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

18 Years
Open (Enrolling)
Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

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Trial Information

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


I. The primary objective of this study is to obtain tumor biopsies before and after therapy
with GDC-0449 (vismodegib) to evaluate the effect of inhibition of hedgehog signaling on
pancreatic cancer stem cells by: evaluating the tumor for number and percentage of
pancreatic cancer stem cells before and after treatment with GDC-0449.


I. To assess progression free survival (PFS) at 3 months following treatment with GDC-0449
and gemcitabine (gemcitabine hydrochloride).

II. To assess response rate to treatment and overall survival in patients with advanced
pancreas cancer treated with GDC-0449 alone and in combination with gemcitabine.

III. To evaluate the toxicity of GDC-0449 alone and in combination with gemcitabine.


Patients receive vismodegib orally (PO) once daily (QD) on days 1-28 and gemcitabine
hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15 (beginning in course
2). Courses repeat every 28 days in the absence of disease progression or unacceptable

After completion of study treatment, patients are followed up for 4 weeks.

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)

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of CD44+CD24+ESA+ cells from needle biopsy calculated using FACS

Outcome Description:

The paired difference between the two time points will be calculated, and the distribution of values is expected to follow a normal distribution. Monotonic transformations of the data, such as the arcsine, may be employed to normalize the distribution if significant deviation from normality is observed. A significant difference from zero (i.e. no change) will be tested for using the standard t-test.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Mark Zalupski

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Michigan


United States: Food and Drug Administration

Study ID:




Start Date:

June 2010

Completion Date:

Related Keywords:

  • Recurrent Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Pancreatic Neoplasms



University of MichiganAnn Arbor, Michigan  48109-0624