Gemcitabine Hydrochloride With or Without Vismodegib in Treating Patients With Recurrent or Metastatic Pancreatic Cancer

PRIMARY OBJECTIVES:

l. To compare the progression-free survival of advanced pancreatic cancer patients treated
with the combination of gemcitabine plus GDC-0449 (vismodegib) versus gemcitabine plus
placebo.

SECONDARY OBJECTIVES:

I. To compare overall survival of advanced pancreatic cancer patients treated with the
combination of gemcitabine plus GDC-0449 versus gemcitabine plus placebo II. To compare the
objective response rate of advanced pancreatic cancer patients treated with the combination
of gemcitabine plus GDC-0449 versus gemcitabine alone.

III. To determine the toxicity experienced by pancreatic cancer patients treated with the
combination of gemcitabine plus GDC-0449.

IV. To determine the activity, in an exploratory analysis, of gemcitabine plus GDC-0449 in
patients who progress on gemcitabine plus placebo.

TERTIARY OBJECTIVES:

I. To determine if tumor immunohistochemical expression patterns of proteins in the Hh
pathway, including sonic hedgehog (Shh), indian hedgehog (Ihh), patched tumor suppressor
gene (PTCH), smoothened protein (SMO), and GLI1 and 2, within pancreatic tissue obtained at
the time of curative intent surgery predict response and prognosticate outcome of patients
treated with or without GDC-0449 at the time of relapse.

II. To determine the prognostic ability (relapse free survival, [RFS]) of these biologic
markers for resected patients in an archival cohort of patients undergoing resection.

III. To determine expression pattern of pancreatic CSC markers, including CD44, CD24, CD133,
aldehyde dehydrogenase (ALDH) and epithelial specific antigen (ESA) by immunohistochemistry
(IHC) on these archival tissues in relation to Hh pathway markers and correlate these with
clinical outcomes.

IV. To determine whether high baseline serum Shh, as well as changes in serum Shh during
treatment, predict treatment efficacy and/or prognosticate clinical outcome.

V. To determine the frequency of mutation of Hh pathway genes, PTCH, SMO, SuFU, and if the
presence or absence of mutations are correlated with clinical outcome.

VI. To determine the frequency of amplification of Hh pathway genes, gene copy number by
quantitative polymerase chain reaction (qPCR) of GLI1 and SMO in those tumors that have high
protein expression as seen by IHC. Gene amplification will be correlated with clinical
outcome.

VII. To determine if there is a correlation of K-ras mutation, and MET and RON expression,
amplification, or mutation status with Hh pathway abnormalities, CSC markers, and clinical
outcomes.

VIII. To determine if baseline contrast perfusion imaging volume transfer constant (Ktrans)
within primary and liver metastatic lesions as measured on a 256-detector computed
tomography (CT) scanner predicts objective response rates, and other clinical endpoints
including progression-free survival (PFS), to treatment with gemcitabine and
GDC-0449/placebo. (University of Chicago ONLY) IX. To determine if treatment with
Gemcitabine and GDC-0449 improves tumor perfusion, as measured by Ktrans, over the course of
treatment by serial CT scans every 2 cycles, compared to tumors treated with Gemcitabine and
placebo. (University of Chicago ONLY) X. To determine if improved tumor perfusion with
GDC-0449 treatment (if observed) improves objective response rates and other clinical
endpoints including PFS. (University of Chicago ONLY)

OUTLINE: This is a multicenter, safety lead-in study (part I) followed by a randomized study
(part II).

An initial 6 patients are enrolled in the part I portion of the study. If no dose-limiting
toxicities occur in these patients, subsequent patients are enrolled in the part II portion
of the study.

PART I (safety lead-in study): Patients receive gemcitabine hydrochloride intravenously (IV)
over 30 minutes on days 1, 8, and 15 and hedgehog antagonist GDC-0449 orally (PO) once daily
(QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

PART II (randomized study): Patients are stratified according to disease status (recurrent
after surgery vs metastatic) and Eastern Cooperative Oncology Group (ECOG) performance
status (0 vs 1). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride 1000 mg/m^2 IV over 30 minutes on days 1,
8, and 15 and placebo PO QD on days 1-28. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity. At the time of disease progression, patients
are unblinded and may crossover to arm II.

ARM II: Patients receive gemcitabine hydrochloride 1000 mg/m^2 IV over 30 minutes on days 1,
8, and 15 and hedgehog antagonist GDC-0449 PO QD on days 1-28. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity.

Tumor tissue, blood, serum, and plasma samples are collected periodically for biomarker and
other analyses.

After completion of study treatment, patients are followed periodically.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed adenocarcinoma of the
pancreas

- 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) as >=
20 mm with conventional techniques or as >= 10 mm with spiral computed tomography
(CT) scan

- Patients must have either:

- Newly diagnosed chemo-naïve metastatic pancreatic cancer; only patients who have
not received any chemotherapy for their metastatic disease are eligible

- Recurrent disease after curative-intent surgery which has now recurred and is
metastatic; patients who have recurrent disease may have received adjuvant
chemotherapy or adjuvant chemoradiation, but may not have received any
chemotherapy for metastatic disease; adjuvant therapy must have been completed
>= 6 months prior to the diagnosis of recurrent disease, or if not adjuvant
therapy received, surgery must have been performed >= 6 months prior to the
diagnosis of recurrent disease

- Age >= 21 years

- Life expectancy > 3 months

- Karnofsky performance status >= 80%

- Granulocytes >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Total bilirubin =< 1.5 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 times upper
limit of normal (ULN) (=< 5 times ULN in the presence of liver metastases)

- Creatinine within normal institutional limit (< 1.5) OR creatinine clearance >= 65
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- International normalized ratio (INR) =< 1.5 (=< 3 for patients on warfarin)

- Patients who are on warfarin anticoagulation are allowed to participate as long as
they fit the following 4 criteria:

- They are therapeutic on a stable warfarin dose

- Their INR target range is no greater than 3

- They are monitored with weekly INR testing

- They have no active bleeding or pathological condition that carries high risk of
bleeding Other anticoagulants, including enoxaparin (Lovenox) and fondaparinux
(Arixtra) are also permitted

- Women of child-bearing potential and men must use at least one form of contraception
(i.e., barrier contraception) at least 4 weeks prior to study entry and then two
forms of contraception (i.e barrier contraception and one other method of
contraception), 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: Women of childbearing potential are required to have a negative
serum pregnancy test (with a sensitivity of at least 25 mIU/mL) within 10-14 days (at
initial screening/consideration for the trial - 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

- Ability to understand and the willingness to sign a written informed consent document

- Patients with recurrent disease after curative-intent surgical resection must have
sufficient archival material for correlative studies (20 unstained 5 micron slides
and 20 unstained 10 micron slides, or an archival tissue block

Exclusion Criteria:

- No prior chemotherapy for metastatic pancreatic cancer; patients who have received
any chemotherapy and/or radiation therapy in the adjuvant setting must have completed
this therapy ≥6 months prior to enrollment on the trial at the time of recurrence

- Patients may not be receiving (or received prior to enrollment) any other
investigational agents for metastatic disease

- Patients with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events

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

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

- 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

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

- No currently active second malignancy other than non-melanoma skin cancer or
carcinoma in-situ of the cervix; patients are not considered to have a "currently
active" malignancy if they have completed therapy and have no evidence of recurrence
for at least 5 years

- Uncontrolled intercurrent illness including, but not limited to,

- Ongoing or active infection,

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would limit compliance with study
requirements

- Pregnant women are excluded from this study; 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