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

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

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.

Study Overview

• Status: Terminated
• Conditions: Pancreatic Adenocarcinoma; Stage III Pancreatic Cancer; Stage IIA Pancreatic Cancer; Stage IIB Pancreatic Cancer
• Intervention / Treatment: Drug: Gemcitabine Hydrochloride; Radiation: Intensity-Modulated Radiation Therapy; Drug: Fluorouracil; Drug: Oxaliplatin; Drug: Leucovorin Calcium; Drug: Irinotecan Hydrochloride

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center-Weiler Hospital

Participation Criteria

Eligibility Criteria

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

Description

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

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: Treatment (FOLFIRINOX, IMRT, and gemcitabine hydrochloride); 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: Gemcitabine Hydrochloride; Given IV; Other Names: Gemzar; dFdCyd; Difluorodeoxycytidine Hydrochloride; LY-188011; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Intensity Modulated RT; Intensity-Modulated Radiotherapy; Drug: Fluorouracil; Given IV; Other Names: 5-FU; 5-Fluracil; Fluracil; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; folinic acid; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Citrovorum Factor; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin; Drug: Irinotecan Hydrochloride; Given IV; Other Names: Campto; Camptosar; U-101440E; CPT-11; Camptothecin 11; Camptothecin-11; CPT 11; Irinomedac

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Albert Einstein College of Medicine
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jennifer Chuy, Montefiore Medical Center-Weiler Hospital

Publications and helpful links

General Publications

• Acuna-Villaorduna A, Shankar V, Wysota M, Jirgal A, Kabarriti R, Bellemare S, Goldman I, Kaubisch A, Aparo S, Goel S, Chuy J. Induction Chemotherapy With FOLFIRINOX Followed by Chemoradiation With Gemcitabine in Patients With Borderline-Resectable Pancreatic Ductal Adenocarcinoma. Cancer Control. 2022 Jan-Dec;29:10732748221134411. doi: 10.1177/10732748221134411.

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2012
• Primary Completion (Actual): November 1, 2021
• Study Completion (Actual): November 1, 2021

Study Registration Dates

• First Submitted: July 9, 2013
• First Submitted That Met QC Criteria: July 9, 2013
• First Posted (Estimated): July 12, 2013

Study Record Updates

• Last Update Posted (Estimated): December 5, 2023
• Last Update Submitted That Met QC Criteria: December 1, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Adenocarcinoma; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Leucovorin; Irinotecan; Calcium; Levoleucovorin; Folic Acid; Calcium, Dietary; Camptothecin; Gemcitabine
• Other Study ID Numbers: 2012-570; 12-017 (Dana-Farber Cancer Institute); NCI-2013-01213 (Registry Identifier: NCI); 5P30CA013330-42 (U.S. NIH Grant/Contract)