Pancreas Cancer: Molecular Profiling as a Guide to Therapy Before and After Surgery (Personalized Medicine)

Study Overview
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Brief Summary
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In this clinical trial, if the doctor knows or suspects that a growth in the pancreas is cancer (adenocarcinoma), then a sample of the growth is tested (the test is called molecular profiling). The results of the test are used by the doctor to recommend therapy (chemotherapy and radiation therapy) that the patient will receive before having surgery to remove the adenocarcinoma. When the patient goes to surgery, the adenocarcinoma that is removed is tested again. The results of that test are used to guide the choice of therapy after surgery. The chemotherapy drugs and the radiation therapy used in this clinical trial are already approved for treatment of pancreas cancer. This trial is intended to establish which treatment is best for a specific patient, based on test results from that patient's actual adenocarcinoma. In the past, the decision as to which treatment the patient will receive was not based on testing of the actual adenocarcinoma. See treatment pathways at http://www.mcw.edu/surgery/patientinfo/Pancreatic-Cancer-Trial.htm. Hypothesis: Resectability rate, overall survival rate and progression-free survival in subjects with adenocarcinoma of the pancreas will be superior for who receive targeted personalized therapy.

Official Title
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A Prospective Phase II Trial of Molecular Profiling to Guide Neoadjuvant Therapy for Resectable and Borderline Resectable Adenocarcinoma of the Pancreas

Conditions
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Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: Milestone 1: Targeted chemotherapy prior to surgery
* Radiation: Milestone 2: Chemoradiotherapy (cXRT)
* Drug: Milestone 3: Targeted chemotherapy prior to surgery
* Radiation: Milestone 3: Chemoradiotherapy (cXRT)
* Drug: Milestone 4: standard FOLFIRINOX chemotherapy prior to surgery
* Radiation: Milestone 4: Chemoradiotherapy (cXRT)
* Drug: Milestone 5: Targeted chemotherapy after surgery
* Radiation: Milestone 5: Chemoradiotherapy (cXRT)
* Drug: Milestone 6: Gemcitabine after surgery
* Radiation: Milestone 6: Chemoradiotherapy (cXRT)
* Radiation: Milestone 7: Chemoradiotherapy (cXRT)
* Drug: Milestone 8: Targeted chemotherapy after surgery
* Drug: Milestone 9: Gemcitabine after surgery
* Other: Milestone 10: No additional therapy after surgery


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 18 years of age or older Able to understand and provide written informed consent Diagnosis of adenocarcinoma of the pancreas or high suspicion of adenocarcinoma of the pancreas based on CT and MRI findings as detailed below by Definition of.... Treatment Eligibility Criteria: Have an Eastern Cooperative Oncology Group performance status less than or equal to 2 Have biopsy-proven resectable or borderline resectable adenocarcinoma of the pancreas Have adequate organ and bone marrow function as defined by: total leukocytes greater than or equal to 3 x1000/μL absolute neutrophil count (ANC) > or equal to 1.5x 1000/μL hemoglobin > or equal to 9 g/dL platelets > or equal to 100 x 1000/μL creatinine clearance >60 mL/min or creatinine < or equal to 1.5 mg/dL bilirubin < or equal to 2 mg/dL or >2 and declining as described in the protocol aspartate transaminases (AST/SGOT) < or equal to3 x upper limit of normal (ULN) alanine transaminases (ALT/SGPT) < or equal to 3 x ULN Female patients must be post menopausal for > 1 year, surgically sterile, or have a negative pregnancy test and used at least one form of contraception for 4 weeks prior to Day 1 of the study, during study treatment and during the first 4 months after study treatment is discontinued. Male patients must be surgically sterile or use barrier contraception during the study and for 4 months after the last dose of any study drug. Definition of Resectable Pancreatic Cancer includes: No evidence of extra-pancreatic disease No evidence of tumor-arterial abutment (celiac, superior mesenteric artery or hepatic artery) If tumor induced narrowing of the superior mesenteric vein, portal vein or superior mesenteric-portal vein confluence is present it must be <50% of the diameter of the vessel Ca19-9 <5000, when bilirubin is <2 (or >2 and declining as described in the protocol) Definition of Borderline Resectable Pancreatic Cancer to include at least one of the following: Tumor abutment < or equal to 180 degrees of the superior mesenteric artery or celiac axis Tumor abutment or encasement (>180 degrees) of a short segment of the hepatic artery Tumor induced narrowing of superior mesenteric vein, portal vein or superior mesenteric-portal vein of >50% of the diameter of the vessel. Short segment occlusion of the superior mesenteric vein, portal vein or superior mesenteric-portal vein confluence with a suitable portal vein above and superior mesenteric vein below, for reconstruction CT or MRI findings suspicious for, but not diagnostic of, metastatic disease (based on multidisciplinary assessment at the Medical College of Wisconsin weekly pancreatic cancer conference) Biopsy proven N1 disease (regional lymph nodes involved) from pre-referral biopsy or endoscopic ultrasound-guided fine needle aspirate Resectable tumor and cancer antigen 19-9 (CA19-9) >5000 Exclusion Criteria: Any patient with one or more of the following will be excluded: Have received chemotherapy or chemoradiation within 5 years prior of study enrollment Have any previous history of another malignancy (other than cured basal or squamous cell carcinoma of the skin or cured in-situ carcinoma of the cervix) within 5 years of study enrollment Uncontrolled comorbidities including, but not limited to, ongoing or active serious infection, symptomatic congestive heart failure, unstable angina, unstable cardiac arrhythmias, psychiatric illness, excessive obesity, or situations that would limit compliance with the study requirements or the ability to willingly give written informed consent Known human immunodeficiency virus, hepatitis B virus, or hepatitis C virus infection Pregnant or breast-feeding patients or any patient with child-bearing potential not using contraception 4 weeks prior to, during and 4 months after study treatment is discontinued

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: Milestones related to therapy<br>Milestone 1: Targeted chemotherapy prior to surgery: 8 weeks targeted chemotherapy; restaging. Milestone 2: Before surgery: Chemoradiotherapy (cRXT); restaging Milestone 3: Before surgery: 8 weeks targeted chemotherapy; restaging; chemoradiotherapy (cXRT); restaging. Milestone 4: standard FOLFIRINOX chemotherapy prior to surgery: 8 weeks FOLFIRINOX (standard chemotherapy); restaging; standard chemoradiotherapy (cXRT); restaging. Milestone 5: After surgery: 8 weeks targeted chemotherapy; restaging; chemoradiotherapy (cXRT); restaging. Milestone 6: Gemcitabine after surgery: 8 weeks standard Gemcitabine (chemotherapy); restaging; chemoradiotherapy (cXRT); restaging. Milestone 7: After surgery: chemoradiotherapy (cXRT); restaging. Milestone 8: Gemcitabine after surgery: 8 weeks Gemcitabine (chemotherapy); restaging; 8 weeks Gemcitabine (chemotherapy); restaging. Milestone 9: No additional therapy after surgery. Milestone 10: After surgery no additional treatment. | Drug: Milestone 1: Targeted chemotherapy prior to surgery<br>* The molecular profile from the biopsy before surgery will point to a particular chemotherapy treatment.<br>* Other names: Capecitabine / nab-paclitaxel;Radiation: Milestone 2: Chemoradiotherapy (cXRT)<br>* A radio-sensitizing chemotherapy agent (either Gemcitabine or Capecitabine) will be given. Using 3D conformal or intensity-modulated radiation therapy (IMRT) techniques, patients will receive a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).<br>* Other names: Capecitabine;Drug: Milestone 3: Targeted chemotherapy prior to surgery<br>* The molecular profile from the biopsy before surgery will point to a particular chemotherapy treatment.<br>* Other names: Capecitabine / nab-paclitaxel;Radiation: Milestone 3: Chemoradiotherapy (cXRT)<br>* A radio-sensitizing chemotherapy agent (either Gemcitabine or Capecitabine) will be given. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).<br>* Other names: Capecitabine;Drug: Milestone 4: standard FOLFIRINOX chemotherapy prior to surgery<br>* A biopsy of the borderline tumor does not provide a molecular profile that can be used to target treatment. The treatment will be standard FOLFIRINOX chemotherapy regimen.<br>* Other names: 5 fluorouracil;Radiation: Milestone 4: Chemoradiotherapy (cXRT)<br>* A radio-sensitizing chemotherapy agent (either Gemcitabine or Capecitabine) will be given. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).<br>* Other names: Capecitabine;Drug: Milestone 5: Targeted chemotherapy after surgery<br>* The molecular profile from the surgical specimen will point to a particular chemotherapy treatment.<br>* Other names: 5-Fluorouracil;Radiation: Milestone 5: Chemoradiotherapy (cXRT)<br>* A radio-sensitizing chemotherapy agent (either Gemcitabine or Capecitabine) will be given. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).<br>* Other names: Capecitabine;Drug: Milestone 6: Gemcitabine after surgery<br>* Chemotherapy treatment with Gemcitabine.<br>* Other names: Gemzar;Radiation: Milestone 6: Chemoradiotherapy (cXRT)<br>* A radio-sensitizing chemotherapy agent (either Gemcitabine or Capecitabine) will be given. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).<br>* Other names: Capecitabine;Radiation: Milestone 7: Chemoradiotherapy (cXRT)<br>* A radio-sensitizing chemotherapy agent (either Gemcitabine or Capecitabine) will be given. Using 3D conformal or IMRT techniques, patients will receive a total dose of 50.4 Gy prescribed to the 95% isodose at 1.8 Gy/fraction (28 fractions).<br>* Other names: Capecitabine;Drug: Milestone 8: Targeted chemotherapy after surgery<br>* The molecular profile from the surgical specimen will point to a particular chemotherapy treatment.<br>* Other names: 5 fluorouracil;Drug: Milestone 9: Gemcitabine after surgery<br>* Chemotherapy treatment with Gemcitabine.<br>* Other names: Gemzar;Other: Milestone 10: No additional therapy after surgery<br>* The molecular profile of the tumor that was removed during surgery points to a lack of treatment affect for available therapies. No additional therapy is recommended.<br>* Other names: Restaged after surgery. No additional therapy.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Completing Therapy Including Surgical Resection. | This outcome measure is the number of subjects completing therapy up to and including surgical resection. In this context, surgical excision of residual tumor is an option in the progression of usual care. Surgery was contraindicated for some participants. This measure is the number of subject who were eligible for and completed the surgical procedure. | At time of surgery (approximately 10 to 20 weeks after screening) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival in Months | This measure is the median time of survival (in months) at five years from the initiation of therapy. Results will be presented for two cohorts: subjects completing neoadjuvant therapy and surgical resection; and subjects completing neoadjuvant therapy but without surgical resection. | 5 years | 
| Progression-free Survival | This measure is the number of subjects not experiencing tumor progression at five years from initiating therapy. | 5 years | 
| Use of Biomarkers to Determine Course of Treatment | The number of subjects for whom a biomarker (i.e., molecular profile) was used to determine the course of treatment. | Initiation of therapy (approximately 4 to 12 weeks after screening) until surgery (approximately 10 to 20 weeks after screening) | 
| Histologic Response to Targeted Chemotherapeutic Regimens in Resected Tumors. | The number of tumors showing a histologic response. Histological response will be measured using the Ryan Score method as defined by the American Joint Committee on Cancer, 7th edition (see Edge, 2010). Grading categories are defined as: Grade 0 (complete response); Grade 1 (near complete response); Grade 2 (partial response); and Grade 3 (poor or no response). | At time of surgery (approximately 10 to 20 weeks after screening) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreas, adenocarcinoma, molecular profile, molecular profiling, pancreatic cancer, pancreas cancer, cancer, molecular target, pancreas head, pancreas neck, pancreas uncinate, pancreas body, pancreas tail