Topical Laser-assisted Combination Chemotherapy for Basal Cell Carcinoma- a Clinical Study

Tolerability of Laser-assisted Cisplatin + 5-fluorouracil- an Exploratory Proof of Concept Study of Topical Combination Chemotherapy for Basal Cell Carcinoma

A prospective clinical, uncontrolled, open-label, explorative phase IIa trial on patients with histologically- confirmed superficial and nodular basal cell carcinoma (BCC) . The study assesses tolerability and tumor clearance after laser-assisted topical delivery of two synergistic chemotherapeutic agents, cisplatin and 5-fluorouracil (5-FU) in BCC patients.

Patients will receive ablative fractional laser (AFL)-assisted cisplatin+5-fluorouracil (5-FU) as a treatment for their cutaneous basal cell carcinoma (BCC). In brief, treatment areas consisting of tumors and a 5 mm margin will undergo AFL exposure (CO2 laser) followed by 60 min topical application of a marketed and commercially available IV cisplatin solution (0.1%) at a dose of 0.25 ml per cm2. After removal of cisplatin, a commercially distributed 5-FU cream (5% Efudix®) will be applied to the treatment area at a dose of 0.125 ml per cm2 and left under occlusion. After skin evaluations on Day 1 and 5 after treatment, the same 5-FU dose will be applied, again left under occlusion. In total, 5-FU will remain on the skin for 7 days after AFL treatment whereafter it will be washed off. An additional repeat AFL-cisplatin+5-FU treatment on Day 30 will be offered if tumors persist, based on clinical evaluation and imaging on Day 30. Outcome measures and methods/techniques are summarized below. Primary outcome: To investigate tolerability of topical AFL-assisted cisplatin+5-FU therapy for BCC by evaluating: I. Severity and duration of clinical local skin reactions including erythema, edema, scabbing, flaking and pustulation assessed by a physician using an established 0-4 point scale (none, mild, moderate, severe) from 0-30 days post-treatment. II. Occurrence of side effects (prolonged erythema/edema, hyper/hypopigmentation, scarring and infection) up to 3 months post-treatment. Secondary outcome: 1) To monitor BCC tumor size and clearance based on clinical assessments and dermoscopy, supported by non-invasive imaging techniques including dynamic optical coherence tomography (D-OCT), reflectance confocal microscopy (RCM), high intensity focused ultrasound (HIFU) and histological analysis up to 3 months post-treatment.

Patients (>18 years) with histologically-verified superficial or nodular basal cell carcinoma (<20 mm on the face/scalp, <50mm on the trunk/extremities)

Patients will receive AFL-assisted cisplatin+5-FU as a treatment for their BCC. In brief, treatment areas consisting of tumors and a 5 mm margin will undergo CO2 laser exposure followed by 60 min topical application of a marketed and commercially available IV cisplatin solution (0.1%) After removal of cisplatin, a commercially distributed 5-FU cream (5%) will be applied to the treatment area at a dose of 0.125 ml per cm2 and left under occlusion. After skin evaluations on Day 1 and 5 after treatment, the same 5-FU dose will be applied, again left under occlusion. In total, 5-FU will remain on the skin for 7 days after AFL treatment whereafter it will be washed off. An additional repeat AFL-cisplatin+5-FU treatment on Day 30 will be offered if tumors persist, based on clinical evaluation and imaging on Day 30.

Non-blinded, clinical evaluation of local erythema, edema, flaking, crusting/scabbing, pustulation, scarring, hypo/hyperpigmentation, infection in treated areas will be performed by a physician using a FDA-approved LSR scale at Days 1, 3-5, 14, 30 and 3 months after AFL exposure. Each parameter was graded on a standardized 5-point severity scale (0-4) representing none, mild, moderate, prominent, and severe. A total composite score reflecting overall LSR severity was then calculated based on the sum of all parameters (minimum score 0- least severe; max score: 24-most severe). lower scores are better.

Tumor clearance (yes or no) will be evaluated clinically at Day 30 and Month 3. If residual tumor is identified at 3 months follow-up, patients will receive conventional treatment according to national guidelines.¨

Clearance (yes or no) will be evaluated using non-invasive dynamic optical coherence tomography, high-intensity focused ultrasound and reflectance confocal microscopy imaging at Day 30 and Month 3. If residual tumor is identified at 3 months follow-up, patients will receive conventional treatment according to national guidelines.

Histological verification of tumor clearance will be performed 3 months after first treatment using tissue sections from a 4 mm punch biopsy. If residual tumor is identified at 3 months follow-up, patients will receive conventional treatment according to national guidelines. NOTE: Overall Number of Participants Analyzed is not consistent with numbers provided in any of the rows in the Participant Flow module since only 18 of the 19 patients consented to undergoing histologicla verification with biopsy. Those, presented data represents patients that underwent biopsy at the 3 month mark.

Inclusion Criteria: Histologically-verified, previously untreated superficial or nodular BCCs on the scalp, face, extremities or trunk >18 years of age at baseline Legally competent, able to give verbal and written informed consent Subject in good general health, is willing to participate and can comply with protocol requirements. Fitzpatrick skin phototype I-III Female subjects of childbearing potential1 must be confirmed not pregnant by a negative urine pregnancy test prior to trial treatment. Exclusion Criteria: High-risk BCC i. Tumors in the following anatomical locations: midface, orbital, ears ii. Size: >20 mm in facial/scalp areas or > 50 mm in non-facial/non-scalp areas iii. Subtype: morpheaform and micronodular BCC iv. History: Gorlin syndrome or immunosuppression Previous treatment of the BCC lesion Known allergy to cisplatin or Efudix® Other skin diseases present in the treatment area Tattoo in the treatment area which may interfere with or confound evaluation of the study History of keloids which is deemed clinically relevant in the opinion of the investigator Fitzpatrick skin phototype IV-VI Lactating or pregnant women