Chemotherapy Plus Proton-chemotherapy for Locally Advanced Pancreatic Cancer

• Sponsor: Loma Linda University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01683422
• Collaborator: (none)
• Enrollment: 9
• Location: 1
• Arm: 1
• Actual Duration (Months): 73.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Cancer	Radiation: Proton, Gemcitabine, Erlotinib, Capecitabine; Radiation: Proton Radiation	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Gemcitabine and Erlotinib (GE) Plus Proton-chemotherapy (PCT) and Capox for Locally Advanced Pancreatic Cancer (LAPC)
• Actual Study Start Date: Jan 2, 2013
• Actual Primary Completion Date: Feb 19, 2019
• Actual Study Completion Date: Feb 19, 2019

Arms and Interventions

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, 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.; Radiation: Proton Radiation

Outcome Measures

Primary Outcome Measures

1. One-year Survival Rate [One year after treatment completed.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Medical Center	Loma Linda	California	United States	92354

Sponsors and Collaborators

• Loma Linda University

Investigators

• Principal Investigator: Gary Yang, MD, [e-mail]

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 27, 2014
• Informed Consent Form - Feb 16, 2012

More Information

Publications

None provided.

• Responsible Party: Gary Yang, MD, MD, Principal Investigator, Loma Linda University
• ClinicalTrials.gov Identifier: NCT01683422
• Other Study ID Numbers: 5110324
• First Posted: Sep 11, 2012
• Last Update Posted: Aug 10, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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
• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine; Capecitabine; Erlotinib Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Proton Radiation
Arm/Group Description	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. Proton Radiation
Period Title: Overall Study
STARTED	9
COMPLETED	9
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Proton Radiation
Arm/Group Description	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. Radiation: Proton Radiation
Overall Participants	9
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	59.6
Sex: Female, Male (Count of Participants)
Female	4 44.4%
Male	5 55.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	6 66.7%
More than one race	2 22.2%
Unknown or Not Reported	1 11.1%
Proton Radiation (Count of Participants)
Count of Participants [Participants]	9 100%

Outcome Measures

1. Primary Outcome

Title	One-year Survival Rate
Description	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.
Time Frame	One year after treatment completed.

Outcome Measure Data

Analysis Population Description

The study enrolled 9 patients between January 2013 and March 2016, when the trial was closed due to poor accrual.

Arm/Group Title	Proton Radiation
Arm/Group Description	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. Radiation: Proton Radiation
Measure Participants	9
Number (95% Confidence Interval) [percentage of participants]	55.6 617.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Proton Radiation
	Comments	In the RTOG 9812 (NCT00003591) for unresectable pancreatic cancer, a one-year survival rate of 43% was observed. There were 109 analyzable patients on NCT00003591 with 61 still at risk for death at one year. Using the method of Dixon and Simon, a sample size of 39 analyzable patients followed over 12 months will ensure at least 90% probability of detecting a minimum of 17% improvement in the one-year survival rate compared to NCT00003591 at the 0.10 significance level (with a one-sided test).
	Type of Statistical Test	Superiority
	Comments	The reported p-value was calculated, and is not attempting to indicate the threshold for statistical significance.
Statistical Test of Hypothesis	p-Value	0.1
	Comments
	Method	t-test, 1 sided
	Comments

Adverse Events

Time Frame	6 years
Adverse Event Reporting Description	Patients with locally advanced pancreatic cancer--9 patients died due to recurrence of disease. Entered as serious Adverse Event (AE)
Arm/Group Title	Proton Radiation
Arm/Group Description	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.
All Cause Mortality
	Proton Radiation
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Serious Adverse Events
	Proton Radiation
	Affected / at Risk (%)	# Events
Total	9/9 (100%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
serious	9/9 (100%)	9
Other (Not Including Serious) Adverse Events
	Proton Radiation
	Affected / at Risk (%)	# Events
Total	0/9 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.