<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/NCT03767439</url>
  </required_header>
  <id_info>
    <org_study_id>AAAS1021</org_study_id>
    <nct_id>NCT03767439</nct_id>
  </id_info>
  <brief_title>Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome</brief_title>
  <official_title>Trial of Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome (BCNS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Columbia University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Columbia University</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 is a single-arm, phase II study to assess the efficacy of combined SMO and PD-1&#xD;
      inhibition with Vismodegib (SMO inhibitor) and Nivolumab (anti-PD-1 antibody) in BCNS&#xD;
      patients (target enrollment of 22 patients), with a primary endpoint of 18-month disease&#xD;
      control rate. The purpose of this study is to test the hypothesis that Nivolumab and&#xD;
      Vismodegib will improve the percentage of BCNS patients who achieve disease control (defined&#xD;
      as total tumor burden &lt;50% of baseline) at 18 months from 50% to 80%. Baseline and&#xD;
      on-treatment biopsies will be obtained to characterize the immune effects of combined SMO and&#xD;
      PD-1 inhibition.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Basal cell carcinoma (BCC) is by far the most common form of human malignancy, affecting more&#xD;
      than 3.5 million Americans each year. Aberrant activation of the Hedgehog (Hh) pathway,&#xD;
      typically through loss of the receptor Patched (PTCH) or oncogenic activation of Smoothened&#xD;
      (SMO), has been identified as the primary driver of BCC growth and development. In&#xD;
      particular, up to 1 in 57,000 individuals in the US are affected by a rare, autosomal&#xD;
      dominant disorder characterized by mutations in protein patched homolog 1 (PTCH1) known as&#xD;
      basal cell nevus syndrome (BCNS). These patients can develop dozens to hundreds of BCCs at&#xD;
      any one time (1-5). Surgical removal of the entire tumor burden is not feasible.&#xD;
&#xD;
      Hh-targeted therapies employing inhibitors of SMO (i.e., Vismodegib, Sonidegib) have shown&#xD;
      remarkable efficacy in reducing tumor burden in BCC patients. However, the sustained clinical&#xD;
      utility of these agents has been hampered by the rapid development of clinical resistance,&#xD;
      significant tumor recurrence, and toxicity. Treatment strategies directed at finding&#xD;
      additional molecular or immunological targets may enhance the possibility of sustained&#xD;
      remission and/or cure of these tumors. Emerging data from our research group and others&#xD;
      suggest the therapeutic efficacy of SMO inhibition may be dependent on immunological&#xD;
      mechanisms. Hh inhibition appears to increase T cell recruitment and activation as well as&#xD;
      upregulate major histocompatibility complex (MHC) class I expression on tumor cells. These&#xD;
      data, together with case reports demonstrating the efficacy of cytotoxic T-lymphocyte&#xD;
      associated protein 4 (CTLA-4) and programmed death-1 (PD-1) inhibition in Hh inhibitor-naïve&#xD;
      and resistant BCCs, support a role for anti-tumor immunity in BCC and underscore the&#xD;
      potential enhanced therapeutic efficacy of combined SMO and immunological checkpoint&#xD;
      inhibition.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Loss of funding&#xD;
  </why_stopped>
  <start_date type="Anticipated">July 2019</start_date>
  <completion_date type="Anticipated">February 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease control rate</measure>
    <time_frame>18 months</time_frame>
    <description>Defined as the percentage of patients achieving a total tumor burden &lt;50% of baseline tumor burden</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total Number of Adverse Reactions</measure>
    <time_frame>18 months</time_frame>
    <description>Testing safety and toxicity assessed using CTCAE v5.0 criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>18 months</time_frame>
    <description>DCR is defined as the percentage of subjects who have achieved complete response (CR), partial response (PR), or stable disease (SD) based on assessments per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DOR)</measure>
    <time_frame>18 months</time_frame>
    <description>For subjects who demonstrate CR or PR, based on assessments per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Basal Cell Nevus Syndrome</condition>
  <arm_group>
    <arm_group_label>Nivolumab, Vismodegib, Ipilimumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive a two week run-in of Vismodegib 150 mg PO daily followed by concurrent Nivolumab 480 mg IV every 4 weeks and Vismodegib 150 mg PO daily.&#xD;
In an exploratory fashion, patients will have the option to receive combination Ipilimumab 1 mg/kg IV every 6 weeks and Nivolumab 360 mg IV every 3 weeks at the time of disease progression.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vismodegib</intervention_name>
    <description>150 mg PO daily</description>
    <arm_group_label>Nivolumab, Vismodegib, Ipilimumab</arm_group_label>
    <other_name>ERIVEDGE</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>480 mg IV every 4 weeks</description>
    <arm_group_label>Nivolumab, Vismodegib, Ipilimumab</arm_group_label>
    <other_name>OPDIVO</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>1 mg/kg IV every 6 weeks</description>
    <arm_group_label>Nivolumab, Vismodegib, Ipilimumab</arm_group_label>
    <other_name>YERVOY</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  10 or more surgically eligible BCCs (SEBS) within the prior 2 years&#xD;
&#xD;
          -  Age &gt; 16 years&#xD;
&#xD;
          -  Karnofsky Performance Score (KPS) &gt; 60%, Eastern Cooperative Oncology Group (ECOG) &lt; 2&#xD;
&#xD;
          -  Prior SMO inhibitor therapy is permitted, but patients must have developed new and/or&#xD;
             progressive lesions on or after therapy&#xD;
&#xD;
          -  Adequate organ function&#xD;
&#xD;
          -  All clinically significant toxicities from prior systemic therapy must be &lt; Grade 1&#xD;
&#xD;
          -  Subjects must agree to undergo four serial tumor biopsies (may be of different tumors)&#xD;
             at baseline, after a two week run-in of Vismodegib, between 4-6 weeks of concurrent&#xD;
             Nivolumab and Vismodegib, and at the time of disease recurrence or progression.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Prior therapy with an immunological checkpoint inhibitor&#xD;
&#xD;
          2. Prior SMO inhibitor therapy is permitted, but patients must have developed new and/or&#xD;
             progressive lesions on or after therapy&#xD;
&#xD;
          3. Routine use of topical (applied to &gt;5% of skin) or systemic therapies that might&#xD;
             interfere with evaluation of the study medication in the prior 4 weeks&#xD;
&#xD;
               1. Topical corticosteroids&#xD;
&#xD;
               2. Systemic or topical retinoids e.g., etretinate, isotretinoin, tazarotene,&#xD;
                  tretinoin, adapalene&#xD;
&#xD;
               3. Topical alpha-hydroxy acids e.g., glycolic acid, lactic acid&#xD;
&#xD;
               4. Systemic or topical 5-fluorouracil or imiquimod to skin above the knees&#xD;
&#xD;
          4. Patients who have not recovered from adverse events (&gt; Grade 1) due to prior&#xD;
             treatments&#xD;
&#xD;
          5. Treatment with any other investigational agents&#xD;
&#xD;
          6. Recent major surgery within 4 weeks prior to starting study treatment. Minor surgeries&#xD;
             such as placement of vascular access are not exclusionary.&#xD;
&#xD;
          7. Known history of hypersensitivity to any of the ingredients in the study medication&#xD;
             formulations&#xD;
&#xD;
          8. Requirement for immunosuppressive corticosteroids at doses exceeding 10 mg prednisone&#xD;
             daily or equivalent prior to first dose of Nivolumab&#xD;
&#xD;
          9. Ongoing or recent (within 5 years) evidence of significant autoimmune disease at&#xD;
             baseline or associated with prior therapy requiring treatment with systemic&#xD;
             immunosuppressive treatments with the exception of:&#xD;
&#xD;
               1. Viligo&#xD;
&#xD;
               2. Childhood asthma that has resolved&#xD;
&#xD;
               3. Residual endocrinopathies requiring replacement therapy&#xD;
&#xD;
               4. Psoriasis that does not require systemic treatment&#xD;
&#xD;
         10. History of solid organ transplant&#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, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
         12. Uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia&#xD;
&#xD;
         13. HIV positive patients on combination antiretroviral therapy&#xD;
&#xD;
         14. Refractory nausea and vomiting, active gastrointestinal disease e.g. inflammatory&#xD;
             bowel disease, or significant bowel resection that would preclude adequate absorption&#xD;
&#xD;
         15. Have evidence of any other significant skin condition, clinical disorder, physical&#xD;
             examination finding, or laboratory finding that, as judged by the investigator, makes&#xD;
             it undesirable for the patient to participate in the study&#xD;
&#xD;
         16. Active treatment for a second malignancy&#xD;
&#xD;
         17. Pregnant women are excluded from this study because nivolumab, ipilimumab and&#xD;
             vismodegib may be teratogenic or have abortifacient effects. Because there is an&#xD;
             unknown but potential risk for adverse events in nursing infants secondary to&#xD;
             treatment of the mother with nivolumab, ipilimumab or vismodegib, breastfeeding should&#xD;
             be discontinued if the mother is receiving study treatment.&#xD;
&#xD;
         18. Male patients unwilling or unable to comply with pregnancy prevention measures&#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>Richard Carvajal, MD.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Columbia University</affiliation>
  </overall_official>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>December 5, 2018</study_first_submitted>
  <study_first_submitted_qc>December 5, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 6, 2018</study_first_posted>
  <last_update_submitted>December 16, 2019</last_update_submitted>
  <last_update_submitted_qc>December 16, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 18, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Columbia University</investigator_affiliation>
    <investigator_full_name>Richard D. Carvajal</investigator_full_name>
    <investigator_title>Assistant Professor of Medicine at the Columbia University Medical</investigator_title>
  </responsible_party>
  <keyword>Nivolumab</keyword>
  <keyword>Vismodegib</keyword>
  <keyword>Basal Cell</keyword>
  <keyword>Basal Cell Nevus Syndrome (BCNS)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nevus</mesh_term>
    <mesh_term>Nevus, Pigmented</mesh_term>
    <mesh_term>Basal Cell Nevus Syndrome</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</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/NCT03767439
org study id: AAAS1021
nct id: NCT03767439
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a single-arm, phase II study to assess the efficacy of combined SMO and PD-1
      inhibition with Vismodegib (SMO inhibitor) and Nivolumab (anti-PD-1 antibody) in BCNS
      patients (target enrollment of 22 patients), with a primary endpoint of 18-month disease
      control rate. The purpose of this study is to test the hypothesis that Nivolumab and
      Vismodegib will improve the percentage of BCNS patients who achieve disease control (defined
      as total tumor burden <50% of baseline) at 18 months from 50% to 80%. Baseline and
      on-treatment biopsies will be obtained to characterize the immune effects of combined SMO and
      PD-1 inhibition.
Basal cell carcinoma (BCC) is by far the most common form of human malignancy, affecting more
      than 3.5 million Americans each year. Aberrant activation of the Hedgehog (Hh) pathway,
      typically through loss of the receptor Patched (PTCH) or oncogenic activation of Smoothened
      (SMO), has been identified as the primary driver of BCC growth and development. In
      particular, up to 1 in 57,000 individuals in the US are affected by a rare, autosomal
      dominant disorder characterized by mutations in protein patched homolog 1 (PTCH1) known as
      basal cell nevus syndrome (BCNS). These patients can develop dozens to hundreds of BCCs at
      any one time (1-5). Surgical removal of the entire tumor burden is not feasible.

      Hh-targeted therapies employing inhibitors of SMO (i.e., Vismodegib, Sonidegib) have shown
      remarkable efficacy in reducing tumor burden in BCC patients. However, the sustained clinical
      utility of these agents has been hampered by the rapid development of clinical resistance,
      significant tumor recurrence, and toxicity. Treatment strategies directed at finding
      additional molecular or immunological targets may enhance the possibility of sustained
      remission and/or cure of these tumors. Emerging data from our research group and others
      suggest the therapeutic efficacy of SMO inhibition may be dependent on immunological
      mechanisms. Hh inhibition appears to increase T cell recruitment and activation as well as
      upregulate major histocompatibility complex (MHC) class I expression on tumor cells. These
      data, together with case reports demonstrating the efficacy of cytotoxic T-lymphocyte
      associated protein 4 (CTLA-4) and programmed death-1 (PD-1) inhibition in Hh inhibitor-naïve
      and resistant BCCs, support a role for anti-tumor immunity in BCC and underscore the
      potential enhanced therapeutic efficacy of combined SMO and immunological checkpoint
      inhibition.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease control rate
time frame: 18 months
description: Defined as the percentage of patients achieving a total tumor burden <50% of baseline tumor burden
measure: Total Number of Adverse Reactions
time frame: 18 months
description: Testing safety and toxicity assessed using CTCAE v5.0 criteria
measure: Disease Control Rate (DCR)
time frame: 18 months
description: DCR is defined as the percentage of subjects who have achieved complete response (CR), partial response (PR), or stable disease (SD) based on assessments per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
measure: Duration of Response (DOR)
time frame: 18 months
description: For subjects who demonstrate CR or PR, based on assessments per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
arm group label: Nivolumab, Vismodegib, Ipilimumab
arm group type: Experimental
description: Patients will receive a two week run-in of Vismodegib 150 mg PO daily followed by concurrent Nivolumab 480 mg IV every 4 weeks and Vismodegib 150 mg PO daily.
In an exploratory fashion, patients will have the option to receive combination Ipilimumab 1 mg/kg IV every 6 weeks and Nivolumab 360 mg IV every 3 weeks at the time of disease progression.
intervention type: Drug
intervention name: Vismodegib
description: 150 mg PO daily
arm group label: Nivolumab, Vismodegib, Ipilimumab
other name: ERIVEDGE
intervention type: Drug
intervention name: Nivolumab
description: 480 mg IV every 4 weeks
arm group label: Nivolumab, Vismodegib, Ipilimumab
other name: OPDIVO
intervention type: Drug
intervention name: Ipilimumab
description: 1 mg/kg IV every 6 weeks
arm group label: Nivolumab, Vismodegib, Ipilimumab
other name: YERVOY
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Richard Carvajal, MD.
role: Principal Investigator
affiliation: Columbia University
responsible party type: Principal Investigator
investigator affiliation: Columbia University
investigator full name: Richard D. Carvajal
investigator title: Assistant Professor of Medicine at the Columbia University Medical
mesh term: Nevus
mesh term: Nevus, Pigmented
mesh term: Basal Cell Nevus Syndrome
mesh term: Syndrome
mesh term: Nivolumab
mesh term: Ipilimumab