Gemcitabine With Abraxane and Other Investigational Therapies in Neoadjuvant Treatment of Pancreatic Adenocarcinoma

Study Overview
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Brief Summary
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This study will evaluate the role of Gemcitabine and Abraxane in the treatment of resectable and borderline-resectable pancreatic cancer by giving the chemotherapy before surgery.

Detailed Description
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This current study proposes to conduct a prospective non-randomized open-label phase II trial using Gemcitabine and Abraxane in the neoadjuvant treatment of resectable and borderline-resectable pancreatic cancer. For patients that are low-risk resectable (based on prediction rule) the plan is to administer 2 cycles of Gemcitabine and Abraxane followed by additional systemic therapy or chemotherapy with radiation therapy (chemoRT), followed by surgical resection. For patients who are either borderline-resectable or high-risk resectable (see schema), the plan is to administer 2 cycles of Gemcitabine and Abraxane followed by chemoradiotherapy concurrent with gemcitabine followed by surgical resection. For those without high-risk features, systemic chemotherapy alone will be administered. The primary endpoints will be R0 surgical resection rate, biochemical (CA 19-9), pathologic and radiologic response rates. Secondary endpoints will include progression-free survival (PFS), overall survival (OS), 30-day post-op mortality, toxicity, quality of life, pain control, and correlative molecular exploratory analysis involving pancreatic tumor and stromal SPARC expression levels. The investigators will also assess the patient, tumor, and clinical characteristics that may predict R0 resectability, thus further refining the predictive rule in high-risk patients as defined by Bao and colleagues. The investigators' hypothesis is that by using targeted and risk-adapted chemotherapy or chemoRT, improved R0 surgical resections can be achieved and effective systemic therapy delivered, which will translate to a significant improvement in overall survival in patients with pancreatic adenocarcinoma, compared to published historical controls.

Official Title
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GAIN-1 Study: Gemcitabine With Abraxane and Other Investigational Therapies in Neoadjuvant Treatment of Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Drug: Chemotherapy
* Drug: Chemotherapy + ChemoRadiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Histologically or cytologically confirmed adenocarcinoma of the pancreas. Patients must have locally advanced pancreatic cancer, classified as either low-risk resectable (LR), high-risk resectable (HR) or borderline resectable (BR) Age between 18 and 90 years at the time of consent. Patients with biliary obstruction must have adequate drainage prior to starting treatment. Patients must have ≤ Grade I peripheral neuropathy (CTCAE v 4.0) Patients must have ≤ ECOG Performance status 2 Pretreatment laboratory parameters: Absolute granulocyte/neutrophil count (AGC/ANC) ≥ 1.8 thou/mm3 Platelet count ≥ 100,000/mm3 Bilirubin < 2 mg/dl ALT/SGPT < 10x upper limit of normal Creatinine < 3 mg/dl Calculated creatinine clearance (via Cockcroft-Gault) > 30 mL/min Baseline CA 19-9 levels Signed study specific, IRB stamped informed consent Exclusion Criteria: • Evidence of any distant metastasis including peritoneal seeding and/or malignant ascites Previous irradiation to the abdomen that would compromise the ability to deliver the prescribed treatment Prior treatment for pancreatic cancer Active, untreated infection Surgical resection of the tumor (not including biopsies) Other malignancy (except non-melanoma skin cancer) that has not been disease-free for at least 5 years. Pregnant and/or breast-feeding women, or patients (men and women) of child-producing potential not willing to use medically acceptable contraception while on treatment and for at least 3 months thereafter. Use of anti-epileptics (drugs such as phenytoin, phenobarbitol and carbamazepine) ECG abnormality with the following: QTC >500, left bundle branch block or any other clinically significant finding that would interfere with protocol therapy. History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Chemotherapy<br>Individuals with low risk disease will receive nab-paclitaxel 100 mg/m2 IV over 30 minutes on days 1, 8, and 15 along with gemcitabine 1000 mg/m2 IV over 30 minutes on days 1, 8, and 15 in an every 28 day cycle for two cycles. Subjects with low risk disease will have an additional two cycles of therapy (4 total cycles) prior to resection. | Drug: Chemotherapy<br>* Nab-paclitaxel 100 mg/m2 IV over 30 minutes on days 1, 8, and 15 along with gemcitabine 1000 mg/m2 IV over 30 minutes on days 1, 8, and 15 in an every 28 day cycle for two cycles. Subjects with low risk disease will have an additional two cycles of therapy (4 total cycles) prior to resection.<br>* Other names: Gemcitabine;|
| Active Comparator: Chemotherapy and ChemoRadiotherapy<br>Individuals with high-risk disease or borderline resectable disease will receive nab-paclitaxel 100 mg/m2 IV over 30 minutes on days 1, 8, and 15 along with gemcitabine 1000 mg/m2 IV over 30 minutes on days 1, 8, and 15 in an every 28 day cycle for two cycles. Subjects with high-risk or borderline resectable disease will receive additional chemotherapy with radiation therapy prior to resection. | Drug: Chemotherapy + ChemoRadiotherapy<br>* Nab-paclitaxel 100 mg/m2 IV over 30 minutes on days 1, 8, and 15 along with gemcitabine 1000 mg/m2 IV over 30 minutes on days 1, 8, and 15 in an every 28 day cycle for two cycles. Subjects with high-risk or borderline resectable disease will receive additional chemotherapy with radiation therapy prior to resection.<br>* Other names: Gemcitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Response Rate | Biochemical response rate (serum CA 19-9). Baseline compared to pre-operative serum CA19-9 values. | 4 - 8 weeks after neoadjuvant therapy | 
| Radiographic Response Rate | Evaluate radiographic response of the measurable disease with repeat imaging at 4 - 8 weeks after therapy. Measurable disease was evaluated using Response Evaluation Criteria In Solid Tumors Criteria (RECIST) 1.1 criteria. Per RECIST v1.1 in target lesions 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; Progressive Disease (PD), >20% growth in the sum of the longest diameter or target lesions or appearance of new lesions; Stable Disease (SD), change in sum of longest diameter of target lesions does not meet criteria for PR or PD. The number of subjects experiencing Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) is reported. | 4 - 8 weeks after neoadjuvant therapy | 
| Pathologic Downstaging and Margin Status | Pathologic stage and margin status after resection. Pathologic downstaging was determined my looking at the rate of R0 (all residual tumor removed during surgery) vs R1 (microscopic tumor present at the resection margin per pathology) resections. | At the time of surgery after neoadjuvant therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90 Day Post-operative Mortality | Evaluate mortality in the first 90 days after surgery | 90 days after surgery |