Photodynamic Therapy and Vismodegib for Multiple Basal Cell Carcinomas

Use of PDT for the treatment of BCC Indications for PDT include superficial and nodular BCC.
Eight randomized clinical trials have reported the results of PDT for superficial or nodular
BCC with a total of 1583 patients. Results of the meta analysis showed overall complete
clearance of PDT was 86.4 % compared to 98.2 % for surgery. The 1 year recurrence for PDT was
10.3 % vs 0. 6% for surgery. Cosmetic outcomes were much better with PDT than surgery. (Wang,
2015).

A randomized controlled trial of PDT with MAL versus surgical excision in 196 patients with
superficial BCC showed a 9.3% recurrence rate for PDT versus a 0% recurrence rate for surgery
at 12 months. However, the good-to-excellent cosmetic outcome was 94% and 60% for patients
treated with PDT and surgical excision, respectively. Similarly, in trials of PDT versus
surgery for nodular BCC, recurrence rates are less than 5% for surgery versus 14% to 30% for
PDT with ALA. As with superficial BCC, cosmetic effects are consistently shown to be more
favorable with PDT with ALA (Wang, 2015). In the largest single institution experience with
1440 nodular and superficial BCCs, PDT using systemically administered porfimer sodium showed
an initial (6-month) complete response rate of 92%, with a recurrence rate of less than 10%
at 4 years. At this same institution, a 92% complete response rate was achieved with PDT with
topical ALA in 330 patients with superficial BCC, but the response rate dropped to 71% in 75
patients with nodular BCC.

In a multicenter randomized trial of PDT with MAL versus cryotherapy for superficial BCC,
complete response rates at 3 months were 97% and 95%, respectively, with 5-year recurrence
rates of 22% and 20% for PDT with MAL and cryotherapy, respectively. In this study, the
excellent-to-good cosmetic outcome was 89% for PDT with MAL and 50% for cryotherapy.

Several clinical studies have reported an increase in the initial response rate with a lower
recurrence rate after repeated PDT sessions. Initial responses usually are apparent between
3-6 months after treatment when the skin has healed over and treatment related changes have
resolved. Cycles of MAL PDT repeated after 3 months for persistent BCC has been shown to
offer high and durable response rates. Both efficacy and safety have also been demonstrated
using repeated sessions with red or blue light at follow up times of 3, 6 and 12 months. At
Roswell Park Cancer Institute, Oseroff and colleagues safely used repeated sessions of ALA
PDT in children with BCNS (multiple BCC), and Gilchrest also reported the benefits of ALA PDT
with red light at 2-4 month interval treatments.

The most common adverse event with either ALA or MAL PDT is the burning or stinging pain
experienced by patients during illumination. Zeitouni and colleagues published their
retrospective and prospective data using a 2 step irradiance approach with ALA/MAL PDT and
red light in non BCNS patients with multiple BCC. Follow up times ranged from 6-24 months.
The 2 step irradiance schedule (bilevel) effectively minimized the treatment related pain and
maintained good clinical outcomes (Zeitouni x 2).

Inclusion Criteria

Patients will be included in the study based on the following criteria:

- Male or non-childbearing potential females, at least 18 years of age (Female patients
who meet at least one of the following criteria are defined as women of
non-childbearing potential)

- ≥ 50 years old and naturally amenorrheic for ≥ 1 year

- Permanent premature ovarian failure confirmed by specialist gynecologist

- Previous bilateral salpingo-oophorectomy or hysterectomy

- XY karyotype, Turner's syndrome, or uterine agenesis

- Diagnosis of BCC with at least 4 nodular lesions that measure 0.5 cm to 5 cm in
diameter, located on the head and neck, trunk or extremities.

- Diagnosis must be confirmed clinically at baseline with 1-2 lesions having been
biopsied no sooner than 2 weeks prior to treatment.

- Patients who may have high burden of disease ie large lesions, who are non-surgical
candidates or who refuse surgery.

- Non-surgical candidates, who may be able to undergo resection of selected single,
individual lesion, but may not tolerate extensive surgery, may have many co
morbidities, may be prone to complications.

- Patients in whom surgery or radiation therapy may be impractical

- Primary lesions may be acceptable for enrollment

- Within normal limit hematopoietic capacity, hepatic and renal function. Values outside
those limits may be allowed at the digression of the PI, if they are determined as not
clinically significant

- Male patients must use condoms at all times, even after a vasectomy, during sexual
intercourse with female partners of reproductive potential during treatment with
vismodegib and for 3 months after the last dose to avoid exposing a pregnant partner
and unborn fetus to vismodegib

- Male patients must agree not to donate sperm during the study and for 3 months after
discontinuation of vismodegib

- Agreement not to donate blood or blood products during the study and for 7 months
after discontinuation of vismodegib.

- Evidence of a personally signed and dated informed consent document indicating that
the subject (or legally acceptable representative) has been informed of all pertinent
aspects of the trial.

- Ability to understand and the willingness to sign a written informed consent document
in English

Exclusion Criteria:

- Women of childbearing potential

- Basal cell carcinomas of aggressive subtypes (infiltrative, morpheaform, micronodular)

- Any BCC that may require Mohs surgery for definitive control

- Subjects with porphyria's or known hypersensitivity to porphyrins

- Subjects with known photosensitivity diseases

- Subjects previously treated with a systemic photosensitizer within 4 months of
screening date

- Subjects who desire to get pregnant a female of childbearing potential within the next
1.5 years

- Uncontrolled concomitant 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.

- Life expectancy less than one year

- Inability or unwillingness to swallow capsules

- Have a history of alcohol of substance abuse, unless in full remission for greater
than 6 months prior to the screening visit (Day 0) when the consent form is signed.

- Known to be infected with human immunodeficiency virus (HIV), hepatitis B or hepatitis
C viruses.

- Currently receiving vismodegib, biologics or chemotherapy

- Currently undergoing treatment with photodynamic therapy, topical chemotherapy agents
including Imiquimod, fluorouracil, Ingenol mebutate (picato) to the selected treatment
lesion sites.

- Subjects who have Gorlins syndrome

- Subjects who have received any type of solid organ transplant

- Subjects taking immunosuppressive medications at the screening visit.

- Participation in other study using an investigational or experimental therapy or
procedure within 4 weeks or 5 half-lives (whichever is longer) before the screening
visit and/or during study participation. Subjects cannot participate in studies of
other investigational or experimental therapies or procedures at any time during their
participation in this study.

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study.

- Subjects unable or unwilling to comply with the study visit schedule and requirements
of the study

- Subjects unable to speak and read the English language

- A subject who, in the opinion of the sponsor-investigator will be uncooperative or
unable to comply with study procedures.