Cancer Stem Cells and Inhibition of Hedgehog Pathway Signaling in Advanced Pancreas Cancer: A Pilot Study of GDC-0449 in Combination With Gemcitabine

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed pancreas cancer

- Patients must have metastatic disease or recurrent disease following surgical therapy

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) >= 20
mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT)
scan

- Patients must have disease accessible for core needle biopsy both prior to initiation
of therapy and on day 21 (+ or - 1 day) of GDC-0449 treatment

- No previous systemic therapy for metastatic pancreas cancer is permitted; prior
neoadjuvant or adjuvant therapy with chemotherapy and/or radiation is allowed
provided that the last day of therapy was at least 6 months prior to registration

- Life expectancy of greater than 12 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 2.0 mg/dl

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal; < 5 x if liver involved in tumor

- Creatinine < 2.0 mg/dl

- The effects of GDC-0449 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because hedgehog (Hh) signal pathway inhibitors
as well as gemcitabine are known to be teratogenic, women of child-bearing potential
and men must use two forms of contraception (i.e., barrier contraception and one
other method of contraception) at least 4 weeks prior to study entry, for the
duration of study participation, and for at least 12 months post-treatment; for
appropriate methods of contraception considered acceptable; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately;

- Pregnancy testing: omen of childbearing potential are required to have a
negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL
beta-human chorionic gonadotropin [bHCG]) within 10-14 days and within 24 hours
prior to the first dose of GDC-0449 (serum or urine); a pregnancy test (serum or
urine) will be administered every 4 weeks if their menstrual cycles are regular
or every 2 weeks if their cycles are irregular while on study within the 24-hour
period prior to the administration of GDC-0449; a positive urine test must be
confirmed by a serum pregnancy test; prior to dispensing GDC-0449, the
investigator must confirm and document the patient's use of two contraceptive
methods, dates of negative pregnancy test, and confirm the patient's
understanding of the teratogenic potential of GDC-0449

- Patients taking medications with narrow therapeutic indices that are metabolized by
cytochrome P450 (CYP450) may be enrolled with caution; GDC-0449 is a substrate of
CYP3A4; however, the in vitro metabolic conversion of GDC-0449 is low; effects of
cytochrome (CYP) inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin,
rifampin, St. John's wart, and troglitazone) on clinical concentrations of GDC-0449
are unknown; likewise, the effects of strong inhibitors of CYP3A4 (e.g.,
clarithromycin, erythromycin, itraconazole, ketoconazole, nefazodone, and
telithromycin) on GDC-0449 clinical concentrations are unknown, and caution should be
exercised when dosing GDC-0449 concurrently with inhibitors of CYP3A4; in addition,
GDC-0449 inhibits CYP2C8, CYP2C9, and CYP2C19 drug metabolism enzymes in vitro at
concentrations that may be clinically relevant; therefore, caution should be
exercised when dosing GDC-0449 concurrently with medications that are substrates of
CYP2C8, CYP2C9, and CYP2C19 and have narrow therapeutic windows

- Ability to understand and willingness to provide written informed consent

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 6 months prior to entering
the study or those who have not recovered from adverse events due to agents
administered more than 6 months earlier

- Patients may not be receiving any other investigational agents

- Patients with known brain metastases

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to GDC-0449 or other agents used in the study

- Patients on anticoagulation with Coumadin are ineligible; however anticoagulation
with enoxaparin is acceptable for study entry

- Patients with malabsorption syndrome or other condition that would interfere with
intestinal absorption; patients must be able to swallow capsules

- Patients with clinically active liver disease, including active viral or other
hepatitis or cirrhosis, are ineligible

- Patients with uncontrolled hypomagnesemia or hypokalemia defined as less than the
lower limit of normal for the institution, despite adequate electrolyte
supplementation are excluded from this study

- Patients with > grade 1 hyponatremia or hypocalcemia are excluded from this study

- Uncontrolled intercurrent 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

- Pregnant women are excluded from this study because GDC-0449 is a Hh pathway
inhibiting agent with the potential for teratogenic or abortifacient effects; because
there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with GDC-0449, breastfeeding should be
discontinued if the mother is treated with GDC-0449; these potential risks may also
apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
GDC-0449; in addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy; appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated