<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/NCT03802747</url>
  </required_header>
  <id_info>
    <org_study_id>18-0710.cc</org_study_id>
    <secondary_id>ESR-17-13132</secondary_id>
    <nct_id>NCT03802747</nct_id>
  </id_info>
  <brief_title>Immunotherapy Combined With Y-90 and SBRT for Colorectal Liver Metastases</brief_title>
  <official_title>Phase I Study of Dual Immune Checkpoint Blockade (Anti-PD-L1 (Durvalumab) (MEDI4736) and Anti-CTLA4 (Tremelimumab) Plus Yttrium-90 (Y-90) Radioembolization &amp; Stereotactic Body Radiation Therapy (SBRT) in Refractory Metastatic MSS (Microsatellite Stable) Colorectal Cancer With Liver Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Colorado, Denver</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Colorado, Denver</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is evaluating the combination of Y-90 radioembolization followed by SBRT with the&#xD;
      immunotherapy drugs, durvalumab and tremelimumab, to improve disease control of liver&#xD;
      metastases for patients with microsatellite stable colorectal cancer.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    PI left the institution&#xD;
  </why_stopped>
  <start_date type="Anticipated">August 2019</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>The first 6 patients will receive durvalumab alone with Y-90 and SBRT followed by 4 months of durvalumab. The next 6 patients will received durvalumab with Y-90 and SBRT followed by 4 months of durvalumab + tremelimumab.Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. There will be no dose escalation. For patients who will receive both Durvalumab and Tremelimumab, the Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses. There will be no dose escalation.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Treatment Related Adverse Events</measure>
    <time_frame>Start of study to 3 months post treatment completion, up to 5 years</time_frame>
    <description>Adverse events related to Y-90, SBRT, and durvalumab plus tremelimumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Dose-Limiting Toxicity of Y-90+SBRT in Combination with Dual Immune Checkpoint Blockade</measure>
    <time_frame>Start of study to 3 months post treatment completion, up to 5 years</time_frame>
    <description>Defined as the rate of &gt;Grade 3 treatment-related adverse events during treatment or within 3 months of treatment completion.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR)</measure>
    <time_frame>Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years</time_frame>
    <description>The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival for Three Months (PFS)</measure>
    <time_frame>Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years</time_frame>
    <description>The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years</time_frame>
    <description>The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival for Two Years (OS)</measure>
    <time_frame>Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years</time_frame>
    <description>Measure of overall survival rate by examining the incidence of death over a two year period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Liver Progression Free Survival for One Year (L-PFS)</measure>
    <time_frame>Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years</time_frame>
    <description>The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathological Response Rates (PRR)</measure>
    <time_frame>Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years</time_frame>
    <description>Measured by the percentage of viable tumor throughout and post treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Tumor Progression (TTP)</measure>
    <time_frame>Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years</time_frame>
    <description>The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Y-90, SBRT, and Durvalumab Alone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Six patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Y-90, SBRT, and Durvalumab + Tremelimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Six patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab + Tremelimumab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab</intervention_name>
    <description>Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity.</description>
    <arm_group_label>Y-90, SBRT, and Durvalumab Alone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Durvalumab and Tremelimumab</intervention_name>
    <description>Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses.</description>
    <arm_group_label>Y-90, SBRT, and Durvalumab + Tremelimumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Y-90 Selective Internal Radiation Therapy (SIRT)</intervention_name>
    <description>Yttrium-90 microsphere therapy consists of resin beads loaded with Yttrium, a pure beta emitter with a 64.2 hour half-life. Radioembolization will be performed as standard of care therapy per current NCCN guidelines.</description>
    <arm_group_label>Y-90, SBRT, and Durvalumab + Tremelimumab</arm_group_label>
    <arm_group_label>Y-90, SBRT, and Durvalumab Alone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Stereotactic Body Radiation Therapy (SBRT)</intervention_name>
    <description>High-dose hypofractionated conformal external beam radiation therapy that is considered a standard of care. SBRT will also be considered for metastases that are persistent and/or progressive after Y-90 based on MR imaging and pathology from tissue biopsies.</description>
    <arm_group_label>Y-90, SBRT, and Durvalumab + Tremelimumab</arm_group_label>
    <arm_group_label>Y-90, SBRT, and Durvalumab Alone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Histologic or cytologic confirmation of metastatic microsatellite stable colorectal&#xD;
             cancer&#xD;
&#xD;
          2. Liver metastases not amenable to resection for which palliative Y-90 and SBRT is&#xD;
             considered appropriate standard therapy&#xD;
&#xD;
          3. Patients should have received at least one prior standard therapy for metastatic&#xD;
             disease. Prior therapies should include regimens containing oxaliplatin and irinotecan&#xD;
             in combination with a fluoropyrimidine if appropriate (e.g., FOLFOX and FOLFIRI or&#xD;
             their variants) unless contraindicated, not tolerated, or declined.&#xD;
&#xD;
          4. Male or female, age 18 or older&#xD;
&#xD;
          5. ECOG performance status of 0 or 1&#xD;
&#xD;
          6. Body weight &gt;30 kg&#xD;
&#xD;
          7. Life expectancy of greater than 6 months&#xD;
&#xD;
          8. 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 ≥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;
          9. Patients must have acceptable organ and marrow function as defined below:&#xD;
&#xD;
               -  Hemoglobin ≥9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count (ANC ≥1.0 x (&gt; 1000 per mm3))&#xD;
&#xD;
               -  Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).&#xD;
&#xD;
               -  Total bilirubin : &lt; 2x upper limit of normal&#xD;
&#xD;
               -  AST (SGOT)/ALT (SGPT): &lt;2.5x institutional upper limit of normal&#xD;
&#xD;
               -  Creatinine: &lt;1.5x upper limit of normal OR Creatinine clearance &gt;40mL/min for&#xD;
                  patients with creatinine levels above institutional normal&#xD;
&#xD;
         10. Ability to understand and willingness to sign a written informed consent document&#xD;
&#xD;
         11. Residual or on-going ≥ Grade 3 treatment-related toxicity from previous chemotherapy&#xD;
             should be resolved.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participation in another clinical study with an investigational drug during the last 4&#xD;
             weeks.&#xD;
&#xD;
          2. Concurrent enrollment in another clinical study, unless it is an observational&#xD;
             (non-interventional) clinical study or during the follow-up period of an&#xD;
             interventional study&#xD;
&#xD;
          3. 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;
               -  Patients with Grade &gt;2 neuropathy will be evaluated on a case-by-case basis after&#xD;
                  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;
          4. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.&#xD;
             Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone&#xD;
             replacement therapy) is acceptable.&#xD;
&#xD;
          5. Major surgical procedure (as defined by the Investigator) within 28 days prior to the&#xD;
             first dose of IP. Note: Local surgery of isolated lesions for palliative intent is&#xD;
             acceptable.&#xD;
&#xD;
          6. History of allogenic organ transplantation.&#xD;
&#xD;
          7. 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 without active disease in the last 5 years may be included but only&#xD;
                  after consultation with the study physician&#xD;
&#xD;
               -  Patients with celiac disease controlled by diet alone&#xD;
&#xD;
          8. Prior therapy with an anti-PD-1 or anti-PD-L1, including durvalumab antibody within 6&#xD;
             months prior to enrollment and anti-CTLA4 (including tremelimumab)&#xD;
&#xD;
          9. Prior abdominal radiotherapy&#xD;
&#xD;
         10. Child-Pugh class B or higher&#xD;
&#xD;
         11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, uncontrolled hypertension, insterstitial lung disease, serious chronic&#xD;
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirements, 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 ≥2 years&#xD;
                  before the first dose of IP and of low potential 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 TB testing in line with&#xD;
             local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),&#xD;
             hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients&#xD;
             with a past or resolved HBV infection (defined as the presence of hepatitis B core&#xD;
             antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for&#xD;
             hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative&#xD;
             for HCV RNA.&#xD;
&#xD;
         16. Current or prior use of immunosuppressive medication within 14 days before the first&#xD;
             dose of durvalumab or 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 &lt;&lt;10 mg/day&gt;&gt; of&#xD;
                  prednisone or its equivalent&#xD;
&#xD;
               -  Steroids as premedication for hypersensitivity reactions (e.g., CT scan&#xD;
                  premedication)&#xD;
&#xD;
         17. 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;
         18. Contraindication to IV contrast&#xD;
&#xD;
         19. Pregnant and breastfeeding women are excluded. Women of child-bearing potential who&#xD;
             are unwilling or unable to use an acceptable method of birth control to avoid&#xD;
             pregnancy from screening to 90 days after the last dose of durvalumab monotherapy or&#xD;
             180 days after the last dose of durvalumab + tremelimumab combination therapy are&#xD;
             excluded. This applies to any woman who has experienced menarche and who has not&#xD;
             undergone successful surgical sterilization or is not postmenopausal (defined as&#xD;
             amenorrhea for at least 12 consecutive months, or women on hormone replacement therapy&#xD;
             with serum FSH levels greater than 35 mIU/mL). A negative urine or serum pregnancy&#xD;
             test must be obtained within 14 days prior to the start of study therapy in all women&#xD;
             of child-bearing potential. Male subjects must also agree to use effective&#xD;
             contraception for the same time period as above.&#xD;
&#xD;
         20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug&#xD;
             excipients.&#xD;
&#xD;
         21. Use of any prohibited concomitant medications, including:&#xD;
&#xD;
               -  Traditional herbal medicines, as their use may result in unanticipated drug-drug&#xD;
                  interactions that may cause or confound assessment of toxicity.&#xD;
&#xD;
               -  Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to Cycle 1 Day&#xD;
                  1 or at any time during the study and for at least 5 months after the last dose&#xD;
                  of durvalumab.&#xD;
&#xD;
               -  Use of steroids to premedicate patients for whom MRI scans with contrast are&#xD;
                  contraindicated (i.e., patients with contrast allergy or impaired renal&#xD;
                  clearance)&#xD;
&#xD;
               -  Immunomodulatory agents, including but not limited to interferons or&#xD;
                  interleukin-2, during the entire study; these agents could potentially increase&#xD;
                  the risk for autoimmune conditions when administered with durvalumab.&#xD;
&#xD;
               -  Immunosuppressive medications, including but not limited to cyclophosphamide,&#xD;
                  azathioprine, methotrexate, and thalidomide; these agents could potentially alter&#xD;
                  the activity and the safety of durvalumab&#xD;
&#xD;
               -  Systemic corticosteroids and tumor necrosis factor-α (TNF-α) inhibitors may&#xD;
                  attenuate potential beneficial immunologic effects of treatment with durvalumab.&#xD;
                  Therefore, in situations where systemic corticosteroids or TNF-α inhibitors would&#xD;
                  be routinely administered, alternatives, including antihistamines, should be&#xD;
                  considered first by the treating physician. If the alternatives are not feasible,&#xD;
                  systemic corticosteroids and TNF-α inhibitors may be administered at the&#xD;
                  discretion of the treating physician (see Section 4.4.2)&#xD;
&#xD;
               -  Initiation or increased dose of granulocyte colony-stimulating factors (e.g.,&#xD;
                  granulocyte colony stimulating factor, granulocyte/macrophage colony-stimulating&#xD;
                  factor, and/or pegfilgrastim) is prohibited.&#xD;
&#xD;
         22. Shunt Fraction greater than 20% (Requires more than 30gy dose to the lungs in order&#xD;
             receive therapeutic dose of Y-90).&#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>Karyn Goodman, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Colorado, Denver</affiliation>
  </overall_official>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>January 8, 2019</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>October 4, 2019</last_update_submitted>
  <last_update_submitted_qc>October 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Liver Metastases</keyword>
  <keyword>Phase 1</keyword>
  <keyword>Durvalumab</keyword>
  <keyword>Tremelimumab</keyword>
  <keyword>Yttrium-90</keyword>
  <keyword>Radioembolization</keyword>
  <keyword>Stereotactic Body Radiation Therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Durvalumab</mesh_term>
    <mesh_term>Tremelimumab</mesh_term>
    <mesh_term>Antibodies, Monoclonal</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/NCT03802747
org study id: 18-0710.cc
secondary id: ESR-17-13132
nct id: NCT03802747
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study is evaluating the combination of Y-90 radioembolization followed by SBRT with the
      immunotherapy drugs, durvalumab and tremelimumab, to improve disease control of liver
      metastases for patients with microsatellite stable colorectal cancer.
allocation: Non-Randomized
intervention model: Single Group Assignment
intervention model description: The first 6 patients will receive durvalumab alone with Y-90 and SBRT followed by 4 months of durvalumab. The next 6 patients will received durvalumab with Y-90 and SBRT followed by 4 months of durvalumab + tremelimumab.Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. There will be no dose escalation. For patients who will receive both Durvalumab and Tremelimumab, the Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses. There will be no dose escalation.
primary purpose: Treatment
masking: None (Open Label)
measure: Incidence of Treatment Related Adverse Events
time frame: Start of study to 3 months post treatment completion, up to 5 years
description: Adverse events related to Y-90, SBRT, and durvalumab plus tremelimumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.
measure: Dose-Limiting Toxicity of Y-90+SBRT in Combination with Dual Immune Checkpoint Blockade
time frame: Start of study to 3 months post treatment completion, up to 5 years
description: Defined as the rate of >Grade 3 treatment-related adverse events during treatment or within 3 months of treatment completion.
measure: Duration of Response (DoR)
time frame: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
description: The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
measure: Progression Free Survival for Three Months (PFS)
time frame: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
description: The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
measure: Overall Response Rate (ORR)
time frame: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
description: The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
measure: Overall Survival for Two Years (OS)
time frame: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
description: Measure of overall survival rate by examining the incidence of death over a two year period.
measure: Liver Progression Free Survival for One Year (L-PFS)
time frame: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
description: The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
measure: Pathological Response Rates (PRR)
time frame: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
description: Measured by the percentage of viable tumor throughout and post treatment
measure: Time to Tumor Progression (TTP)
time frame: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years
description: The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.
arm group label: Y-90, SBRT, and Durvalumab Alone
arm group type: Experimental
description: Six patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab.
arm group label: Y-90, SBRT, and Durvalumab + Tremelimumab
arm group type: Experimental
description: Six patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab + Tremelimumab.
intervention type: Drug
intervention name: Durvalumab
description: Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity.
arm group label: Y-90, SBRT, and Durvalumab Alone
intervention type: Drug
intervention name: Durvalumab and Tremelimumab
description: Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses.
arm group label: Y-90, SBRT, and Durvalumab + Tremelimumab
intervention type: Drug
intervention name: Y-90 Selective Internal Radiation Therapy (SIRT)
description: Yttrium-90 microsphere therapy consists of resin beads loaded with Yttrium, a pure beta emitter with a 64.2 hour half-life. Radioembolization will be performed as standard of care therapy per current NCCN guidelines.
arm group label: Y-90, SBRT, and Durvalumab + Tremelimumab
arm group label: Y-90, SBRT, and Durvalumab Alone
intervention type: Drug
intervention name: Stereotactic Body Radiation Therapy (SBRT)
description: High-dose hypofractionated conformal external beam radiation therapy that is considered a standard of care. SBRT will also be considered for metastases that are persistent and/or progressive after Y-90 based on MR imaging and pathology from tissue biopsies.
arm group label: Y-90, SBRT, and Durvalumab + Tremelimumab
arm group label: Y-90, SBRT, and Durvalumab Alone
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Karyn Goodman, MD
role: Principal Investigator
affiliation: University of Colorado, Denver
country: United States
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Neoplasm Metastasis
mesh term: Durvalumab
mesh term: Tremelimumab
mesh term: Antibodies, Monoclonal
sharing ipd: No