Evaluation of Ingenol Mebutate for Actinic Cheilitis Treatment

Squamous cell carcinoma is the most common malignant neoplasm in the head and neck region, and when present in the lower lip, it is usually associated with prolonged exposure to UV radiation of lip vermilion surface especially in white patients (patients with genodermatosis such as xeroderma pigmentosum have extreme sensitivity to UV radiation, characterized by an even higher risk and patients presenting radiodermatites that can evolve to squamous cell carcinoma). Ingenol mebutate is a natural medicine derived from the sap of the pepense euphoria and much used for its medicinal properties.

The objective of this study was to determine the toxicity profile and the maximum tolerated dose (MTD) of ingenol mebutate for treatment of actinic cheilitis in patients of the Oncology Dermatology Session of the National Cancer Institute of Brazil (INCA) through a phase 1 clinical trial of type 3 + 3 and to determine the therapeutic response with a dose below the maximum tolerated dose (MTD) of metamato of ingenuity, for the treatment of aortic cheilitis in patients of the Oncology Dermatology Session of the National Cancer Institute (INCA) through a prospective clinical trial and phase randomized trial (phase 2).

Actinic cheilitis is a major potentially carcinogenic disorder of the lower lip and several reports of clinical cases with excellent results for the treatment of this lesion that can differentiate to squamous cell carcinoma of the lip. However, clinical trials are lacking to define the optimal dosage of the drug for a therapeutic modality and to define its true efficacy in controlled studies of this pre-malignant labial lesion.

• Ingenol mebutate gel (Drug), also known as Picato: 3+3 phase 1 design as described above. After the maximum tolerated dose is defined, the phase 2 segment of the study will take place. Simon's Phase 2 study design tool was used, reinforced by Jung's admissible study designs for phase 2 clinical trials. Considering the margin of error of 0.05 and study power of 80%, and estimating the probability of placebo partial response of 15% and partial response to ingenol mebutate in 45%, the optimized number of patients to be recruited is 19. Six patients will be seen in the first stage of this segment of the study, and if only one patient or none has a partial response, the study will be promptly discontinued. Otherwise, the second and final stage of segment of the study will include an additional thirteen patients who will be treated.

Primary outcomes

• Actinic cheilitis response to treatment [Twelve months]: A 45% partial response to ingenol mebutate

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients with diagnosis of actinic cheilitis .
* Histopathological report compatible with the clinical diagnosis.
* Sign the informed consent to be a part of the study.
* Comply with the attendance at the clinical settings during the days the patient will be medicated (D1, D2 and D3), D5, D8, two months, six months and one year after treatment.

Exclusion Criteria:

* Patients younger than 18 years of age.
* Patients without confirmed diagnosis of actinic cheilitis.
* Patients previously treated with ingenol mebutate for actinic cheilitis, including those in the present study, previously excluded at some point during phases 1 or 2.
* Presence of recurrent lesions, prior or during treatment.
* Immunosuppression.
* Use of topical corticosteroids.
* Presence of markedly hyperkeratotic or ulcerated lesions in the clinical evaluation
* Patients presenting with atypical histology (moderate to severe epithelial dysplasia) at the lips.

• Daniel Cohen Goldemberg, PhD, Principal investigator, Researcher