Vismodegib for Treatment of Basal Cell Carcinoma

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.

The safety, preliminary efficacy, and pharmacokinetics of Vismodegib was assessed in an
open-label, multicenter, two-stage Phase I trial1. Patients had solid tumors refractory to
therapy. An expansion cohort was included for patients with locally advanced or metastatic
BCC (n=33). Patients received continuous administration of Vismodegib at 150 mg/day (n=17),
270 mg/day (n=15), or 540 mg/day (n=1) beginning on Day 1. Patients were treated until
disease progression, intolerable toxicities, or withdrawal from the study. Response
assessments for radiologically measurable disease, RECIST version 1.0 was used. CR or PR
determined on 2 consecutive occasions ≥4 weeks apart. Locally advanced tumors assessed on
Dermatological Examination. CR defined as disappearance of a palpable or visible tumor; PR
defined as a reduction of >50% in tumor diameter. Results from this pilot study
demonstrated that oral vismodegib could clear or reduce the tumor burden of BCCs with a CR
in 2, PR in 16, SD in 11 and PD in 4 in patients followed over a 20 month period. No
dose-limiting toxic events or grade 5 events were observed with a single grade 4 adverse
event (asymptomatic hyponatremia) reported. The more significant and frequent adverse events
were GI related with dysgeusia and muscle spasm reported.

Recently, one Phase II single-arm, non-randomized trial of single-agent vismodegib at 150
mg/day to progression or intolerance with 104 patients enrolled: (33 mBCC, 71 LA BCC) using
the primary endpoint: Independent Review Facility (IRF) assessed overall response rate (ORR)
and the secondary endpoints: Investigator-assessed ORR, progression-free survival (PFS),
overall survival (OS), duration of response, and safety was also recently completed and it
was announced that the study met its primary endpoint (ORR) and showed shrinkage of tumors
in a pre-defined percentage of patients2. A preliminary safety assessment showed the most
common adverse events were consistent with previous experience with vismodegib. The most
common adverse events were muscle spasms, hair loss, altered taste sensation, weight loss,
fatigue, nausea, decreased appetite and diarrhea. A detailed safety assessment is ongoing.

Since these are slow-growing tumors which are expected to respond favorably to treatment,
and since all lesions will be surgically excised by MMS within 6 months of initial
consultation, this study will not affect the current standard of care in the management of
BCC.

After target tumor site is identified guided by either the plastic template or tattoo
performed pre treatment the original lesion will be delineated using the template and
concentric circles of two millimeters drawn around the central target area. A punch biopsy
of the center of the lesion will then be performed and thereafter the lesion will be excised
using standard Mohs procedures, with the excised tissue evaluated histologically to confirm
the presence or absence of tumor. If there is residual tumor found histologically or there
is scarring or there is significant inflammation present histologically additional layers
will be performed using the 2mm concentric circles as a guide until all tumor is deemed to
have been removed. The final wound size at the completion of Mohs surgery (i.e., upon
reaching tumor-free tissue margins) will then be determined using the pre-treatment
concentric margins, and compared to the lesion size at the initiation of treatment both for
treatment and placebo areas. In addition, the histological extent of the lesion will be
compared to the expected sub clinical extension as documented by Wolf and Zitelli as
previously noted. Any subject who discontinued treatment prematurely should be encouraged to
return to the clinic for the excision. Only subjects who have no histological evidence of
BCC will be considered complete responders. Note that post excision antibiotics and
analgesics administered to the subject prophylactically for infection and pain at the
excision site must be recorded on the concomitant medication page of the CRF.

Inclusion Criteria:

1. Willing and able to give informed consent.

2. At least 18 years of age.

3. Have a confirmed BCC at one of listed anatomical sites which must be biopsy-confirmed
at the study site and meets this criteria:

- non-infected

- minimum tumor area of 0.5 cm2 in an anatomic location at risk for significant
deformity or functional impairment with surgery.

- macroscopically (clinically) consistent with BCC

- histologically consistent with BCC

- suitable for treatment with Mohs surgical excision

- identifiable by subject or reliable subject representative

4. Free of any significant physical abnormalities (e.g., tattoos) at treatment site.

5. Willing and able to participate in the study as an outpatient, making frequent visits
to clinic during treatment and follow-up periods and comply with study requirements,
including:

- Consenting to biopsy of the lesion at baseline, if needed, before beginning
study drug treatment

- Attend all scheduled clinic visits during pre-study, treatment, and follow-up
periods

- Will delay excision of the target tumor site until time mandated in the
protocol, unless evidence of disease progression or lack of drug tolerability

- Post-excisional follow-up visits until the area is healed to investigator's
satisfaction

6. Female of reproductive potential must use 2 forms of acceptable contraception
(including one acceptable barrier method with spermicide) during therapy and for 7
months after completing therapy.

7. Male patients must use condoms at all times, with spermicide, even after vasectomy,
during sexual intercourse with females during treatment and for 2 months after the
last dose.

8. Agrees not to donate blood or blood products during the study and for 7 months after
last dose.

Exclusion Criteria:

1. Prior treatment with GDC-0449 or any HH Pathway Inhibitor

2. Have evidence of clinically significant, unstable cardiovascular or
immunosuppressive, hematologic, hepatic, neurologic, renal, endocrine,
collagen-vascular, or gastrointestinal abnormalities or disease. Subjects with
clinically stable medical conditions including, but not limited to, controlled
hypertension, diabetes mellitus type II, hypercholesterolemia, or osteoarthritis,
will be allowed to enter the study.

3. Have any dermatological disease at treatment site that may be exacerbated by
treatment with vismodegib or cause difficulty with examination (e.g., psoriasis,
eczema).

4. Inability or unwillingness to swallow capsules

5. Pregnancy or lactation

6. Have a desire to conceive in the future.

7. Patients with known Gorlin's (basal cell nevus) syndrome or clinical suspicion of
Gorlin's Syndrome)

8. Recent (i.e., within the past 28 days), current, or planned participation in another
experimental drug study

9. Have active chemical dependency or alcoholism..

10. Have received following treatments for BCC in the treatment area within designated
time period before study treatment initiation:

Treatment Time Period:

Prescribed topical retinoids 4 weeks Surgical excision 4 weeks Curettage 4 weeks Cryo
destruction or chemo destruction 4 weeks

11. Received treatment for non-melanoma skin cancer or precancerous condition [squamous
cell carcinoma (SCC), or actinic keratosis (AK)] within treatment area within 4 weeks
of study treatment initiation, or currently have SCC, malignant melanoma (MM), or any
other dermatological condition in treatment area that requires treatment.

12. Received any cancer chemotherapy within 6 months before study treatment initiation
(subject must not currently have any evidence of cancer, other than skin cancer).

13. Received any of the following treatments within 4 weeks before study treatment
initiation:

- Interferon or interferon inducers

- Immunomodulators or immunosuppressive therapies

- Cytotoxic drugs

- Investigational drugs

- Drugs known to have major organ toxicity

- Oral corticosteroids

- Inhaled corticosteroids (> 1200 Xg/day for beclomethasone, or > 600 Xg/day for
fluticasone)

- Topical steroids in treatment area