Chemotherapy Plus Proton-chemotherapy for Locally Advanced Pancreatic Cancer

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

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.

Study Overview

• Status: Terminated
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Radiation: Proton Radiation; Radiation: Proton, Gemcitabine, Erlotinib, Capecitabine

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. No evidence of tumor extension to the celiac axis, hepatic artery or superior mesenteric artery.
  2. No evidence of tumor encasement or occlusion of the superior mesenteric vein (SMV) or the SMV/portal vein confluence
  3. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Proton Radiation; 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 Radiation; Radiation: Proton, Gemcitabine, Erlotinib, Capecitabine; 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.

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Loma Linda University
• Investigators: Principal Investigator: Gary Yang, MD, gyang@llu.edu

Publications and helpful links

General Publications

• Sanghvi SM, Coffman AR, Hsueh CT, Kang J, Park A, Solomon NL, Garberoglio CA, Reeves ME, Slater JD, Yang GY. A phase II trial of gemcitabine and erlotinib followed by ChemoProton therapy plus capecitabine and oxaliplatin for locally advanced pancreatic cancer. J Gastrointest Oncol. 2022 Aug;13(4):1989-1996. doi: 10.21037/jgo-22-327.

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2013
• Primary Completion (Actual): February 19, 2019
• Study Completion (Actual): February 19, 2019

Study Registration Dates

• First Submitted: February 17, 2012
• First Submitted That Met QC Criteria: September 10, 2012
• First Posted (Estimate): September 11, 2012

Study Record Updates

• Last Update Posted (Actual): August 10, 2021
• Last Update Submitted That Met QC Criteria: August 7, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; Erlotinib Hydrochloride; Capecitabine
• Other Study ID Numbers: 5110324

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes