GDC-0449 and Erlotinib Hydrochloride With or Without Gemcitabine Hydrochloride in Treating Patients With Metastatic Pancreatic Cancer or Solid Tumors That Cannot Be Removed by Surgery

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of erlotinib hydrochloride and Hedgehog antagonist
GDC-0449 with or without gemcitabine hydrochloride in patients with unresectable solid
tumors.

SECONDARY OBJECTIVES:

I. To describe the adverse events profile associated with these treatment regimens.

II. To describe the responses in patients treated with these regimens. III. To assess the
effect of erlotinib hydrochloride and Hedgehog antagonist GDC-0449 on selected biomarkers in
circulating tumor cells and tumor biopsy samples from patients with metastatic pancreatic
cancer.

IV. To assess the effect of erlotinib hydrochloride and Hedgehog antagonist GDC-0449 on
fludeoxyglucose F 18 positron emission tomography imaging in patients with metastatic
pancreatic cancer.

V. To study the association between clinical (toxicity and/or tumor response or activity) and
biologic (pharmacodynamic) results associated with erlotinib hydrochloride and Hedgehog
antagonist GDC-0449 in patients with metastatic pancreatic cancer.

OUTLINE: This is a dose-escalation study of erlotinib hydrochloride.

Patients receive Hedgehog antagonist GDC-0449 orally (PO) once daily (QD) and erlotinib
hydrochloride PO QD on days 1-28. Some patients also receive gemcitabine hydrochloride IV
over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

Patients treated at the maximum tolerated dose undergo fludeoxyglucose F 18 positron emission
tomography at baseline and on day 28. These patients also undergo tumor tissue and blood
sample collection at baseline and periodically during study for correlative laboratory
studies. Samples are analyzed for tyrosine phosphorylated or total MAP-K, EGFR, AKT, and
other potential biomarkers of activity/response and for levels of genes transcriptionally
activated (e.g., BCL-2, GLI, BFL-1/A1, 4-1BB, PTC1) by immunofluorescence, IHC, and
quantitative-PCR.

After completion of study therapy, patients are followed at 3 months.

Inclusion Criteria:

- Histologic proof of a solid tumor that is now unresectable, not amenable to any other
standard therapies, or patient refuses standard therapy

- Metastatic adenocarcinoma of the pancreas amenable to biopsies (cohort II MTD
only)

- Absolute neutrophil count (ANC) >= 1,500/μL

- Platelets >= 100,000/μL

- Total bilirubin =< upper limit of normal (ULN)

- Aspartate aminotransferase (AST) =< 3 times upper limit of normal (ULN)

- Creatinine =< 1.5 times ULN

- Hemoglobin >= 9.0 g/dL

- International Normalized Ratio (INR) within normal limits (for patients treated at the
MTD)

- Ability to provide informed consent

- Willingness to return to Mayo Clinic for follow up

- Life expectancy >= 12 weeks

- Willingness to provide the biologic specimens as required by the protocol

- Negative serum pregnancy test done =< 7 days prior to registration

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

- Able to swallow or have medication administered through a G-tube and absorb the
medication

- Participant agrees to use an acceptable form of contraception; acceptable forms of
contraception:

- Latex condom (always used with spermicide)

- Diaphragm (always used with spermicide)

- Cervical cap (always used with spermicide)

Acceptable forms of secondary contraceptions, when used along with a barrier method:

- Hormonal contraception methods, including pills, patches, rings, or injections except
progestin-only containing pills (i.e. "Mini-pill")

- Tubal ligation

- Partner's vasectomy

- Intrauterine device (IUD) (non-progesterone T)

- Vaginal sponge (containing spermicide)

- 100% commitment to abstinence

Unacceptable forms of contraception for women of childbearing potential:

- Oral contraception containing progestins only

- IUD progesterone T

- Female condom

- Natural family planning (rhythm method) or breastfeeding

- Fertility awareness

- Withdrawal

- Cervical shield

- Willing to abstain from smoking

- Willing to complete a daily pill diary

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- 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

- Any of the following prior therapies:

- Chemotherapy =< 4 weeks prior to registration

- Mitomycin C/nitrosoureas =< 6 weeks prior to registration

- Immunotherapy =< 4 weeks prior to registration

- Biologic therapy =< 4 weeks prior to registration

- Radiation therapy =< 4 weeks prior to registration

- Radiation to > 25% of bone marrow

- Failure to fully recover from acute, reversible effects of prior therapy regardless of
interval since last treatment

- New York Heart Association classification III or IV

- Seizure disorder

- Central nervous system (CNS) metastases if not stable for at least 2-3 months based on
imaging, clinical assessment, and use of steroids, or seizure disorder

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception until 12 months after last study drug dose

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (utilized for a non-Food and Drug Administration
[FDA]-approved indication and in the context of a research investigation)

- Current therapy with a CYP3A4 inhibitor or inducer

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients receiving highly active antiretroviral therapy (HAART) treatment

- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm

- Active other malignancy, excepting non-melanotic skin cancer or carcinoma-in-situ of
the cervix; if there is a history of prior malignancy, they must not be receiving
other specific treatment (other than hormonal therapy) for their cancer

- History of myocardial infarction =< 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

- Abnormalities of the cornea based on history (e.g., dry eye syndrome, Sjogren's
syndrome), congenital abnormality (e.g., Fuch's dystrophy), abnormal slit-lamp
examination using a vital dye (e.g., fluorescein, Bengal Rose), and/or an abnormal
corneal sensitivity test (Schirmer test or similar tear production test)

- More than 2 prior chemotherapy regimens for the current metastatic malignancy; full
dose chemotherapy used in conjunction with concurrent radiation therapy will be
included as prior therapy; Note: prior hormonal therapy (e.g. leuprolide, aromatase
inhibitors, tamoxifen) will be allowed and not included as a prior chemotherapy

- Previous therapy with a hedgehog inhibitor