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Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome

Primary Purpose

Basal Cell Nevus Syndrome

Status
Withdrawn
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Vismodegib
Nivolumab
Ipilimumab
Sponsored by
Columbia University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Basal Cell Nevus Syndrome focused on measuring Nivolumab, Vismodegib, Basal Cell, Basal Cell Nevus Syndrome (BCNS)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 10 or more surgically eligible BCCs (SEBS) within the prior 2 years
  • Age > 16 years
  • Karnofsky Performance Score (KPS) > 60%, Eastern Cooperative Oncology Group (ECOG) < 2
  • Prior SMO inhibitor therapy is permitted, but patients must have developed new and/or progressive lesions on or after therapy
  • Adequate organ function
  • All clinically significant toxicities from prior systemic therapy must be < Grade 1
  • Subjects must agree to undergo four serial tumor biopsies (may be of different tumors) at baseline, after a two week run-in of Vismodegib, between 4-6 weeks of concurrent Nivolumab and Vismodegib, and at the time of disease recurrence or progression.

Exclusion Criteria:

  1. Prior therapy with an immunological checkpoint inhibitor
  2. Prior SMO inhibitor therapy is permitted, but patients must have developed new and/or progressive lesions on or after therapy
  3. Routine use of topical (applied to >5% of skin) or systemic therapies that might interfere with evaluation of the study medication in the prior 4 weeks

    1. Topical corticosteroids
    2. Systemic or topical retinoids e.g., etretinate, isotretinoin, tazarotene, tretinoin, adapalene
    3. Topical alpha-hydroxy acids e.g., glycolic acid, lactic acid
    4. Systemic or topical 5-fluorouracil or imiquimod to skin above the knees
  4. Patients who have not recovered from adverse events (> Grade 1) due to prior treatments
  5. Treatment with any other investigational agents
  6. Recent major surgery within 4 weeks prior to starting study treatment. Minor surgeries such as placement of vascular access are not exclusionary.
  7. Known history of hypersensitivity to any of the ingredients in the study medication formulations
  8. Requirement for immunosuppressive corticosteroids at doses exceeding 10 mg prednisone daily or equivalent prior to first dose of Nivolumab
  9. Ongoing or recent (within 5 years) evidence of significant autoimmune disease at baseline or associated with prior therapy requiring treatment with systemic immunosuppressive treatments with the exception of:

    1. Viligo
    2. Childhood asthma that has resolved
    3. Residual endocrinopathies requiring replacement therapy
    4. Psoriasis that does not require systemic treatment
  10. History of solid organ transplant
  11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  12. Uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia
  13. HIV positive patients on combination antiretroviral therapy
  14. Refractory nausea and vomiting, active gastrointestinal disease e.g. inflammatory bowel disease, or significant bowel resection that would preclude adequate absorption
  15. Have evidence of any other significant skin condition, clinical disorder, physical examination finding, or laboratory finding that, as judged by the investigator, makes it undesirable for the patient to participate in the study
  16. Active treatment for a second malignancy
  17. Pregnant women are excluded from this study because nivolumab, ipilimumab and vismodegib may be teratogenic or have abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, ipilimumab or vismodegib, breastfeeding should be discontinued if the mother is receiving study treatment.
  18. Male patients unwilling or unable to comply with pregnancy prevention measures

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Nivolumab, Vismodegib, Ipilimumab

    Arm 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.

    Outcomes

    Primary Outcome Measures

    Disease control rate
    Defined as the percentage of patients achieving a total tumor burden <50% of baseline tumor burden

    Secondary Outcome Measures

    Total Number of Adverse Reactions
    Testing safety and toxicity assessed using CTCAE v5.0 criteria
    Disease Control Rate (DCR)
    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.
    Duration of Response (DOR)
    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.

    Full Information

    First Posted
    December 5, 2018
    Last Updated
    December 16, 2019
    Sponsor
    Columbia University
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03767439
    Brief Title
    Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome
    Official Title
    Trial of Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome (BCNS)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    December 2019
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Loss of funding
    Study Start Date
    July 2019 (Anticipated)
    Primary Completion Date
    December 2019 (Anticipated)
    Study Completion Date
    February 2020 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    Columbia University

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    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.
    Detailed Description
    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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Basal Cell Nevus Syndrome
    Keywords
    Nivolumab, Vismodegib, Basal Cell, Basal Cell Nevus Syndrome (BCNS)

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Nivolumab, Vismodegib, Ipilimumab
    Arm Type
    Experimental
    Arm 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(s)
    Vismodegib
    Other Intervention Name(s)
    ERIVEDGE
    Intervention Description
    150 mg PO daily
    Intervention Type
    Drug
    Intervention Name(s)
    Nivolumab
    Other Intervention Name(s)
    OPDIVO
    Intervention Description
    480 mg IV every 4 weeks
    Intervention Type
    Drug
    Intervention Name(s)
    Ipilimumab
    Other Intervention Name(s)
    YERVOY
    Intervention Description
    1 mg/kg IV every 6 weeks
    Primary Outcome Measure Information:
    Title
    Disease control rate
    Description
    Defined as the percentage of patients achieving a total tumor burden <50% of baseline tumor burden
    Time Frame
    18 months
    Secondary Outcome Measure Information:
    Title
    Total Number of Adverse Reactions
    Description
    Testing safety and toxicity assessed using CTCAE v5.0 criteria
    Time Frame
    18 months
    Title
    Disease Control Rate (DCR)
    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.
    Time Frame
    18 months
    Title
    Duration of Response (DOR)
    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.
    Time Frame
    18 months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: 10 or more surgically eligible BCCs (SEBS) within the prior 2 years Age > 16 years Karnofsky Performance Score (KPS) > 60%, Eastern Cooperative Oncology Group (ECOG) < 2 Prior SMO inhibitor therapy is permitted, but patients must have developed new and/or progressive lesions on or after therapy Adequate organ function All clinically significant toxicities from prior systemic therapy must be < Grade 1 Subjects must agree to undergo four serial tumor biopsies (may be of different tumors) at baseline, after a two week run-in of Vismodegib, between 4-6 weeks of concurrent Nivolumab and Vismodegib, and at the time of disease recurrence or progression. Exclusion Criteria: Prior therapy with an immunological checkpoint inhibitor Prior SMO inhibitor therapy is permitted, but patients must have developed new and/or progressive lesions on or after therapy Routine use of topical (applied to >5% of skin) or systemic therapies that might interfere with evaluation of the study medication in the prior 4 weeks Topical corticosteroids Systemic or topical retinoids e.g., etretinate, isotretinoin, tazarotene, tretinoin, adapalene Topical alpha-hydroxy acids e.g., glycolic acid, lactic acid Systemic or topical 5-fluorouracil or imiquimod to skin above the knees Patients who have not recovered from adverse events (> Grade 1) due to prior treatments Treatment with any other investigational agents Recent major surgery within 4 weeks prior to starting study treatment. Minor surgeries such as placement of vascular access are not exclusionary. Known history of hypersensitivity to any of the ingredients in the study medication formulations Requirement for immunosuppressive corticosteroids at doses exceeding 10 mg prednisone daily or equivalent prior to first dose of Nivolumab Ongoing or recent (within 5 years) evidence of significant autoimmune disease at baseline or associated with prior therapy requiring treatment with systemic immunosuppressive treatments with the exception of: Viligo Childhood asthma that has resolved Residual endocrinopathies requiring replacement therapy Psoriasis that does not require systemic treatment History of solid organ transplant Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Uncontrolled hypocalcemia, hypomagnesemia, or hypokalemia HIV positive patients on combination antiretroviral therapy Refractory nausea and vomiting, active gastrointestinal disease e.g. inflammatory bowel disease, or significant bowel resection that would preclude adequate absorption Have evidence of any other significant skin condition, clinical disorder, physical examination finding, or laboratory finding that, as judged by the investigator, makes it undesirable for the patient to participate in the study Active treatment for a second malignancy Pregnant women are excluded from this study because nivolumab, ipilimumab and vismodegib may be teratogenic or have abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab, ipilimumab or vismodegib, breastfeeding should be discontinued if the mother is receiving study treatment. Male patients unwilling or unable to comply with pregnancy prevention measures
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Richard Carvajal, MD.
    Organizational Affiliation
    Columbia University
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

    Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome

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