Neurofibromatosis type 1 (NF1) is the most common genetic tumor predisposition syndrome, affecting up to 1 in 2500 individuals. Cutaneous neurofibromas are benign with self-limited growth; however, tumor burden may be excessive, tumors do not regress, and they can be disfiguring, painful, and itchy. Currently, the only treatment is surgery or laser ablation; however, outcomes are limited by the number of tumors that can be simultaneously removed, operating room availability, and painful recovery, with significant risk of regrowth. There is a strong need for noninvasive topical treatments for cutaneous neurofibromas. Diphencyprone (DPCP) is a "hapten" medication, a small molecule that activates the immune system when applied topically, which has been investigated as a cutaneous immunotherapy for other skin conditions.

This is an open label Phase I study looking at safety and tolerability of this treatment as a primary endpoint, and tumor treatment as a secondary endpoint. Approximately 30 subjects will be enrolled at a single center within the US. Subjects with a clinical diagnosis of NF1 who have measurable disease and at least 4 cutaneous neurofibromas, will have DPCP applied topically to their neurofibromas once weekly for 10 weeks.

Each subject after consent will undergo a biopsy of one cutaneous neurofibroma prior to treatment. The participant will then undergo a sensitization treatment to "normal" skin as well as one neurofibroma to activate the immune system against the trial drug. 14 days after sensitization, patients will begin the first of 10 weekly treatment doses to a minimum of 3, up to 20 cutaneous neurofibromas. The participant may require up to 2 additional sensitization exposures. When the investigator has determined that sensitization has occurred, each subject will have a skin biopsy of one treated neurofibroma 3 days after initial treatment on Day 17 in order to investigate cellular and molecular effects of the treatment. The remainder of treatments will be applied once weekly on days 21, 28, 35, 42, 49, 56, 63, 70, and 77. The followup visit will occur on Day 107. Tumors will be photographed at screening and at each treatment visit, and in addition, whole body photography will be performed on Day 0 and Day 107 to assess for off-target effects on cutaneous neurofibromas that were not directly treated. On Day 107, a third cutaneous neurofibroma will be biopsied for molecular and immunohistopathological outcomes.

Inclusion Criteria

• Clinically diagnosed NF1 as per the expertise of the study team.

• At least four cutaneous neurofibromas greater than 4 mm in size that are able to be biopsied.

• Age ≥ 18 years.

• Ability to understand and the willingness to sign a written informed consent.

• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

• A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

  1. Has not undergone a hysterectomy or bilateral oophorectomy; or
  2. Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months).

Exclusion Criteria

• Subjects may not be receiving any other investigational agents.
• Subjects taking any of the following systemic therapies within 2 weeks of enrollment: corticosteroids, immunosuppressants, and/or any other medications (systemic or topical) that may affect the outcome of the study in the opinion of the investigator.
• Subjects with any underlying diseases or dermatological conditions of the affected areas that require the use of interfering topical or systemic therapy, or that may impair immune responses such as HIV or lymphadenectomy of the axillary lymph node basin that drains the skin where DPCP is to be applied.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to DPCP, or any of the other components of the DPCP ointment formulation.
• 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.
• Subjects must not be pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices).

Immediately following publication. No end date.

Investigators whose proposed use of the data has been approved by an independent review committee ('learned intermediary') identified for this purpose.

Any purpose. Specify Other Mechanism PI to be contacted