Chemotherapy Plus Proton-chemotherapy for Locally Advanced Pancreatic Cancer

Study Overview
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Brief Summary
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The current trial will provide important data on the recurrence rates and patterns of failure using state of the art target agent, chemotherapy and proton beam technology for patients with Locally Advanced Pancreatic Cancer (LAPC). A median survival of 10 months or greater would be considered evidence of a regimen potentially worthy of further study as a new treatment paradigm in one arm in a future phase III trial.

Detailed Description
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The current trend toward using the biology of the disease as it becomes evident over a period of chemotherapy to better select patients who will benefit from chemoradiotherapy (CRT) seems to be the most pragmatic way to proceed, until we have a better means of predicting tumor behavior and more active systemic agents. This has led to increased interest in treatment regimens incorporating induction chemotherapy with target agent followed by CRT and additional chemotherapy for diseases that carry a high risk for systemic relapse. The PA.3 trial was the first phase III trial in advanced pancreatic cancer to show a survival advantage with the addition of a second drug, in this case the oral Epidermal growth factor receptor (EGFR) inhibitor Erlotinib to gemcitabine. The approval provides an important proof of concept regarding the use of newer targeted therapies in pancreatic cancer 7. Proton beam therapy may result in lower toxicity, enhanced efficacy and could contribute to improved local control of patients with LAPC. The capecitabine and oxaliplatin ((CapOx)) regimen utilized in this trial has been proven to be active in gemcitabine-pretreated patients with advanced pancreatic cancer. The current trial will provide important data on the recurrence rates and patterns of failure using state of the art target agent, chemotherapy and proton beam technology for patients with LPAC. A median survival of 10 months or greater would be considered evidence of a regimen potentially worthy of further study as a new treatment paradigm in one arm in a future phase III trial. Patients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas, as defined by 2012 National Comprehensive Cancer Network (NCCN) guidelines, were included. Patients received neoadjuvant gemcitabine 1000 mg/m2 IV on days 1, 8, 15, 22, 29, 36, and 43 and erlotinib 100 mg by mouth every day for 1-43 days (GE). If there was no evidence of metastatic disease after GE, then patients preceded with proton therapy to 50.4 Gy in 28 fractions with concurrent capecitabine 825 mg/m2 twice per day (PCT). This was followed with maintenance oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice per day on days 2 to 15 (CapOx) for 4 cycles. The primary study objective was 1-year overall survival (OS). The benchmark was 43% 1-year survival as demonstrated in Radiation Therapy Oncology Group (RTOG/NRG) 98- 12. The Kaplan-Meier method was used to estimate the one-year OS and the median OS and progression-free survival (PFS).

Official Title
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A Phase II Trial of Gemcitabine and Erlotinib (GE) Plus Proton-chemotherapy (PCT) and Capox for Locally Advanced Pancreatic Cancer (LAPC)

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Radiation: Proton, Gemcitabine, Erlotinib, Capecitabine
* Radiation: Proton Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed unresectable non-metastatic adenocarcinoma of the pancreas The American Joint Committee on Cancer (AJCC) stage I-III with unresectable or borderline unresectable disease as defined by NCCN guidelines Radiological resectability is defined by the following criteria on abdominal imaging: No evidence of tumor extension to the celiac axis, hepatic artery or superior mesenteric artery. No evidence of tumor encasement or occlusion of the superior mesenteric vein (SMV) or the SMV/portal vein confluence No evidence of visceral or peritoneal metastases Borderline and Unresectable cases would be defined as those that do not meet the criteria in section and also show no evidence of distant metastatic or intraperitoneal disease. Eastern Cooperative Oncology Group performance status of ≤ 2 Age > 18 years Adequate hematologic reserve, hepatic reserve and renal function White Blood Cell (WBC) > 2,000 cells/mm3 Absolute Neutrophil Count (ANC) > 1,500 cells/mm3 Platelets > 100,000 cells/mm3 Serum bilirubin ≤ 2.5 mg/dL Serum creatinine ≤ 2 x upper limit of normal (ULN), or creatinine clearance (Ccr) ≥ 30ml/min Alanine aminotransferase (ALT) < 3 times ULN Aspartate transaminase (AST) < 3 times ULN Albumin > 3.2 g/dl Patient must sign study-specific informed consent Exclusion Criteria: AJCC stage IV with metastatic disease Eastern Cooperative Oncology Group performance status of > 2 Age < 18 years WBC < 2,000 cells/mm3 ANC < 1,500 cells/mm3 Platelets > 100,000 cells/mm3 Serum bilirubin > 2.5 mg/dL Serum creatinine > 2 x upper limit of normal (ULN), or creatinine clearance (Ccr) ≥ 30ml/min ALT > 3 times ULN AST > 3 times ULN Albumin < 3.2 g/dl

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: Proton Radiation<br>Pre-Proton-chemotherapy (PCT) Patients will receive a combination of the agents (Gemcitabine plus Erlotinib) for 8 weeks prior to PCT Gemcitabine 1000 mg/m2 IV, days 1, 8, 15, 29, 36 and 43 Erlotinib 100 mg po qd days 1-43 PCT to be started in 4 to 8 weeks after completion of Pre-PCT Proton therapy: 50.4 Gy/28 fractions (1.8 Gy per fraction) once a day for 5 ½ weeks. Chemotherapy: Capecitabine 825mg/m2 po bid M-F, starting on day 1 of proton therapy until proton therapy completed Post-PCT to be started in 4 to 6 weeks after completion of PCT Oxaliplatin 130 mg/m2, day 1 Capecitabine 1000 mg/m2 po bid on days 2 to 15 for 14 days The CapOx regimen (Capecitabine plus Oxaliplatin) is repeated every 3 weeks for 4 cycles | Radiation: Proton, Gemcitabine, Erlotinib, Capecitabine<br>* Gemcitabine 1000 mg/m2 iv, days 1, 8, 15, 29, 36 and 43 Erlotinib 100 mg po qd days 1-43 Capecitabine 825mg/m2 po bid M-F, starting on day 1 of proton therapy until proton therapy completed. Post-proton chemotherapy: To be started in 4 to 6 weeks after completion of proton chemotherapy. Oxaliplatin 130 mg/m2 po bid on days 2 to 15 for 14 days. The CapOx regimen (Capcitabine plus Oxaliplatin) is repeated every 3 weeks for 4 cycles.<br>Radiation: Proton Radiation<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| One-year Survival Rate | Subjects will be followed after treatment completed to determine length of survival rate. The primary study objective was 1-year overall survival (OS, failure: death due to any cause). The Kaplan-Meier method was used to estimate the one-year OS. Secondary Objectives were the frequency of serious adverse events, disease control rate and progression-free survival. | One year after treatment completed. |