of treatment-related adverse events
time frame: up to 24 months
description: Summary tables for AEs will include only AEs that started or worsened during the on-treatment period, the treatment-emergent AEs graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0)
measure: Progression-free survival
time frame: Up to 24 months
description: Progression will be calculated in months from date of first dose of protocol therapy to date of first documented radiographic and/or clinical disease progression or death from any cause. For cases without progression, follow-up will be censored at the date of last disease assessment without progression, unless death occurs within a short period of time following the date last known progression-free, in which case the death will be counted as a failure. The 'short period of time' will generally be no more than 3 months. For patients discontinued from study for other reasons than progression or death, progression-free survival will be censored at the date last known to be progression-free
measure: Duration of overall response (DOR)
time frame: Up to 24 months
description: The period measured from the time that measurement criteria are met for complete or partial response (whichever status is recorded first) until the first date that recurrent or progressive disease is objectively documented, taking as reference the smallest measurements recorded since treatment started
measure: Overall survival (OS)
time frame: Up to 24 months
description: Survival will be measured from the date of entry on study and from first dose of protocol therapy to the date of death due to any cause. Censoring will be performed using the date of last known contact for those who are alive at the time of analysis
arm group label: Arm I (hypofractionated RT, durvalumab)
arm group type: Experimental
description: Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive durvalumab IV over 1 hour on day 1. Treatment repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
arm group label: Arm II (hypofractionated RT, durvalumab, tremelimumab)
arm group type: Experimental
description: Patients undergo standard of care hypofractionated RT over 5 fractions QD for 5 days in the absence of disease progression or unacceptable toxicity. Within 3-10 days after completion of RT, patients receive tremelimumab IV over 1 hour and durvalumab IV over 1 hour on day 1. Treatment with durvalumab repeats every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients who complete the first dose of tremelimumab and demonstrate clinical benefit based upon radiographic tumor regression and/or other clinical response without progression for at least 6 cycles or 6 months on treatment, whichever is shorter, and subsequently have evidence of progressive disease during the durvalumab monotherapy portion may receive a repeat dose of tremelimumab at the next scheduled cycle of treatment with durvalumab per physician discretion.
intervention type: Biological
intervention name: Durvalumab
description: Given IV
arm group label: Arm I (hypofractionated RT, durvalumab)
arm group label: Arm II (hypofractionated RT, durvalumab, tremelimumab)
other name: Imfinzi
other name: Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
other name: MEDI-4736
other name: MEDI4736
intervention type: Radiation
intervention name: Hypofractionated Radiation Therapy
description: Undergo hypofractionated RT
arm group label: Arm I (hypofractionated RT, durvalumab)
arm group label: Arm II (hypofractionated RT, durvalumab, tremelimumab)
other name: Hypofractionated Radiotherapy
other name: hypofractionation
intervention type: Biological
intervention name: Tremelimumab
description: Given IV
arm group label: Arm II (hypofractionated RT, durvalumab, tremelimumab)
other name: Anti-CTLA4 Human Monoclonal Antibody CP-675,206
other name: CP-675
other name: CP-675,206
other name: CP-675206
other name: Ticilimumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mary Feng, MD
role: Principal Investigator
affiliation: University of California, San Francisco
last name: Hewitt Chang
phone: (415) 514-1571
email: Hewitt.Chang@ucsf.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of California, San Francisco
investigator full name: Mary Feng, MD
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
mesh term: Durvalumab
mesh term: Ipilimumab
mesh term: Tremelimumab
mesh term: Immunoglobulins
mesh term: Antibodies, Monoclonal
mesh term: Immunoglobulin G
sharing ipd: No