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

Study Overview
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Brief Summary
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This randomized phase I/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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer

Intervention / Treatment
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* Drug: vismodegib
* Drug: gemcitabine hydrochloride
* Other: hydrocortisone/placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (gemcitabine hydrochloride and placebo)<br>Patients receive gemcitabine hydrochloride 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. | Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;Other: hydrocortisone/placebo<br>* Given PO<br>|
| Experimental: Arm II (gemcitabine hydrochloride and vismodegib)<br>Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and vismodegib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: vismodegib<br>* Given PO<br>* Other names: Hedgehog antagonist GDC-0449;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Time from randomization to disease progression or death from any cause. Estimated in the two treatment groups by the Kaplan-Meier method and compared using a stratified logrank test. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization to death from any cause. Estimated in the two treatment groups by the Kaplan-Meier method and compared using a stratified logrank test. | Up to 3 years | 
| Objective Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 6 months | 
| Incidence of Adverse Events | Details are provided in Adverse Events section below. Reported here are percentage of patients in each arm with any grade 1 or higher adverse event, regardless of attribution. | Up to 3 years | 
| Activity (Overall Response Rate) in Crossover Patients | RECIST response rate in patients after crossover from placebo to vismodegib arm. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 6 months |