<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/NCT03282188</url>
  </required_header>
  <id_info>
    <org_study_id>MO15/121</org_study_id>
    <nct_id>NCT03282188</nct_id>
  </id_info>
  <brief_title>REO13 Melanoma With of Without GM-CSF</brief_title>
  <official_title>A Clinical Study to Evaluate the Biological Effects of Intravenous Wild-type Reovirus (Reolysin®), With of Without GM-CSF, in Advanced Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Leeds</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Yorkshire Cancer Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Leeds</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Open-label, non-randomised, single centre study which will assess the presence of reovirus&#xD;
      (Reolysin®), following intravenous administration with or without Granulocyte-macrophage&#xD;
      colony-stimulating factor (GM-CSF) given to patients prior to surgery for metastatic&#xD;
      melanoma. All patients will receive an initial low 'immunisation' dose of intravenous&#xD;
      reovirus. Patients will be enrolled sequentially in to each of the two cohorts receiving&#xD;
      either reovirus alone, or reovirus plus GM-CSF. For this study we anticipate 8-16 evaluable&#xD;
      patients, up to 8 for each group. The endpoints of this study will compare the 2 treatment&#xD;
      groups for reovirus tumour infiltration and replication. Compare the neutralising antibody&#xD;
      development and cell-mediated immune response and identify any adverse events and laboratory&#xD;
      toxicities.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, non-randomised, single centre study of intravenous reovirus&#xD;
      (Reolysin®) with or without Granulocyte-macrophage colony-stimulating factor (GM-CSF) given&#xD;
      to patients prior to surgery for metastatic melanoma. Patients will be eligible if undergoing&#xD;
      surgery for local control of lymph node involvement (with or without stage 4 metastases) or&#xD;
      if planned for resection of cutaneous, subcutaneous, musculoskeletal or visceral metastases&#xD;
      for local control, palliation of symptoms or personal choice.&#xD;
&#xD;
      All patients will receive an initial low 'immunisation' dose of intravenous reovirus (1x108&#xD;
      TCID50), to ensure that neutralising antibody (NAB) levels have risen by the time a full&#xD;
      cycle of reovirus +/- GM-CSF is given. All patients will receive only 1 cycle of treatment&#xD;
      which will comprise: i) For reovirus alone patients (Group A), 1x1010 TCID50 as a 1-hour IV&#xD;
      infusion on 2 consecutive days; ii) For reovirus plus GM-CSF patients (Group B), subcutaneous&#xD;
      GM-CSF (50mcg/day) for 3 days, followed by 2 days of reovirus. Both doses of reovirus will be&#xD;
      at 1x1010 TCID50.&#xD;
&#xD;
      Patients will be enrolled sequentially into each of the two cohorts receiving intravenous&#xD;
      reovirus alone, or reovirus plus GM-CSF. The addition of GM-CSF is designed to address&#xD;
      effects on the translational objectives/endpoints of this study, rather than primary&#xD;
      toxicity, although all patients will be monitored for safety. Clinical assessment will be&#xD;
      performed at screening (within 14 days of start of treatment), at day 1 (1st GM-CSF&#xD;
      dose/none), day 8 and at the final study visit (40 days (+/- 14 days) post treatment with&#xD;
      reovirus). Safety bloods will be taken at screening, at treatment (Day 1), before each dose&#xD;
      of reovirus (Day 4 &amp; 5), at Day 8 and at the final study visit (Day 40). Immunological&#xD;
      assays, including reovirus antibody levels, will be performed before low-dose reovirus&#xD;
      priming (Day -10 to -6), pre-treatment on Day 1, on Day 4 and 5 (pre-reovirus infusion and 60&#xD;
      minutes post-infusion), Day 8, and at the final study visit (Day 40). Patients with&#xD;
      accessible skin or subcutaneous metastases will be asked for an optional additional&#xD;
      pre-treatment biopsy which will be taken before low-dose reovirus priming.&#xD;
&#xD;
      All procedures will be performed as an outpatient or day case, apart from surgery in melanoma&#xD;
      patients requiring admission as part of standard clinical care. Imaging will be as for&#xD;
      standard clinical care only. Following surgical resection the tumour will be assessed for&#xD;
      viral status and anti-tumour effects by e.g. standard histology, immunohistochemistry, RT-PCR&#xD;
      and electron microscopy. Further imaging and follow-up beyond the final study visit (Day 40&#xD;
      +/- 14 days) will be as for standard clinical care only.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Withdrawn by Sponsor&#xD;
  </why_stopped>
  <start_date type="Anticipated">October 2017</start_date>
  <completion_date type="Anticipated">July 2018</completion_date>
  <primary_completion_date type="Anticipated">July 2018</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>
    <intervention_model_description>This is a open-label, non-randomised, single centre study.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Comparison between treatment groups of reovirus tumour infiltration by immunohistochemistry (IHC)</measure>
    <time_frame>Through study completion, an average of 18 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Comparison between treatment groups of reovirus tumour replication, as assessed by qRT-PCR</measure>
    <time_frame>Through study completion, an average of 18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison between treatment groups of neutralising antibody development development and cell-mediated immune response</measure>
    <time_frame>Through study completion, an average of 18 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison between treatment groups of cell-mediated immune response</measure>
    <time_frame>Through study completion, an average of 18 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Melanoma</condition>
  <condition>Cancer of Skin</condition>
  <arm_group>
    <arm_group_label>GROUP A (Reovirus only)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group A patients will receive an initial low 'immunisation' dose of intravenous reovirus (1x108 TCID50), to ensure that neutralising antibody (NAB) levels have risen by the time a full cycle of reovirus is given. Group A patients will then receive only 1 cycle of treatment which will comprise of reovirus only at 1x1010 TCID50 as a 1-hour IV infusion on 2 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>GROUP B (Reovirus plus GM-CSF)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group B patients will receive an initial low 'immunisation' dose of intravenous reovirus (1x108 TCID50), to ensure that neutralising antibody (NAB) levels have risen by the time a full cycle of reovirus plus GM-CSF is given. Group B patients will be given a subcutaneous injection of GM-CSF (50mcg/day) for 3 days, followed by only 1 cycle of treatment which will comprise of reovirus at 1x1010 TCID50 as a 1-hour IV infusion on 2 consecutive days</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Reolysin</intervention_name>
    <description>Reolysin® is a proprietary isolate of Reovirus Type 3 Dearing, a non-enveloped human reovirus with a genome that consists of 10 segments of double-stranded RNA. The human reovirus possesses an innate ability to replicate specifically in transformed cells possessing an activated Ras signalling pathway, a situation often found in malignant cells. Reovirus has been shown to reach and target melanoma cancer cells.</description>
    <arm_group_label>GROUP A (Reovirus only)</arm_group_label>
    <arm_group_label>GROUP B (Reovirus plus GM-CSF)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GM-CSF</intervention_name>
    <description>GM-CSF is a recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast (S. cerevisiae) expression system. GM-CSF is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. GM-CSF is a key cytokine in the differentiation of dendritic cells. It has been used as an immune adjuvant in therapeutic vaccines in pre-clinical and clinical studies, administered as cytokine released from gene-transduced tumour or stromal cells or as recombinant protein. At low doses GM-CSF may enhance migration and differentiation of dendritic cells to local antigen presentation, and is a potent adjuvant to generate specific systemic anti-tumour efficacy.</description>
    <arm_group_label>GROUP B (Reovirus plus GM-CSF)</arm_group_label>
    <other_name>LEUKINE</other_name>
    <other_name>Sargramostim</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Be male or female subjects with histologically diagnosed melanoma.&#xD;
&#xD;
          2. Be at least 18 years of age.&#xD;
&#xD;
          3. Be appropriate for resection of advanced melanoma (Stage 3/4). Patients may or may not&#xD;
             have more widespread metastatic disease.&#xD;
&#xD;
          4. Have completed any previous systemic chemotherapy, radiotherapy or surgery (except&#xD;
             biopsies) at least 28 days before entry into the study.&#xD;
&#xD;
          5. Have NO continuing acute toxic effects of any prior radiotherapy, chemotherapy, or&#xD;
             surgical procedures, i.e., all such effects must have resolved to Common Terminology&#xD;
             Criteria for Adverse Events (CTCAE, Version 4.0) Grade ≤1.&#xD;
&#xD;
          6. Have an ECOG Performance Score of 0 or 1.&#xD;
&#xD;
          7. Have a life expectancy of at least 3 months.&#xD;
&#xD;
          8. Have baseline laboratory results at the time of consent as follows:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) ≥ 1.5 x 109 [SI units 109/L]&#xD;
&#xD;
               2. Platelets ≥ 100 x109 [SI units 109/L] (without platelet transfusion)&#xD;
&#xD;
               3. Haemoglobin ≥ 9.0 g/dL [SI units gm/L] (with or without RBC transfusion)&#xD;
&#xD;
               4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
               5. Bilirubin ≤ 1.5 x ULN&#xD;
&#xD;
               6. AST/ALT ≤ 2.5 x ULN&#xD;
&#xD;
               7. Negative serum pregnancy test for females of childbearing potential.&#xD;
&#xD;
          9. Have signed informed consent.&#xD;
&#xD;
         10. Be willing and able to comply with scheduled visits, the treatment plan, and&#xD;
             laboratory tests&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Be on concurrent therapy with any other investigational anticancer agent while on&#xD;
             study.&#xD;
&#xD;
          2. Be on immunosuppressive therapy other than steroids.&#xD;
&#xD;
          3. Have known HIV infection or hepatitis B or C.&#xD;
&#xD;
          4. Be pregnant or breast feeding. Female patients must agree to use effective&#xD;
             contraception, be surgically sterile, or be postmenopausal. Male patients must agree&#xD;
             to use effective contraception or be surgically sterile.&#xD;
&#xD;
          5. Have clinically significant cardiac disease (New York Heart Association, Class III or&#xD;
             IV) including clinically significant arrhythmia, uncontrolled angina pectoris, or&#xD;
             myocardial infarction within 1 year prior to study entry.&#xD;
&#xD;
          6. Have dementia or altered mental status that would prohibit informed consent.&#xD;
&#xD;
          7. Have any other severe, acute, or chronic medical or psychiatric condition or&#xD;
             laboratory abnormality that may increase the risk associated with study participation&#xD;
             or study drug administration or may interfere with the interpretation of study results&#xD;
             and, in the judgment of the Principal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>August 30, 2017</study_first_submitted>
  <study_first_submitted_qc>September 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <last_update_submitted>May 1, 2018</last_update_submitted>
  <last_update_submitted_qc>May 1, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 4, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Leeds</investigator_affiliation>
    <investigator_full_name>Christy Ralph</investigator_full_name>
    <investigator_title>Associate Professor and Medical Oncology Consultant</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Skin Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sargramostim</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/NCT03282188
org study id: MO15/121
nct id: NCT03282188
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Open-label, non-randomised, single centre study which will assess the presence of reovirus
      (Reolysin®), following intravenous administration with or without Granulocyte-macrophage
      colony-stimulating factor (GM-CSF) given to patients prior to surgery for metastatic
      melanoma. All patients will receive an initial low 'immunisation' dose of intravenous
      reovirus. Patients will be enrolled sequentially in to each of the two cohorts receiving
      either reovirus alone, or reovirus plus GM-CSF. For this study we anticipate 8-16 evaluable
      patients, up to 8 for each group. The endpoints of this study will compare the 2 treatment
      groups for reovirus tumour infiltration and replication. Compare the neutralising antibody
      development and cell-mediated immune response and identify any adverse events and laboratory
      toxicities.
This is an open-label, non-randomised, single centre study of intravenous reovirus
      (Reolysin®) with or without Granulocyte-macrophage colony-stimulating factor (GM-CSF) given
      to patients prior to surgery for metastatic melanoma. Patients will be eligible if undergoing
      surgery for local control of lymph node involvement (with or without stage 4 metastases) or
      if planned for resection of cutaneous, subcutaneous, musculoskeletal or visceral metastases
      for local control, palliation of symptoms or personal choice.

      All patients will receive an initial low 'immunisation' dose of intravenous reovirus (1x108
      TCID50), to ensure that neutralising antibody (NAB) levels have risen by the time a full
      cycle of reovirus +/- GM-CSF is given. All patients will receive only 1 cycle of treatment
      which will comprise: i) For reovirus alone patients (Group A), 1x1010 TCID50 as a 1-hour IV
      infusion on 2 consecutive days; ii) For reovirus plus GM-CSF patients (Group B), subcutaneous
      GM-CSF (50mcg/day) for 3 days, followed by 2 days of reovirus. Both doses of reovirus will be
      at 1x1010 TCID50.

      Patients will be enrolled sequentially into each of the two cohorts receiving intravenous
      reovirus alone, or reovirus plus GM-CSF. The addition of GM-CSF is designed to address
      effects on the translational objectives/endpoints of this study, rather than primary
      toxicity, although all patients will be monitored for safety. Clinical assessment will be
      performed at screening (within 14 days of start of treatment), at day 1 (1st GM-CSF
      dose/none), day 8 and at the final study visit (40 days (+/- 14 days) post treatment with
      reovirus). Safety bloods will be taken at screening, at treatment (Day 1), before each dose
      of reovirus (Day 4 & 5), at Day 8 and at the final study visit (Day 40). Immunological
      assays, including reovirus antibody levels, will be performed before low-dose reovirus
      priming (Day -10 to -6), pre-treatment on Day 1, on Day 4 and 5 (pre-reovirus infusion and 60
      minutes post-infusion), Day 8, and at the final study visit (Day 40). Patients with
      accessible skin or subcutaneous metastases will be asked for an optional additional
      pre-treatment biopsy which will be taken before low-dose reovirus priming.

      All procedures will be performed as an outpatient or day case, apart from surgery in melanoma
      patients requiring admission as part of standard clinical care. Imaging will be as for
      standard clinical care only. Following surgical resection the tumour will be assessed for
      viral status and anti-tumour effects by e.g. standard histology, immunohistochemistry, RT-PCR
      and electron microscopy. Further imaging and follow-up beyond the final study visit (Day 40
      +/- 14 days) will be as for standard clinical care only.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: This is a open-label, non-randomised, single centre study.
primary purpose: Basic Science
masking: None (Open Label)
measure: Comparison between treatment groups of reovirus tumour infiltration by immunohistochemistry (IHC)
time frame: Through study completion, an average of 18 months
measure: Comparison between treatment groups of reovirus tumour replication, as assessed by qRT-PCR
time frame: Through study completion, an average of 18 months
measure: Comparison between treatment groups of neutralising antibody development development and cell-mediated immune response
time frame: Through study completion, an average of 18 months
measure: Comparison between treatment groups of cell-mediated immune response
time frame: Through study completion, an average of 18 months
arm group label: GROUP A (Reovirus only)
arm group type: Experimental
description: Group A patients will receive an initial low 'immunisation' dose of intravenous reovirus (1x108 TCID50), to ensure that neutralising antibody (NAB) levels have risen by the time a full cycle of reovirus is given. Group A patients will then receive only 1 cycle of treatment which will comprise of reovirus only at 1x1010 TCID50 as a 1-hour IV infusion on 2 consecutive days.
arm group label: GROUP B (Reovirus plus GM-CSF)
arm group type: Experimental
description: Group B patients will receive an initial low 'immunisation' dose of intravenous reovirus (1x108 TCID50), to ensure that neutralising antibody (NAB) levels have risen by the time a full cycle of reovirus plus GM-CSF is given. Group B patients will be given a subcutaneous injection of GM-CSF (50mcg/day) for 3 days, followed by only 1 cycle of treatment which will comprise of reovirus at 1x1010 TCID50 as a 1-hour IV infusion on 2 consecutive days
intervention type: Biological
intervention name: Reolysin
description: Reolysin® is a proprietary isolate of Reovirus Type 3 Dearing, a non-enveloped human reovirus with a genome that consists of 10 segments of double-stranded RNA. The human reovirus possesses an innate ability to replicate specifically in transformed cells possessing an activated Ras signalling pathway, a situation often found in malignant cells. Reovirus has been shown to reach and target melanoma cancer cells.
arm group label: GROUP A (Reovirus only)
arm group label: GROUP B (Reovirus plus GM-CSF)
intervention type: Drug
intervention name: GM-CSF
description: GM-CSF is a recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF) produced by recombinant DNA technology in a yeast (S. cerevisiae) expression system. GM-CSF is a hematopoietic growth factor which stimulates proliferation and differentiation of hematopoietic progenitor cells. GM-CSF is a key cytokine in the differentiation of dendritic cells. It has been used as an immune adjuvant in therapeutic vaccines in pre-clinical and clinical studies, administered as cytokine released from gene-transduced tumour or stromal cells or as recombinant protein. At low doses GM-CSF may enhance migration and differentiation of dendritic cells to local antigen presentation, and is a potent adjuvant to generate specific systemic anti-tumour efficacy.
arm group label: GROUP B (Reovirus plus GM-CSF)
other name: LEUKINE
other name: Sargramostim
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
responsible party type: Principal Investigator
investigator affiliation: University of Leeds
investigator full name: Christy Ralph
investigator title: Associate Professor and Medical Oncology Consultant
mesh term: Melanoma
mesh term: Skin Neoplasms
mesh term: Sargramostim