A single arm, open-label, phase II, multicentre study to assess the safety of vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma (BCC).

Basal cell carcinoma (BCC) is the most common malignancy. Almost all of these
cases are small BCCs that can be effectively treated by dermatologists using
several surgical modalities. However, in a small subset of patients, invasion
of the BCC into subcutaneous structures can occur. In some cases, this results
from neglect of indolent BCCs, whereas in other cases patients may develop
particularly aggressive BCCs that recur and progress despite standard surgical
treatment. If further surgical resection is not possible, there is no approved
therapy and no standard of care exists. Although palliative radiation therapy
may be used, its use may be limited by the location of the tumor and the
involved structures, as well as prior cumulative radiation dosage. Locally
advanced BCC can be associated with significant morbidity as the result of
chronic pain, risk of bacterial infection and sepsis, bleeding/oozing, and
compromise of function, resulting from invasion of structures such as the ear,
nose and eye. In some cases, invasion can progress to involve critical organs
such as the meninges, brain, and spinal cord, resulting in death.
Metastatic BCC is extremely rare, with a reported metastasis rate ranging from
0.0028% to 0.55%. A total of approximately 300 cases of metastatic BCC have
been reported in the literature. Once metastasis is detected, survival can be
short for some patients, with a range of 8 to 14 months reported by some
Investigators. No standard therapy for metastatic BCC exists, although there is
anecdotal use of chemotherapeutic agents such as platinum compounds.
The Hedgehog (Hh) signaling pathway presents a novel and potentially beneficial
target for cancer therapy. Two mutations commonly found in BCC result from
either the inactivation of the PTCH1 receptor or the activation of SMO protein.
Both have the same functional consequence, i.e., the uncontrolled activation of
the Hh signaling pathway in the absence of the Hh protein. High expression
levels of Hh target genes, such as GLI1 and PTCH1, are found in nearly all
cases of human BCC examined, suggesting that activation of this pathway is a
causal event in the initiation of tumor formation. These data suggest that
blocking the Hh signaling pathway at the level or downstream of SMO may provide
a therapeutic benefit in the treatment of BCC. Vismodegib (also known as
GDC-0449) is a small molecule antagonist of the Hh signaling pathway.
Vismodegib binds to and inhibits SMO, thereby preventing the Hh signal.
Vismodegib has proven to be efficacious in nonclinical tumor models of both
mutated and ligand-overexpressing tumors as well as in preious phase
II-studies.

The primary objective of this phase II study is to assess the safety of
vismodegib in patients with (inoperable) locally advanced BCC or metastatic
BCC.

Enrolled patients will receive continuous once-daily oral dosing of vismodegib
at a dosage of 150 mg per administration. One cycle of therapy will be defined
as 28 days of treatment. All patients will receive study drug until the
development of progressive disease (as determined by the Investigator),
unacceptable toxicity, consent withdrawal, death, reasons deemed by the
treating physician, or study termination by the Sponsor. The trial will consist
of a Screening Period (Day *28 to *1), a Treatment Phase, an End of Treatment
Visit when the patient received the last dose of vismodegib and thereafter
discontinues vismodegib (regardless of when it occurs), and one Safety
Follow-Up Visit 30 days, 3, 6, 9 and 12 months after the last dose of
vismodegib.

Enrolled patients will receive continuous once-daily oral dosing of vismodegib
at a dosage of 150 mg per administration. One cycle of therapy will be defined
as 28 days of treatment. All patients will receive study drug until the
development of PD (as determined by the Investigator), unacceptable toxicity,
consent withdrawal, death, reasons deemed by the treating physician, or study
termination by the Sponsor (Roche).

For participating patients there is no guarantee that health will improve.
Based on experience with vismodegib (GDC-0449) in a very small number of
patients with advanced basal cell carcinoma, researchers believe that it may be
of benefit to patients with basal cell carcinomas. Because people respond
differently to therapy and because the study drug is experimental, no one can
know in advance if there will be a benefit. It is possible that the condition
may get worse. We do know that the information from this study will help
doctors learn more about vismodegib (GDC-0449) as a treatment for advanced
basal cell carcinoma. This information could help other people who have a
similar medical condition in the future.
There may be side effects from the drugs or procedures used in this study, and
they may vary from person to person. Doctors and the study sponsor do not know
all the side effects that may happen, and unknown side effects could occur.
During participation in this study, patients are at risk for the side effects
mentioned in section E9 of this form.