Placebo-controlled, Double Blind Study to Assess Efficacy and Safety of Oral Vismodegib for the Treatment of Basal Cell Carcinoma Preceding Excision by Mohs Micrographic Surgery (MMS)

Basal cell carcinoma (BCC) is the most common cutaneous malignancy. In the United States alone, the incidence of these tumors approaches or exceeds one million cases each year, and continues to increase. Actinic damage is the primary causal factor, and 85% of all lesions are located in cosmetically-sensitive areas such as the face, head, and neck. Although these tumors do not usually metastasize, their high prevalence and morbidity have established them as a significant public health problem. In addition a small percentage can cause significant morbidity or mortality.

Treatment goals for BCC focus on complete tumor removal and minimization of cosmetic and functional defects. Among the multiple therapeutic options available, including both excisional and ablative approaches, MMS is the most definitive treatment modality. MMS involves excision of the clinically apparent neoplastic lesion, processing and staining of horizontal frozen sections, stepwise microscopic analysis, meticulous mapping, and re-excision of residual neoplasm until tumor-free margins are obtained. Unlike all other excisional techniques, MMS allows visualization of the entire surgical margin, thus ensuring complete removal of the lesion while maximally preserving the surrounding normal skin.

Unfortunately, because many tumors show significant sub clinical extension, the resulting surgical defect after completion of MMS can be significantly larger than the presenting lesion, often necessitating complex, costly, and time-consuming repairs, and compromising the final cosmetic appearance or function. In addition, tumors in low-risk locations, which typically undergo simple excisions, nonetheless can require significant circumferential margins of normal tissue to ensure complete removal, again impacting cosmesis, function and or cost. Likewise, aggressive tumors such as sclerosing/morpheaform or recurrent BCC's can result in significant post surgical defects and associated morbidity and decreased function.

Presently, the treatment of BCC, whether by excisional or ablative means, incurs an estimated annual cost in excess of $600 million. An effective oral agent for the treatment of BCC could serve as an adjunct modality in the removal of primary or recurrent lesions and may be expected to significantly decrease cosmetic disfigurement as well as reduce treatment-associated costs. In fact, studies such as this one may ultimately show that oral treatment results in complete elimination of selected neoplastic lesions, thereby eliminating altogether the need for surgery in some lesions.

Vismodegib, (GDC-0449) is an orally delivered small molecule hedgehog pathway inhibitor. In tumor growth Hedgehog binding to PCTH1 (Patched) stops PCTH1 from inhibiting SMO (smoothened) signaling. In the absence of PCTH1 (e.g. loss of PCTH1 mutations) SMO signaling occurs constitutively, stimulating GLI1 (Glioma-Associated Oncogene-1) thus promoting tumor growth. Vismodegib inhibits SMO signaling through direct interaction with SMO thus preventing the activation of GLI1 and thus inhibiting tumor growth in Basal Cell Carcinomas. The investigators anticipate our study to demonstrate the feasibility, efficacy, and safety of Vismodegib in the oral treatment of BCC.