Vitamin D as a Nutritional Neoadjuvant During Photodynamic Therapy of Basal Cell Carcinoma

The overall hypothesis is that PDT could provide exceptional benefit in patients with Basal
Cell Nevus Syndrome (BCNS) and multiple BCC tumors because PDT is nonmutagenic, nonscarring,
and can be safely repeated many times. The specific study hypothesis is that Vitamin D might
be useful as a neoadjuvant to improve tumor responses to PDT. In preclinical studies, the
investigators showed that epithelial tumors are more responsive to aminolevulinic acid
(ALA)-based PDT when "primed" by pre-exposure to the dietary form of Vitamin D
(cholecalciferol, D3). This study will test the hypothesis that oral D3 supplements,
administered over a relatively short time, can boost the effectiveness of PDT for cutaneous
(BCC) in this patient population. Patients with BCNS and multiple BCC, or normal patients
with at least 3 BCC tumors, will be enrolled. They will receive three PDT treatments, at
two-month intervals, over a 6 month period.

Primary Objective

• To determine tumor clinical clearance rates after neoadjuvant D3/PDT, and after PDT alone.
To accomplish this, the first two PDT treatments in each study patient will be randomized,
i.e. one PDT session will be performed after D3 pretreatment, the other without any
pretreatment.

Secondary Objective(s)

- To assess the level of PpIX accumulation in BCC lesions at various treatment visits, in
the absence or presence of neoadjuvant D3. (Fluorescence dosimetry measurements)

- To assess tolerability of the technique. (Pain scale measurements)

- To assess patient satisfaction with the technique. (Cosmetic result, and questionnaire)

- To assess D3 serum levels (in serum) and VDR status (in leukocyte DNA), and correlate
these results to clinical outcomes.

Study Design:

In this clinical study, each patient will serve as his or her own control with respect to BCC
tumor responsiveness to neoadjuvant D3 supplementation. The first two PDT treatments will be
randomized. Thus, patients in Group A will take D3 pills prior to the first PDT treatment,
and placebo pills prior to the second PDT treatment. For patients in Group B, the order is
reversed. Total amounts of D3 supplementation given will be adjusted, based upon serum
25-hydroxy-D3 levels found at baseline. Patients with VD deficiency will take 14 days of
neoadjuvant D3, vs. only 5 days if the initial VD level is normal.

Inclusion Criteria:

- diagnosis of Basal Cell Nevus Syndrome (BCNS) as defined in the Consensus Statement
from the first International colloquium on BCNS.

- Major Criteria are:

- (1) BCC prior to age 20 years, or excessive number of BCCs out of proportion
to prior sun exposure and skin type;

- (2) keratocyst of the jaw prior to age 20;

- (3) palmar or plantar pitting;

- (4) lamellar calcification of the falx cerebri;

- (5) medulloblastoma;

- (6) first degree relative with BCNS;

- (7) Patched-1 (PTCH1) gene mutation.

- Minor Criteria are:

- (1) rib anomalies, or other specific skeletal malformations including
kyphoscoliosis and short 4th metacarpals;

- (2) macrocephaly;

- (3) cleft/lip or palate;

- (4) fibroma of the heart or ovary;

- (5) ocular abnormalities;

- For diagnosis of BCNS, the patient must have either 2 major criteria, one major
and two minor criteria.

- At least three BCC tumors, two of which are biopsy-proven

- Female subjects must not become pregnant during the study

- Subjects must be able to understand and willing to sign a written informed consent
document

Exclusion Criteria:

- Pregnant or nursing.

- At risk for hypercalcemia (renal disease, sarcoidosis, etc.)

- Taking vismodegib or a hedgehog pathway inhibitor; must stop at least 1 month prior.

- Taking any topical treatment on their BCC tumors; must stop at least one month prior.

- Taking Vitamin D or multivitamin supplements; must stop at least one month prior.

- Currently undergoing treatment for other cancers with medical or radiation therapy.

- Patients with a known hypersensitivity to 5-aminolevulinic acid or any component of
the study material.

- Patients with history of a photosensitivity disease, such as porphyria cutanea tarda.

- Currently participating in another clinical trial.