Nivolumab With Vismodegib in Patients With Basal Cell Nevus Syndrome

Phase 2

Withdrawn

• Conditions: Basal Cell Nevus Syndrome
• Interventions: Drug: Vismodegib; Drug: Nivolumab; Drug: Ipilimumab

• Registration Number: NCT03767439
• Lead Sponsor: Columbia University

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.

Study Timeline

• Study First Submitted: 2018-12-05
• Study First Submitted QC: 2018-12-05
• Study First Posted: 2018-12-06
• Study Start: 2019-07
• Status Verified: 2019-12
• Primary Completion: 2019-12
• Last Update Submitted: 2019-12-16
• Last Update Posted: 2019-12-18
• Study Completion: 2020-02

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nivolumab, Vismodegib, Ipilimumab	Vismodegib	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.
Nivolumab, Vismodegib, Ipilimumab	Nivolumab	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.
Nivolumab, Vismodegib, Ipilimumab	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.

Primary Outcome Measures

Name	Time	Method
Disease control rate	18 months	Defined as the percentage of patients achieving a total tumor burden \<50% of baseline tumor burden

Secondary Outcome Measures

Name	Time	Method
Total Number of Adverse Reactions	18 months	Testing safety and toxicity assessed using CTCAE v5.0 criteria
Disease Control Rate (DCR)	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.
Duration of Response (DOR)	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.