Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

This randomized phase II trial is studying gemcitabine hydrochloride and vismodegib to see how well they work compared with gemcitabine hydrochloride alone in treating patients with recurrent or metastatic pancreatic cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vismodegib may slow the growth of tumor cells. It is not yet known whether giving gemcitabine hydrochloride together with vismodegib is more effective than gemcitabine hydrochloride alone in treating patients with pancreatic cancer

Further Study Information

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.

Eligibility Criteria

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

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Hedy L. Kindler

Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01064622
Information obtained from ClinicalTrials.gov on March 24, 2013

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