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Basal Cell Nevus SyndromePhase 2NCT03767439

Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome

A Phase 2 study testing Vismodegib, Nivolumab and Ipilimumab in people with Basal Cell Nevus Syndrome, run by Columbia University.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Basal Cell Nevus Syndrome
What is being tested?
Vismodegib, Nivolumab and Ipilimumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
Jul 2019to Feb 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 26Show fewer
  • 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

About this study

Official title: Trial of Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome (BCNS)

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.

Read the 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.

Being tested
Vismodegib, Nivolumab, Ipilimumab
Keywords
Nivolumab, Vismodegib, Basal Cell, Basal Cell Nevus Syndrome (BCNS)
Medical subject headings
Basal Cell Nevus Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VismodegibDrug

    Also called ERIVEDGE

    150 mg PO daily

  • NivolumabDrug

    Also called OPDIVO

    480 mg IV every 4 weeks

  • IpilimumabDrug

    Also called YERVOY

    1 mg/kg IV every 6 weeks

Study groups in NCT03767439
Study groupRoleWhat they receive
Nivolumab, Vismodegib, IpilimumabExperimentalPatients 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.
Receives: Drug: Vismodegib; Drug: Nivolumab; Drug: Ipilimumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Disease control rate

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

    Measured: 18 months

Secondary outcomes (3)

  1. Total Number of Adverse Reactions

    Testing safety and toxicity assessed using CTCAE v5.0 criteria

    Measured: 18 months

  2. 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.

    Measured: 18 months

  3. 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.

    Measured: 18 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Dec 2018
  2. Study startJul 2019 (estimated)
  3. Primary completionDec 2019 (estimated)
  4. Study completionFeb 2020 (estimated)

Why it stopped: Loss of funding

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03767439
Sponsor's protocol ID
AAAS1021
Status last verified
Dec 2019
First submitted
5 Dec 2018
Last updated
18 Dec 2019
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vismodegib, Nivolumab and Ipilimumab in people with Basal Cell Nevus Syndrome, run by Columbia University.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 18 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Disease control rate (time frame: 18 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03767439.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2019.

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