Hypofractionated Stereotactic Body Radiation & Fluorouracil or Capecitabine for Locally Advanced Pancreatic Cancer

A Randomized Phase II Study of the Efficacy and Safety of Hypofractionated Stereotactic Radiotherapy and 5FU or Capecitabine With and Without Zometa in Patients With Locally Advanced Pancreatic Adenocarcinoma

Pancreatic cancer, most commonly adenocarcinoma, is the fourth leading cause of cancer death in the United States. The mainstay of management centers on surgical resection (if resectable) and although low (15% to 20%), resectability rates are associated with dismal survival. An estimated 80% to 85% of the patients recur after surgical resection, leading to a median survival of 20 to 24 months and potentially even less depending on lymph nodal involvement or positive margins. The rationale for utilizing neoadjuvant therapy, commonly fluoropyrimidine-based or gemcitabine based chemotherapy or Chemoradiotherapy (CRT), involves possibly down staging borderline resectable and unresectable patients, potentially making them resectable candidates.

This randomized phase II trial will study how well hypofractionated stereotactic body radiation therapy (SBRT) and fluorouracil or capecitabine with or without zoledronic acid work in treating participants with pancreatic cancer that has spread to nearby tissue or lymph nodes. Hypofractionated stereotactic body radiation therapy is a specialized radiation therapy that sends higher doses of x-rays over a shorter period of time directly to the tumor using smaller doses over several days which may cause less damage to normal tissue. Drugs used in chemotherapy, such as fluorouracil and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Zoledronic acid is used in cancer patients to reduce cancer symptoms and may make tumor cells more sensitive to radiation. Giving hypofractionated stereotactic body radiation therapy and fluorouracil or capecitabine with or without zoledronic acid may work better in treating pancreatic cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Pancreatic Adenocarcinoma; Recurrent Pancreatic Carcinoma; Stage III Pancreatic Cancer AJCC v6 and v7; Stage IV Pancreatic Cancer AJCC v6 and v7; Stage I Pancreatic Cancer AJCC v6 and v7; Stage IA Pancreatic Cancer AJCC v6 and v7; Stage IB Pancreatic Cancer AJCC v6 and v7; Stage II Pancreatic Cancer AJCC v6 and v7; Stage IIA Pancreatic Cancer AJCC v6 and v7; Stage IIB Pancreatic Cancer AJCC v6 and v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Radiation: Stereotactic Body Radiation Therapy; Drug: Zoledronic Acid; Drug: Capecitabine; Drug: Fluorouracil

Detailed Description

Pancreatic cancer, most commonly adenocarcinoma, is the fourth leading cause of cancer death in the United States. The mainstay of management centers on surgical resection (if resectable) and although low (15% to 20%), resectability rates are associated with dismal survival. An estimated 80% to 85% of the patients recur after surgical resection, leading to a median survival of 20 to 24 months and potentially even less depending on lymph nodal involvement or positive margins. The rationale for utilizing neoadjuvant therapy, commonly fluoropyrimidine-based or gemcitabine based chemotherapy or Chemoradiotherapy (CRT), involves possibly down staging borderline resectable and unresectable patients, potentially making them resectable candidates.

This randomized phase II trial will study how well hypofractionated stereotactic body radiation therapy (SBRT) and fluorouracil or capecitabine with or without zoledronic acid work in treating participants with pancreatic cancer that has spread to nearby tissue or lymph nodes. Hypofractionated stereotactic body radiation therapy is a specialized radiation therapy that sends higher doses of x-rays over a shorter period of time directly to the tumor using smaller doses over several days which may cause less damage to normal tissue. Drugs used in chemotherapy, such as fluorouracil and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Zoledronic acid is used in cancer patients to reduce cancer symptoms and may make tumor cells more sensitive to radiation. Giving hypofractionated stereotactic body radiation therapy and fluorouracil or capecitabine with or without zoledronic acid may work better in treating pancreatic cancer.

The primary study objective is to evaluate the efficacy of hypofractionated radiation therapy concurrently with zoledronic acid (Zometa) and fluorouracil or capecitabine. Other study objectives include examining the toxicity of Zometa when used concurrently with hypofractionated radiation therapy, evaluating local failure-free survival and overall survival, determining surgical resection and tumor response rates, measuring Zometa pharmacokinetics, evaluating tumor and organ motion and determining the effect those on the dosimetry, local control and survival. Post-treatment follow-up is for 30 days, then every 3 months for the first year, every 4 months for the second year, and every 6 months thereafter.

• Study Type: Interventional
• Enrollment (Actual): 46
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Pathologically confirmed pancreatic adenocarcinoma, either initially diagnosed or recurrent locally advanced disease. The maximum dimension of the treatment target must be =<10 cm. Locally advanced disease defined as: T 1-2N+MO or T3-4 NxMo, or borderline resectable and unresectable adenocarcinoma without distant metastatic disease or resectable T3-4 NxMo disease or M1 with controlled distant disease
• Inoperable conditions with resectable disease (T1-2NoMo)
• Karnofsky performance status of 60% or better. Received recent chemotherapy for pancreatic cancer or completed chemotherapy > 5 years ago for malignancies other than pancreatic cancer with no evidence of the second malignancy at study entry
• Radiation therapy completed > 5 years ago for malignancies other than pancreatic cancer and whose radiation therapy field is not overlapping with the 20% isodose line of current radiation field and no evidence of the second malignancy at study entry
• All malignant disease must be able to be encompassed within a single irradiation field
• Absolute neutrophil count (ANC) greater than or equal to 1500/uL
• Radiographically assessable disease
• Platelet count greater than or equal to 100,000/uL
• Serum creatinine less than or equal to 2.0 mg/dL and total bilirubin less than or equal to 2.0 mg/dL in the absence of biliary obstruction. If biliary obstruction is present, biliary decompression will be required, either endoscopic placement of a biliary stent or percutaneous transhepatic. Once biliary drainage has been established, institution of protocol therapy may proceed when the total bilirubin falls to 4.0 mg/dL or lower
• Calculated creatinine clearance of >= 35.
• Awareness of the neoplastic nature of his/her disease and willingly provide written, informed consent after being informed of the procedure to be followed, the experimental nature of the therapy, alternatives, potential benefits, side-effects, risks, and discomforts

Exclusion Criteria:

• Known allergy to Zometa or to anti-emetics appropriate in conjunction with protocol-directed therapy
• Uncontrolled inter-current illness that might jeopardize the ability of the subject to receive the protocol therapy with reasonable safety. This may include, but not limited to, ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia
• Pregnant and nursing women
• Prior malignancy except adequately treated basal cell or squamous cell skin cancer, adequately treated non-invasive carcinomas, or be disease-free for at least 5 years from other cancers
• Active duodenal ulcer or bleeding or history of a gastrointestinal fistula or perforation or other significant bowel problems (severe nausea, vomiting, inflammatory bowel disease and significant bowel resection)
• Known human immunodeficiency virus (HIV) infection, or hepatic insufficiency
• Not currently receiving or have received Zometa within 3 weeks prior to study treatment with Zometa

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm A (chemotherapy, radiation therapy); Participants undergo hypofractionated stereotactic body radiation therapy in 5 fractions on days 1-5. Participants receive fluorouracil IV over 24 hours on day 1 weekly for 4 weeks or capecitabine by mouth every 12 hours starting the evening before day 1 of radiation therapy for 4 weeks as per standard of care. Participants then undergo surgery 6-8 weeks after completion of radiation therapy.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Radiation: Stereotactic Body Radiation Therapy; Undergo hypofractionated stereotactic radiotherapy; Other Names: SBRT; SABR; Stereotactic Ablative Body Radiation Therapy; Drug: Capecitabine; Given by mouth (PO); Other Names: Xeloda; Ro 09-1978/000; Drug: Fluorouracil; Given Intravenously (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
Experimental: Arm B (zoledronic acid, chemotherapy, radiation therapy); Participants receive zoledronic acid IV over a minimum of 15 minutes 1 week prior to radiation therapy. Participants undergo hypofractionated stereotactic body radiation therapy and receive treatment with fluorouracil IV or capecitabine by mouth as in Arm A. Participants then undergo surgery 6-8 weeks after completion of radiation therapy.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Radiation: Stereotactic Body Radiation Therapy; Undergo hypofractionated stereotactic radiotherapy; Other Names: SBRT; SABR; Stereotactic Ablative Body Radiation Therapy; Drug: Zoledronic Acid; Given IV; Other Names: Reclast; Zometa; CGP 42446; CGP42446A; [1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene]bisphosphonic Acid; NDC-Zoledronate; ZOL 446; Drug: Capecitabine; Given by mouth (PO); Other Names: Xeloda; Ro 09-1978/000; Drug: Fluorouracil; Given Intravenously (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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local control With and Without Zometa at Four Months in Follow-up	Local control of tumor will be determined by four dimensional (4D) computed tomography (CT) scans and comparison made between participants receiving Zometa and those who don't.	At 4 months in follow-up
Local control With and Without Zometa at Eight Months in Follow-up	Local control of tumor will be determined by four dimensional (4D) computed tomography (CT) scans and comparison made between participants receiving Zometa and those who don't.	At 8 months in follow-up
Local control With and Without Zometa at Twelve Months in Follow-up	Local control of tumor will be determined by four dimensional (4D) computed tomography (CT) scans and comparison made between participants receiving Zometa and those who don't.	At 12 months in follow-up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose of Zoledronic Acid	Maximum tolerated dose of zoledronic acid will be determined by dose limiting toxicities according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Safety variables to be analyzed are adverse events (AE) and serious adverse events (SAE). AEs and SAEs will be tallied for overall frequency (number and percentage of subjects), worst reported severity, and relationship to study drugs.	Up to 30 days after surgery
Local Failure-free Survival With and Without Zometa	Time to local failure (disease progression or recurrence determined by imaging, or death) will be analyzed using Kaplan-Meier method between participants receiving Zometa and those who don't.	From date of administration of study drug to the date of local failure, assessed up to 5 years
Overall Survival With and Without Zometa	Time to death will be analyzed using Kaplan-Meier method between participants receiving Zometa and those who don't.	From date of administration of study drug to the date of death, assessed up to 5 years
Surgically Complete Resection Rate With and Without Zometa	The number and proportion of participants undergoing complete resection (negative margin) will be determined between participants receiving Zometa and those who don't.	Immediately after surgery
Pathologic Response After Resection With and Without Zometa	The pathologic response will be scored from 0-9 by a pathologist, 0 is no response and 9 is complete response between participants receiving Zometa and those who don't.	Immediately after surgery
Change in Tumor Size after Stereotactic Body Radiation Therapy With and Without Zometa	Tumor size will be measured on computed tomography (CT)/magnetic resonance imaging (MRI) before and after stereotactic body radiation therapy (SBRT) and compared between participants receiving Zometa and those who don't.	Within 1 month prior to SBRT and 4-5 weeks after SBRT
Change of maximum and average Standardized Uptake Values after Stereotactic Body Radiation Therapy With and Without Zometa	The maximum and average standardized uptake values SUV will be measured on Positron Emission Tomography (PET) before and after Stereotactic Body Radiation Therapy (SBRT) and will be compared between participants receiving Zometa and those who don't.	Within 1 month prior to SBRT and 4-5 weeks after SBRT
Tumor and Organ Motion	The amplitude of 3D tumor/organ motion will be measured using four dimensional (4D) computed tomography (CT) scans.	Immediately prior to stereotactic body radiation therapy (SBRT)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
RNA Sequence Assessment of Gene Expression of Cholesterol Biosynthesis for Resection With or Without Zometa	Change in expression of genes involved in cholesterol biosynthesis in participants who undergo resection will be assessed between participants receiving Zometa and those who don't.	Up to 5 years
Pharmacokinetics of Zoledronic Acid	The concentration of plasma zoledronic acid will be measured in participants who received zoledronic acid.	At 0 and 1 hours post-zoledronic acid dose, and before stereotactic body radiation therapy (SBRT) treatments on days 2, 3, 4, and 5

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Chi Lin, MD, PhD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2016
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: February 28, 2017
• First Submitted That Met QC Criteria: March 2, 2017
• First Posted (Actual): March 8, 2017

Study Record Updates

• Last Update Posted (Actual): May 25, 2025
• Last Update Submitted That Met QC Criteria: May 20, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Carcinoma; Pancreatic Neoplasms; Adenocarcinoma; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Bone Density Conservation Agents; Capecitabine; Zoledronic Acid; Fluorouracil; Imidazole
• Other Study ID Numbers: 0552-16-FB; P30CA036727 (U.S. NIH Grant/Contract); NCI-2016-01360 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

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