Hedgehog Inhibitors for Metastatic Adenocarcinoma of the Pancreas

Study Overview
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Brief Summary
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This is an open-label, single arm, multi-center, Phase II trial to evaluate the progression free survival in patients with metastatic adenocarcinoma of the pancreas treated with a hedgehog inhibitor (GDC-0449) in combination with chemotherapy (gemcitabine and nab-Paclitaxel).

Detailed Description
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The emergence of new small molecules with capacity of blocking the Hedgehog signaling pathway provides a novel therapeutic approach in pancreatic adenocarcinoma treating the primary tumor, stroma, systemic metastases and pancreatic cancer stem cells by hedgehog pathway inhibition. This phase 2 clinical trial will evaluate the progression free survival (PFS) in patients with previously untreated metastatic pancreatic adenocarcinoma. We hypothesize that the combination of cytotoxic agents (gemcitabine and nab-paclitaxel) with the Hedgehog inhibitor GDC-0449 may increase PFS. This study includes correlative studies to attempt to understand the stem cell biology and mechanism for any observed clinical benefits with the use of Hedgehog inhibitor GDC-0449. These include changes in the hedgehog pathway and changes in pancreatic cancer stem cell markers with pre and post treatment biopsies. The safety of GDC-0449 when combined with chemotherapy gemcitabine and nab-paclitaxel will also be assessed by evaluating adverse event rate. Following the determination of eligibility patients will receive the following treatment: One cycle of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 (28 days cycle) then Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days cycle in combination with oral GDC-0449 150 mg daily Patients may continue on treatment regimen until they experience progressive disease or unacceptable toxicity, require palliative radiotherapy, withdraw consent or the physician feels it is not longer in their best interest to continue on treatment.

Official Title
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A Phase II Study of Gemcitabine and Nab-Paclitaxel in Combination With GDC-0449 (Hedgehog Inhibitor) in Patients With Previously Untreated Metastatic Adenocarcinoma of the Pancreas

Conditions
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Metastatic Pancreatic Cancer

Intervention / Treatment
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* Drug: Gemcitabine, nab-Paclitaxel, GDC-0449


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas. Patients with islet cells tumors are excluded. Biopsy within 14 days of starting treatment. Patient has 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 CT scan. Patient has NOT received previous radiotherapy, surgery or chemotherapy or investigational drug therapy for the treatment of metastatic disease. If the patient received radiotherapy, chemotherapy or investigational therapy in the adjuvant setting it should be completed 3 weeks prior to enrollment. If a patient received gemcitabine in the adjuvant setting, tumor recurrence must have occurred at least six months after completing the last dose of gemcitabine Age >18 years. Life expectancy of greater than 1 month. ECOG performance status 0 or 1 (Karnofsky >70%). Patients must have adequate organ and marrow function Exclusion Criteria: Patient had received chemotherapy or radiotherapy for metastatic disease Patient is receiving other investigational agents. Patient has known brain metastases, unless previously treated and well controlled for at least three months (defined as clinically stable, no edema, no steroids and stable in 2 scans at least 4 weeks apart) History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449 or other agents used in the study. Patients taking medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®) are ineligible. Uncontrolled illness including, but not limited to, ongoing or active infection requiring IV antibiotics, symptomatic congestive heart failure not controlled with medication, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Pregnant women are excluded Patient has undergone a major surgery, other than diagnostic surgery (i.e. surgery done to obtain a biopsy for diagnosis without removal of an organ) within four weeks prior to Day 1 of treatment on this study. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk from treatment complications

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine, nab-paclitaxel, GDC-0449<br>Gemcitabine and nab-Paclitaxel in combination with GDC-0449 (Vismodegib) | Drug: Gemcitabine, nab-Paclitaxel, GDC-0449<br>* One cycle of Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 (28 days cycle) then Gemcitabine 1000 mg/m2 and nab-Paclitaxel 125 mg/m2 on days 1, 8, and 15 every 28 days cycle in combination with oral GDC-0449 150 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival With the Combination of GDC-0449 With Gemcitabine and Nab-paclitaxel. | Number of months from time first therapy received to the earliest documented disease progression or death from any cause. | 6 years | 
| Safety of Combination Therapy in Patients With Metastatic Adenocarcinoma of the Pancreas as Assessed by Number of Grade 3 or 4 Adverse Events | Number of grade 3 or 4 adverse events as defined by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE v4.0) that occur after Cycle 2, Day 1 | 6 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Overall Survival | Total number of months alive. | 6 years | 
| Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Tumor Response | Number of participants with complete (CR) or partial (PR) response as defined by RECIST criteria. | 6 years | 
| Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Changes in Pancreatic Cancer Stem Cell | Change in number of Pancreatic cancer stem cells in tissue and peripheral blood in tissue biopsy and peripheral blood. | 6 years | 
| Efficacy of Combination of GDC-0449 With Gemcitabine and Nab-Paclitaxel as Assessed by Hedgehog Signaling Pathway Downregulation | Hedgehog signaling pathway downregulation as measured by Gli-1 and Patch expression | 6 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenocarcinoma, Hedgehog, Neoplasms, Digestive System Diseases, Neoplasms by Site, Digestive System Neoplasms, Neoplasms by Histologic Type, Pancreatic Neoplasms, Pancreatic Diseases, Carcinoma