Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic tumor predisposition syndrome affecting about 1 in 2500 people. Affected patients develop a variety of skin findings including café-au-lait macules, axillary freckling, and cutaneous neurofibromas (cNFs). These patients also have an increased risk of malignant tumors including gliomas and soft tissue sarcomas. However, the cNFs, of which a patient can have thousands, are often cited as the most burdensome sign. Despite their benign nature, these tumors can be physically bothersome and cause significant emotional distress. To date, there are no effective pharmacotherapies for these tumors. This is a single-center, phase I, open label trial to evaluate the safety, tolerability, and efficacy of diphencyprone (DPCP), a topical hapten that induces a delayed-type hypersensitivity skin reaction, for the treatment of cNFs in adults with NF1. Methods: This trial is enrolling NF1 patients aged 18 and older with at least four cNFs greater than 4mm. Subjects taking systemic immunosuppressants, those with underlying immunodeficiency or uncontrolled intercurrent illnesses, and those who are pregnant or nursing are excluded from the study. DPCP 0.04% ointment is administered topically once weekly to up to 20 cNFs in a localized area for 10 weeks. The primary endpoint is to determine the safety and tolerability of DPCP ointment in the treatment of cNFs. Adverse events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. To assess subjective tolerability, subjects score their symptoms, including pain, stinging, burning, and pruritus from 0 (none) to 3 (severe). Efficacy and tumor regression are assessed using the Response Evaluation Criteria in Solid Tumors guidelines in conjunction with photographs and manual tri-axial tumor measurements. Additionally, qualitative assessments are made by the study team using 3D whole-body photography. One treated tumor is tracked throughout the study with optical coherence tomography (OCT) imaging. Skin biopsies of a cNF and surrounding tissue are collected at baseline, on Day 17 after treatment initiation, and four weeks post-treatment for exploratory endpoints. Quantitative RT-PCR and single-cell RNA sequencing studies will assess gene expression changes in immune and tumor cell-related genes pre- and post-treatment with DPCP. Immunohistochemistry and proteomic profiling will be performed to characterize changes in the tumor microenvironment. Genetic testing for the NF1 germline mutation will be correlated with treatment response. Enrollment is ongoing with a target of 20 participants. Since September 2022, the study has enrolled 12 patients and five have completed the study. Clinical trial information: NCT05438290.