Phase II Study of Radiation Therapy and Vismodegib for Advanced Head/Neck Basal Cell Carcinoma

This is a single arm, multi-center Phase II clinical trial to assess the safety and
demonstrate the efficacy of a combined modality approach using radiation therapy after
induction and concurrently with systemic administration of vismodegib, which may increase the
rates of complete response and sustained local control in patients with locally advanced BCC

Inclusion Criteria:

1. Patients with locally advanced BCC of the head and neck, consisting of at least one
histologically or cytologically confirmed lesion greater than or equal to 20 mm in
longest diameter that is considered to be inoperable or to have a medical
contraindication to surgery, in the opinion of a Mohs dermatologic surgeon, head and
neck surgeon, or plastic surgeon. Locally advanced disease is considered to include
involved lymph nodes of the neck. A patient with regionally involved lymph nodes in
the neck is considered eligible. The patient should be considered a candidate for
radiotherapy and should not have medical contraindications to receipt of radiation
therapy.

If a patient has distant metastatic spread of BCC (e.g., spread to distant areas
outside the regional lymph nodes, clearly non contiguous areas of bone involvement, or
distant metastasis to lung, brain, or other visceral organs), the patient should be
considered as having distant metastasis and is not eligible.

Note: All lesions that the investigator proposes to follow as target lesions during
the course of the study must have previously been histologically confirmed as BCC.

Acceptable contraindications to surgery include:

- BCC that has recurred in the same location after two or more surgical procedures
and successful curative resection is deemed unlikely

- Complete surgical resection is not possible or is deemed excessively morbid (e.g.
invasion into cranial nerves or skull base, proximity to brain, spinal canal, or
orbit)

- Anticipated substantial morbidity and/or major deformity from surgery (e.g.
removal of a major facial structure, such as nose, ear, eyelid, eye, or jaw; or
requirement for upper limb amputation)

- Medical contraindication to surgery

- Patient refusal of surgery due to anticipated morbidity

- Other conditions considered to be contraindicating must be discussed with Data
Coordinator before enrolling the patient.

2. Prior radiation therapy is acceptable but there cannot be major overlap of the
previously irradiated tissues with the new radiation treatment volumes anticipated to
be delivered for the purposes of this protocol, in such a way that curative intent
with radiation cannot be met. Furthermore, the total dose from all radiation delivered
and expected to be delivered should not exceed the suggested dose constraints given
for normal structures.

3. Zubrod Performance Status 0-2

4. Age of greater than or equal to 18 years

5. Adequate bone marrow and organ function defined as follows:

Adequate bone marrow function:

leukocytes: > 3,000/mcL absolute neutrophil count: greater than or equal to 1000
cells/mm3 platelets: greater than or equal to 75,000 cells/mm3 hemoglobin: greater
than or equal to 8.5 g/dl (recommended cutoff subject to judgment of medical
oncologist), but cannot be transfusion dependent

Adequate hepatic function:

total bilirubin: less than or equal to 1.5x institutional ULN or within 3x the ULN for
patients with Gilbert disease AST(SGOT): < 3 X institutional upper limit of normal
ALT(SGPT): < 3 X institutional upper limit of normal

Adequate renal function:

creatinine: within normal institutional limits OR creatinine clearance: > 60
mL/min/1.73 m2 for patients with creatinine levels above institutional normal

6. Agreement not to donate blood or blood products during the study and for 7 months
after discontinuation of vismodegib; for male patients, agreement not to donate sperm
during the study and for 7 months after discontinuation of vismodegib.

7. For male patients, agreement not to donate sperm during the study and for 3 months
after the final dose of vismodegib. Male patients must use condoms at all times, even
after a vasectomy, during sexual intercourse with pregnant partners or female partners
of reproductive potential during treatment with vismodegib. Vismodegib is present in
semen. It is not known if the amount of vismodegib in semen can cause embryo-fetal
harm.

8. Verify the pregnancy status of females of reproductive potential within 7 days prior
to initiating vismodegib. For women of childbearing potential, a negative pregnancy
test within 7 days prior to commencement of dosing is required. Women of reproductive
potential are required to use two forms of acceptable contraception (including one
acceptable barrier method with spermicide) during therapy and for 7 months after
completing therapy. Acceptable forms of primary contraception include the following:
Combination hormonal contraceptives, subcutaneous hormonal implant, hormonal patch,
hormonal contraceptives (levonorgestre-releasing intrauterine system,
medroxyprogesterone acetate depot), tubal sterilization, vasectomy, and intrauterine
device (IUD). Acceptable forms of barrier contraception include the following: any
male condom (with spermicide) or diaphragm (with spermicide).

Exclusion Criteria:

1. Patients with distant metastasis (e.g. spread to distant areas outside the regional
lymph nodes, clearly non contiguous areas of bone involvement, or distant metastasis
to lung, brain, liver or other visceral organs) are ineligible.

2. Patients with nevoid BCC syndrome (Gorlin syndrome) should not enroll in this study.

3. A patient with a known other malignancy is eligible if there is a negligible risk for
disease progression or death within one year, there is no active ongoing treatment for
this malignancy, and the malignancy and/or any anticipated future treatments would not
interfere with protocol-mandated evaluations at 1 year.

4. Prior vismodegib or other antagonists of the Hh pathway;

5. Concurrent non-protocol-specified anti-tumor therapy (e.g., chemotherapy, other
targeted therapy, topical therapy such as 5-Fluorouracil or imiquimod, radiation
therapy, surgery, or photodynamic therapy.

- For patients with multiple cutaneous BCCs at baseline that are not designated by
the investigator as target lesions, treatment of these non-target BCCs with
surgery may be permitted but must be discussed with Data Coordinator prior to any
surgical procedure.

6. Recent (within 4 weeks of Registration), current, or planned participation in another
experimental drug study.

7. Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields in such a way that curative intent with radiation cannot be
met

8. Inability or unwillingness to swallow capsules; Patients with any condition that may
impair the ability to swallow or absorb oral medications/investigational product
including:

- any lesion, whether induced by tumor, radiation or other conditions, which makes
it difficult to swallow capsules or pills;

- prior surgical procedures affecting absorption including, but not limited to
major resection of stomach or small bowel;

- active peptic ulcer disease;

- malabsorption syndrome

9. Pregnant or lactating women. Patients who are unable or are unwilling to adhere to the
required contraceptive methods are excluded from the study.

- Women of reproductive potential are required to use two forms of acceptable
contraception (including one acceptable barrier method with spermicide) during
therapy and for 7 months after completing therapy. Acceptable forms of primary
contraception include the following: Combination hormonal contraceptives,
subcutaneous hormonal implant, hormonal patch, hormonal contraceptives
(levonorgestre-releasing intrauterine system, medroxyprogesterone acetate depot),
tubal sterilisation, vasectomy and intrauterine device (IUD). Acceptable forms of
barrier contraception include the following: Any male condom (with spermicide) or
diaphragm (with spermicide).

- 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 2 months after the last dose to avoid exposing
a pregnant partner and unborn fetus to vismodegib.

10. Life expectancy of <1 year

11. Patients with widespread superficial multifocal BCC who are considered unresectable
due to breadth of involvement and do not have a single definable area of disease
amenable to radiation therapy targeting.

Note: If an area including one or more lesions is definable for radiation therapy
targeting, the patient may be eligible for treatment on study using the designated
target lesion(s) identified by the investigator.

12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection or psychiatric illness/social situations that would limit compliance with
study requirements;

13. History of other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates use of an investigational drug or that might affect interpretation of
the results of the study or renders the patient at high risk form treatment
complications

14. HIV-positive patients on combination antiretroviral therapy, because of the potential
for pharmacokinetic interactions with vismodegib;