A Multi-Center, Double Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine Plus GDC-0449 (NSC 747691), a Hh Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer (10052747)

Trial Information

A Multi-Center, Double Blind, Placebo-Controlled, Randomized Phase II Trial of Gemcitabine Plus GDC-0449 (NSC 747691), a Hh Pathway Inhibitor, in Patients With Metastatic Pancreatic Cancer (10052747)

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 Shh, Ihh, PTCH, 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,
ALDH and ESA by 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
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 CT scanner
predicts objective response rates, and other clinical endpoints including PFS, to treatment
with Gemctibine 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 IV over 30 minutes
on days 1, 8, and 15 and oral hedgehog antagonist GDC-0449 once daily 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 ECOG performance status (0 vs 1). Patients are randomized
to 1 of 2 treatment arms.

ARM I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15
and oral placebo once daily 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 IV over 30 minutes on days 1, 8, and 15
and oral hedgehog antagonist GDC-0449 once daily 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.