<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/NCT03297463</url>
  </required_header>
  <id_info>
    <org_study_id>2016LS172</org_study_id>
    <nct_id>NCT03297463</nct_id>
  </id_info>
  <brief_title>Radiation Therapy With Combination Immunotherapy for Relapsed/Refractory Metastatic Melanoma</brief_title>
  <official_title>A Phase 1b/2 Study of Hypofractionated Radiation and Combination Immunotherapy for Relapsed/Refractory Metastatic Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Masonic Cancer Center, University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Masonic Cancer Center, University of Minnesota</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 1b/2 study designed to evaluate combination of the human T-cell cytokine&#xD;
      Interleukin-2 (IL-2) and a checkpoint inhibitor Ipilimumab immediately following a course of&#xD;
      hypofractionated palliative radiation therapy in the management of unresectable,&#xD;
      relapsed/refractory metastatic melanoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The sequential administration of Interleukin-2 (IL-2) following radiation therapy offers a&#xD;
      rational immunologic priming strategy to expand antigen primed T cells under the growth&#xD;
      promoting effects of Interleukin-2 therapy.&#xD;
&#xD;
      This clinical trial is designed to evaluate the combination of the T cell cytokine&#xD;
      Interleukin-2 and the checkpoint inhibitor Ipilimumab in sequential combination following a&#xD;
      course of hypofractionated palliative radiation therapy. The addition of single dose&#xD;
      Ipilimumab offers rational timing of CTLA-4 checkpoint blockade to decrease activity of&#xD;
      regulatory and suppressor T cell subsets following IL-2 based immunotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Replaced by another study.&#xD;
  </why_stopped>
  <start_date type="Actual">January 31, 2018</start_date>
  <completion_date type="Anticipated">February 1, 2020</completion_date>
  <primary_completion_date type="Anticipated">February 1, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Phase 1: Maximum Tolerated Dose (MTD)</measure>
    <time_frame>Cycle 2 Day 1</time_frame>
    <description>Incidence of Adverse Events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 1: Maximum Tolerated Dose (MTD)</measure>
    <time_frame>Cycle 2 Day 15</time_frame>
    <description>Incidence of Adverse Events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 1: Maximum Tolerated Dose (MTD)</measure>
    <time_frame>30 days after last IL-2</time_frame>
    <description>Incidence of Adverse Events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2: Objective Response Rate (ORR)</measure>
    <time_frame>Day 35</time_frame>
    <description>Disease re-assessment includes physical examination, as well as radiographic response assessment (RECIST v1.1) of non-irradiated target lesions using CT (or PET/CT) and/or at MRI.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase 2: Objective Response Rate (ORR)</measure>
    <time_frame>30 days after last IL-2</time_frame>
    <description>Disease re-assessment includes physical examination, as well as radiographic response assessment (RECIST v1.1) of non-irradiated target lesions using CT (or PET/CT) and/or at MRI.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Every 3 Months until 2 Years from 1st IL-2 Dose</time_frame>
    <description>Incidence of PFS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Every 3 Months until 2 Years from 1st IL-2 Dose</time_frame>
    <description>Incidence of OS</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Metastatic Melanoma</condition>
  <condition>Pulmonary Metastases</condition>
  <condition>Hepatic Metastases</condition>
  <condition>Brain Metastases</condition>
  <arm_group>
    <arm_group_label>Phase Ib (Dose Escalation)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II (Dose Expansion)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Interleukin-2 &amp; Ipilimumab (P-Ib)</intervention_name>
    <description>Phase Ib:&#xD;
- Ipilimumab will be administered in a 3 + 3 dose escalation design.&#xD;
The starting dose will be 0.3 mg/kg administered within 7 days of day 1 cycle 2 ALdesleukin (IL-2).&#xD;
If dose limiting autoimmune toxicities (DLTs) are not observed, the next cohort will receive 1.5 mg/kg.&#xD;
The final cohort will receive 3 mg/kg, in the event that cohort 2 does not exhibit DLTs.&#xD;
In the event of excessive toxicity in cohort 1, then a -1 dose level of 0.1 mg/kg may be evaluated in subsequent cohorts. Cohort sizes will increase to 6 patients if 1 of 3 patients in a cohort experience a DLT.&#xD;
Once the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) is declared, no staggering of enrollment is required for accrual.</description>
    <arm_group_label>Phase Ib (Dose Escalation)</arm_group_label>
    <other_name>IL-2</other_name>
    <other_name>Yervoy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Interleukin-2 &amp; Ipilimumab (P-II)</intervention_name>
    <description>Phase II:&#xD;
- Interleukin-2 &amp; Ipilimumab will be administered at the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D).</description>
    <arm_group_label>Phase II (Dose Expansion)</arm_group_label>
    <other_name>IL-2</other_name>
    <other_name>Yervoy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Biopsy-proven unresectable, metastatic melanoma refractory to standard immunotherapy&#xD;
             drugs or regimens, including prior treatment with Aldesleukin (IL-2), GM-CSF,&#xD;
             Ipilimumab, Nivolumab, Pembrolizumab, and/or Imlygic (T-VEC).&#xD;
&#xD;
          -  Prior clinical trial participation or treatment with molecularly targeted agents (i.e.&#xD;
             Vemurafenib/Cobimetinib, Dabrafenib/Trametinib) or chemotherapy (i.e. Temozolomide,&#xD;
             Dacarbazine, Platinum, or Taxanes) is permitted.&#xD;
&#xD;
          -  Must have a minimum of 3 radiographically distinct (&gt;1.5 cm) lesions measurable by&#xD;
             RECIST 1.1 at time of study enrollment (&gt;5 preferred).&#xD;
&#xD;
               -  A maximum of 2 metastases per treated organ may be targeted for HD-XRT, but must&#xD;
                  be separated by more than 5 cm of normal tissue&#xD;
&#xD;
               -  At least 2 non-irradiated lesions are required for systemic response assessments&#xD;
&#xD;
          -  Pulmonary metastases: Pulmonary metastasis permissible. Appropriate candidates with&#xD;
             lung lesions may be considered for ablative hypofractionation using SBRT.&#xD;
&#xD;
          -  Hepatic metastases: Hepatic metastasis permissible. Appropriate candidates with&#xD;
             metastasis to liver may be considered for ablative hypofractionation using SBRT.&#xD;
&#xD;
          -  Brain metastases: Brain metastases may be treated using Gamma Knife Radiosurgery (GKR)&#xD;
             or whole brain radiation therapy (WBRT) per the treating radiation oncologist. Total&#xD;
             radiation dose and number of fractions will be determined by the treating radiation&#xD;
             oncologist based on anatomic and dosing constraints. MRI of the vertebral column is&#xD;
             required for all patients with suspected epidural tumor extension.&#xD;
&#xD;
          -  Must have sufficient archival tissue block material (1.5 x 1.5 x 1.5 cm) and/or newly&#xD;
             obtained core or excisional biopsy of tumor tissue; minimum of 2 cores.&#xD;
&#xD;
          -  ECOG performance status 0 or 1 (appendix 2)&#xD;
&#xD;
          -  Age 18 to 85 years of age; &gt; 85 years of age must be approved by Principal&#xD;
             Investigator.&#xD;
&#xD;
          -  Adequate organ function within 14 days of registration (30 days for pulmonary and&#xD;
             cardiac assessments) defined as:&#xD;
&#xD;
               -  Hematologic: Leukocytes ≥ 3,000/mcL, ANC ≥ 1,000/mcL, Hemoglobin ≥ 9.0 g/dL,&#xD;
                  Platelets ≥ 120,000/mcL&#xD;
&#xD;
               -  Renal: Serum creatinine ≤ 1.8 mg/dL; for patients with a creatinine &gt; 1.5 mg/dL&#xD;
                  or a history of renal dysfunction, an estimated glomerular filtration rate ≥ 35&#xD;
                  mL/min/1.73 m2 is required&#xD;
&#xD;
               -  Hepatic: AST, ALT, and alkaline phosphatase ≤ 10 x upper limit of normal and&#xD;
                  total bilirubin ≤ 2.0 mg/dL Pulmonary: oxygen saturation ≥90% on room air;&#xD;
                  corrected DLCO and FEV1, ≥ 50% predicted&#xD;
&#xD;
               -  Cardiac: Absence of clinical decompensated congestive heart failure or&#xD;
                  uncontrolled arrhythmia; left ventricular ejection fraction (echocardiogram&#xD;
                  within 6 months permitted) ≥ 40%. QTc must be &lt; 450 ms in males and &lt; 470 ms in&#xD;
                  females.&#xD;
&#xD;
          -  Time from last anti-tumor treatment to first radiation treatment at least 1 week.&#xD;
&#xD;
          -  Recovery from previous cancer treatment (≤ Grade 1 by CTCAE 4.0 criteria) prior to&#xD;
             first radiation treatment&#xD;
&#xD;
          -  Women of childbearing potential and males with partners of childbearing potential must&#xD;
             agree to the use of barrier methods of contraception, hormonal contraceptives, or to&#xD;
             abstain from heterosexual activity for the duration of study participation.&#xD;
&#xD;
          -  Ability to understand and provide voluntary written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast feeding. The agents used in this study have the potential to harm a&#xD;
             fetus. Radiation is a known teratogen. There is insufficient information regarding&#xD;
             potential for fetal harm during immunotherapy at this time. Biological females of&#xD;
             childbearing potential must have a negative serum pregnancy test within 14 days of&#xD;
             registration.&#xD;
&#xD;
          -  Diagnosis of immunodeficiency&#xD;
&#xD;
          -  Concurrent use of high dose steroids; chronic steroid use of &lt; 2 mg dexamethasone or&#xD;
             equivalent per day is permissible&#xD;
&#xD;
          -  Concurrent malignancy requiring active treatment, except basal cell carcinoma of the&#xD;
             skin, squamous cell carcinoma of the skin or carcinoma in situ&#xD;
&#xD;
          -  Prior organ allograft or allogeneic transplantation&#xD;
&#xD;
          -  Autoimmune disease&#xD;
&#xD;
          -  Uncontrolled intercurrent or psychiatric illness or social situation that would limit&#xD;
             compliance with study requirements&#xD;
&#xD;
          -  Live vaccines within 30 days prior to the first dose of IL-2 and while participating&#xD;
             in the trial. Examples of live vaccines include, but are not limited to, measles,&#xD;
             mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine.&#xD;
             Seasonal influenza vaccines for injection are generally killed virus vaccines and are&#xD;
             allowed. However, intranasal influenza vaccines (eg, Flu - Mist®) are live attenuated&#xD;
             vaccines, and are not allowed.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Domingo-Musibay Evidio, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Masonic Cancer Center, University of Minnesota</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Masonic Cancer Center - University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>September 26, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 29, 2017</study_first_posted>
  <last_update_submitted>July 30, 2018</last_update_submitted>
  <last_update_submitted_qc>July 30, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ipilimumab</mesh_term>
    <mesh_term>Interleukin-2</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03297463
org study id: 2016LS172
nct id: NCT03297463
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
This is a Phase 1b/2 study designed to evaluate combination of the human T-cell cytokine
      Interleukin-2 (IL-2) and a checkpoint inhibitor Ipilimumab immediately following a course of
      hypofractionated palliative radiation therapy in the management of unresectable,
      relapsed/refractory metastatic melanoma.
The sequential administration of Interleukin-2 (IL-2) following radiation therapy offers a
      rational immunologic priming strategy to expand antigen primed T cells under the growth
      promoting effects of Interleukin-2 therapy.

      This clinical trial is designed to evaluate the combination of the T cell cytokine
      Interleukin-2 and the checkpoint inhibitor Ipilimumab in sequential combination following a
      course of hypofractionated palliative radiation therapy. The addition of single dose
      Ipilimumab offers rational timing of CTLA-4 checkpoint blockade to decrease activity of
      regulatory and suppressor T cell subsets following IL-2 based immunotherapy.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Phase 1: Maximum Tolerated Dose (MTD)
time frame: Cycle 2 Day 1
description: Incidence of Adverse Events
measure: Phase 1: Maximum Tolerated Dose (MTD)
time frame: Cycle 2 Day 15
description: Incidence of Adverse Events
measure: Phase 1: Maximum Tolerated Dose (MTD)
time frame: 30 days after last IL-2
description: Incidence of Adverse Events
measure: Phase 2: Objective Response Rate (ORR)
time frame: Day 35
description: Disease re-assessment includes physical examination, as well as radiographic response assessment (RECIST v1.1) of non-irradiated target lesions using CT (or PET/CT) and/or at MRI.
measure: Phase 2: Objective Response Rate (ORR)
time frame: 30 days after last IL-2
description: Disease re-assessment includes physical examination, as well as radiographic response assessment (RECIST v1.1) of non-irradiated target lesions using CT (or PET/CT) and/or at MRI.
measure: Progression-free survival (PFS)
time frame: Every 3 Months until 2 Years from 1st IL-2 Dose
description: Incidence of PFS
measure: Overall survival (OS)
time frame: Every 3 Months until 2 Years from 1st IL-2 Dose
description: Incidence of OS
arm group label: Phase Ib (Dose Escalation)
arm group type: Experimental
arm group label: Phase II (Dose Expansion)
arm group type: Experimental
intervention type: Drug
intervention name: Interleukin-2 & Ipilimumab (P-Ib)
description: Phase Ib:
- Ipilimumab will be administered in a 3 + 3 dose escalation design.
The starting dose will be 0.3 mg/kg administered within 7 days of day 1 cycle 2 ALdesleukin (IL-2).
If dose limiting autoimmune toxicities (DLTs) are not observed, the next cohort will receive 1.5 mg/kg.
The final cohort will receive 3 mg/kg, in the event that cohort 2 does not exhibit DLTs.
In the event of excessive toxicity in cohort 1, then a -1 dose level of 0.1 mg/kg may be evaluated in subsequent cohorts. Cohort sizes will increase to 6 patients if 1 of 3 patients in a cohort experience a DLT.
Once the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) is declared, no staggering of enrollment is required for accrual.
arm group label: Phase Ib (Dose Escalation)
other name: IL-2
other name: Yervoy
intervention type: Drug
intervention name: Interleukin-2 & Ipilimumab (P-II)
description: Phase II:
- Interleukin-2 & Ipilimumab will be administered at the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D).
arm group label: Phase II (Dose Expansion)
other name: IL-2
other name: Yervoy
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Domingo-Musibay Evidio, MD
role: Principal Investigator
affiliation: Masonic Cancer Center, University of Minnesota
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
mesh term: Ipilimumab
mesh term: Interleukin-2