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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)


Phase 2
21 Years
N/A
Open (Enrolling)
Both
Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

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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.


Inclusion Criteria:



- Histologically or cytologically confirmed pancreatic adenocarcinoma meeting 1 of the
following criteria:

- Newly diagnosed, metastatic disease

- Recurrent disease

- Patients with recurrent disease after surgical resection must have
sufficient archived tissue available for correlative studies

- Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1
dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques
or as ≥ 10 mm with spiral CT scan

- No known brain metastases

- Karnofsky performance status 80-100%

- Life expectancy > 3 months

- Granulocytes ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

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

- AST/ALT ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases)

- INR ≤ 1.5 (≤ 3 for patients on warfarin)

- Serum creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 65 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use at least one method of contraception for ≥ 4 weeks prior
to, and then double-method of contraception during and for ≥ 12 months after
completion of study treatment

- Able to swallow capsules

- No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia, defined
as less than the lower limit of normal despite adequate electrolyte supplementation

- No malabsorption syndrome or other condition that would interfere with intestinal
absorption

- No clinically active liver disease, including active viral or other hepatitis or
cirrhosis

- No "currently active" second malignancy other than nonmelanoma 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 ≥ 5 years

- No concurrent uncontrolled illness including, but not limited to, any of the
following:

- 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

- No cerebrovascular accident within the past 6 months

- No recent myocardial infarction

- No 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

- No blood donation for ≥ 12 months after completion of study treatment

- Other concurrent anticoagulants (including enoxaparin [Lovenox] and fondaparinux
[Arixtra]) allowed

- No prior Hedgehog SMO inhibitor

- No prior chemotherapy for metastatic disease

- Prior adjuvant chemotherapy or adjuvant chemoradiotherapy allowed provided patient
did not receive chemotherapy for metastatic disease AND adjuvant therapy was
completed ≥ 6 months before the diagnosis of recurrent disease

- Prior surgery allowed provided patient did not receive adjuvant therapy AND surgery
was completed ≥ 6 months prior to the diagnosis of recurrent disease

- No other concurrent investigational agents

- No other concurrent anticancer agents or therapies

- No concurrent ketoconazole or grapefruit juice

- No concurrent combination antiretroviral therapy for HIV-positive patients

- Concurrent warfarin allowed provided patient is on a stable therapeutic dose of
warfarin, INR is in the target range (≤ 3), INR testing is performed weekly, and
patient has no active bleeding or pathological condition that carries a high risk of
bleeding

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Description:

Estimated in the two treatment groups by the Kaplan-Meier (1958) method and compared using a stratified logrank test.

Outcome Time Frame:

Time from randomization to disease progression or death from any cause, assessed up to 3 years

Safety Issue:

No

Principal Investigator

Hedy Kindler

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago Comprehensive Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-01454

NCT ID:

NCT01064622

Start Date:

September 2009

Completion Date:

Related Keywords:

  • Adenocarcinoma of the Pancreas
  • Recurrent Pancreatic Cancer
  • Stage IV Pancreatic Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Pancreatic Neoplasms

Name

Location

Weill Medical College of Cornell UniversityNew York, New York  10021
Central Illinois Hematology Oncology CenterSpringfield, Illinois  62701
City of Hope Medical CenterDuarte, California  91010
University of PittsburghPittsburgh, Pennsylvania  15261
Tower Cancer Research FoundationBeverly Hills, California  90211
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Decatur Memorial HospitalDecatur, Illinois  62526
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Illinois CancerCare-PeoriaPeoria, Illinois  61615
Fort Wayne Medical Oncology and Hematology Inc - State BoulevardFort Wayne, Indiana  46845
University of Maryland Greenebaum Cancer CenterBaltimore, Maryland  21201
University of Michigan University HospitalAnn Arbor, Michigan  48109
Saint Joseph Medical CenterTowson, Maryland  21204