- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03767439
Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome
Trial of Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome (BCNS)
Study Overview
Status
Conditions
Intervention / Treatment
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.
Study Type
Phase
- Phase 2
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Nivolumab, Vismodegib, Ipilimumab
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. |
150 mg PO daily
Other Names:
480 mg IV every 4 weeks
Other Names:
1 mg/kg IV every 6 weeks
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Disease control rate
Time Frame: 18 months
|
Defined as the percentage of patients achieving a total tumor burden <50% of baseline tumor burden
|
18 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Total Number of Adverse Reactions
Time Frame: 18 months
|
Testing safety and toxicity assessed using CTCAE v5.0 criteria
|
18 months
|
Disease Control Rate (DCR)
Time Frame: 18 months
|
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.
|
18 months
|
Duration of Response (DOR)
Time Frame: 18 months
|
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.
|
18 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Richard Carvajal, MD., Columbia University
Study record dates
Study Major Dates
Study Start (Anticipated)
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Carcinoma
- Neoplasms, Glandular and Epithelial
- Disease
- Cysts
- Congenital Abnormalities
- Genetic Diseases, Inborn
- Musculoskeletal Diseases
- Stomatognathic Diseases
- Bone Diseases
- Neoplastic Syndromes, Hereditary
- Nevi and Melanomas
- Jaw Diseases
- Abnormalities, Multiple
- Bone Diseases, Developmental
- Odontogenic Cysts
- Jaw Cysts
- Bone Cysts
- Carcinoma, Basal Cell
- Neoplasms, Basal Cell
- Syndrome
- Nevus
- Basal Cell Nevus Syndrome
- Nevus, Pigmented
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Immune Checkpoint Inhibitors
- Nivolumab
- Ipilimumab
Other Study ID Numbers
- AAAS1021
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Basal Cell Nevus Syndrome
-
Ascend Biopharmaceuticals LtdSuspendedBasal Cell Carcinoma in Basal Cell Nevus SyndromeUnited States
-
HedgePath Pharmaceuticals, Inc.CompletedBasal Cell Carcinoma in Basal Cell Nevus SyndromeUnited States
-
Sol-Gel Technologies, Ltd.TerminatedBasal Cell Nevus SyndromeUnited States, France, Belgium, Denmark, Germany, Italy, Netherlands, Spain, United Kingdom
-
Edward Maytin, MD, PhDDUSA Pharmaceuticals, Inc.CompletedBasal Cell Nevus SyndromeUnited States
-
UCSF Benioff Children's Hospital OaklandGenentech, Inc.CompletedBasal Cell Nevus Syndrome | Gorlin SyndromeUnited States
-
PellePharm, Inc.CompletedBasal Cell Nevus SyndromeUnited States, Spain, Germany, United Kingdom, Italy, France, Belgium, Canada, Denmark, Netherlands
-
University Health Network, TorontoCompletedBasal Cell Nevus SyndromeCanada
-
MelanomaPRO, RussiaPrivolzhsky Research Medical UniversityRecruitingNevus | Nevus, Pigmented | Melanoma (Skin) | Basal Cell Carcinoma | Squamous Cell Carcinoma | Bowen's Disease | Nevus, Spitz | Melanoma in Situ | Nevus Halo | Spot PigmentedRussian Federation
-
QLT Inc.NovartisTerminatedNevoid Basal Cell Carcinoma Syndrome | Basal Cell Carcinoma | Gorlin Syndrome
-
Massachusetts General HospitalCompletedBasal Cell Carcinoma | Squamous Cell Carcinoma | Atypical NevusUnited States
Clinical Trials on Vismodegib
-
Genentech, Inc.Completed
-
University of Michigan Rogel Cancer CenterCompletedCarcinoma, Basal CellUnited States
-
Genentech, Inc.Completed
-
Hoffmann-La RocheCompletedBasal Cell CarcinomaItaly, Czechia, Hungary, Belgium, Canada, Ireland, Mexico, Portugal, Slovenia, Spain, Turkey, Brazil, Bosnia and Herzegovina, Romania, United Kingdom, Germany, Israel, France, Greece, Russian Federation, Lithuania, Netherlands, Norway, Colomb... and more
-
Sidney Kimmel Comprehensive Cancer Center at Johns...CompletedProstate CancerUnited States
-
SRH Wald-Klinikum Gera GmbHCompletedBasal Cell CarcinomaGermany
-
University Hospital, LilleHoffmann-La RocheCompletedBasal Cell CarcinomaFrance
-
University of ArizonaGenentech, Inc.CompletedBasal Cell CarcinomaUnited States
-
Hoffmann-La RocheTerminatedBasal Cell CarcinomaUnited States
-
Hoffmann-La RocheWithdrawnIdiopathic Pulmonary Fibrosis