Gemcitabine Hydrochloride, and Radiation Therapy in Patients With Borderline Resectable Pancreatic Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well combination chemotherapy, gemcitabine hydrochloride, and radiation therapy before surgery works in treating patients with pancreatic cancer that has not spread to other places in the body and can be removed by surgery. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, irinotecan hydrochloride, oxaliplatin, and gemcitabine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Fluorouracil, irinotecan hydrochloride, and gemcitabine hydrochloride may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy and gemcitabine hydrochloride with radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the efficacy, measured as the proportion of R0 resections, of fluorouracil-leucovorin calcium-irinotecan hydrochloride-oxaliplatin (FOLFIRINOX) chemotherapy regimen followed by gemcitabine based chemoradiotherapy when used as preoperative therapy in patients with borderline resectable adenocarcinoma of the pancreas. SECONDARY OBJECTIVES: I. To measure the overall response rate (ORR). II. To evaluate overall survival (OS). III. To evaluate progression free survival (PFS). IV. To evaluate safety and toxicity associated with chemotherapy and radiotherapy. V. To assess adverse events related to surgery. VI. To assess the proportion of patients able to undergo resection. VII. To assess proportion of patients requiring vascular reconstruction. OUTLINE: CHEMOTHERAPY REGIMEN: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1, and fluorouracil IV over 46 hours on days 1-3. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving disease progression proceed to chemoradiotherapy. CHEMORADIOTHERAPY REGIMEN: Beginning 4-6 weeks after completion of chemotherapy, patients undergo intensity-modulated radiation therapy (IMRT) on 5 consecutive days per week for a total of 28 fractions and receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Treatment continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 30 months.

Official Title
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A Phase II Trial of Preoperative FOLFIRINOX Followed by Gemcitabine Based Chemoradiotherapy in Patients With Borderline Resectable Pancreatic Adenocarcinoma

Conditions
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Pancreatic Adenocarcinoma, Stage IIA Pancreatic Cancer, Stage IIB Pancreatic Cancer, Stage III Pancreatic Cancer

Intervention / Treatment
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* Drug: Fluorouracil
* Drug: Gemcitabine Hydrochloride
* Radiation: Intensity-Modulated Radiation Therapy
* Drug: Irinotecan Hydrochloride
* Drug: Leucovorin Calcium
* Drug: Oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed adenocarcinoma of the pancreas Only patients that have not received any prior treatment for pancreas cancer are eligible for this treatment protocol Patients are not required to have measurable disease by traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria, as lesions in the pancreas are notoriously hard to measure radiographically; however, patients must have disease which is evaluable for resection Disease should be determined as borderline resectable according to the Expert Consensus Statement published by Callery et al: No distant metastasis Venous involvement of the superior mesenteric vein (SMV)/portal vein demonstrating tumor abutment with or without impingement and narrowing of the lumen, encasement of the SMV/portal vein but without encasement of the nearby arteries, or short segment venous occlusion resulting from either tumor thrombus or encasement but with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction Gastroduodenal artery encasement up to the hepatic artery with either short segment encasement or direct abutment of the hepatic artery, without extension to the celiac axis Tumor abutment of the superior mesenteric artery (SMA) not to exceed greater than 180 degrees of the circumference of the vessel wall Life expectancy of greater than 6 months Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%) Leukocytes >= 3,000/microliter (mcL) Absolute neutrophil count >= 1,500/mcL Platelets >= 100,000/mcL Total bilirubin =< 2 mg/dl Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal Ability to understand and the willingness to sign a written informed consent document Patients may not be receiving any other concurrent chemotherapy, immunotherapy, or radiotherapy Exclusion Criteria: Patients who have had prior chemotherapy or radiotherapy for the treatment of pancreas cancer Patients may not be receiving any other investigational agents Evidence of extent of pancreatic cancer beyond that defined as borderline resectable above (locally advanced or distant disease); peripancreatic lymph node involvement, either confirmed or suspected, will not be considered distant disease unless the lymph node involvement extends outside of the field of resection Patients with known brain metastases should be excluded from this clinical trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-fluorouracil, oxaliplatin, irinotecan or gemcitabine Any concurrent active malignancy other than non-melanoma skin cancers or carcinoma-in-situ of the cervix; patients with previous malignancies but without evidence of disease for > 3 years will be allowed to enter the trial; patients with a history of a T1a or b prostate cancer (detected incidentally at transurethral resection of the prostate [TURP] and comprising less than 5% of resected tissue) may participate if the prostate-specific antigen (PSA) remained within normal limits since TURP removal Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

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: Treatment (FOLFIRINOX, IMRT, and gemcitabine hydrochloride)<br>CHEMOTHERAPY REGIMEN: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1, and fluorouracil IV over 46 hours on days 1-3. Treatment repeats every 14 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving disease progression proceed to chemoradiotherapy. CHEMORADIOTHERAPY REGIMEN: Beginning 4-6 weeks after completion of chemotherapy, patients undergo IMRT on 5 consecutive days per week for a total of 28 fractions and receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Treatment continues in the absence of disease progression or unacceptable toxicity. | Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY-188011;Radiation: Intensity-Modulated Radiation Therapy<br>* Undergo IMRT<br>* Other names: Intensity-Modulated Radiotherapy;Drug: Irinotecan Hydrochloride<br>* Given IV<br>* Other names: U-101440E;Drug: Leucovorin Calcium<br>* Given IV<br>* Other names: Wellcovorin;Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving R0 Resection (R0 Resection Rate) | The percentage of participants achieving R0 resection, defined as the absence of gross and microscopic tumor involvement in the resection margins, will be determined for those participants who receive at least one cycle of FOLFIRINOX chemotherapy. A 90% confidence interval will be determined. | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Related to Surgery | Adverse events related to surgical resection will be documented and evaluated using the Clavien-Dindo classification scale. The Clavien-Dindo Classification is used to rank the severity of a surgical complication with higher Grades indicative of more intense interventional therapy needed to correct the complication. Scale grades range from Grade I to Grade V. Grade I complications are usually mild and consist of any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological intervention. Grade II complications require pharmacological treatment with drugs other than such allowed for Grade I. Grade III complications require surgical, endoscopic, or radiological intervention, Grade IV are indicative of life-threatening complications requiring ICU management and Grade V signify death of patient. | Up to 30 months | 
| Toxicities Associated With Chemotherapy and Radiotherapy | The number of patients who experienced treatment related adverse events will be determined for all patients who received at least one cycle of FOLFIRINOX chemotherapy. These events will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | Up to 30 months | 
| Overall Survival (OS) | Median Overall Survival defined as the the duration of time from diagnosis to the time of death from any cause will be determined. | Up to 60 months | 
| Overall Response Rate | Overall Response Rate, defined as the percentage of patients that achieved Partial Response (PR) or Complete Response (CR) as per the Response evaluation in solid tumors criteria, was assessed using RECIST Version 1.1 criteria. Complete Response (CR) is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is defined as having at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Higher percentages of PR and CR are associated with more favorable outcomes | Up to 30 months | 
| Progression Free Survival (PFS) | Progression-free Survival defined as the duration of time from start of treatment to time of disease progression will be analyzed. Median progression free survival will be presented. | From start of treatment to time of progression, assessed up to 60 months | 
| Percentage of Patients Able to Undergo Resection | The percentage of participants with resectable or borderline resectable disease to undergo resection will be determined. The ability for patients to complete preoperative therapy and undergo resection is correlated with more favorable overall survival outcomes. | Up to 30 months | 
| Vascular Reconstruction | The percentage of patients who underwent pancreaticoduodenectomy requiring vascular reconstruction will be evaluated. | Up to 30 months |