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Hypofractionated Stereotactic Body Radiation Therapy and Fluorouracil or Capecitabine With or Without Zoledronic Acid in Treating Patients With Locally Advanced Pancreatic Cancer

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ClinicalTrials.gov Identifier: NCT03073785
Recruitment Status : Recruiting
First Posted : March 8, 2017
Last Update Posted : March 14, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Chi Lin, MD, University of Nebraska

Tracking Information
First Submitted Date  ICMJE February 28, 2017
First Posted Date  ICMJE March 8, 2017
Last Update Posted Date March 14, 2019
Actual Study Start Date  ICMJE September 16, 2016
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 23, 2017)
  • Local control [ Time Frame: At 4 months ]
    Will be observed.
  • Local control [ Time Frame: At 8 months ]
    Will be observed.
  • Local control [ Time Frame: At 12 months ]
    Will be observed.
Original Primary Outcome Measures  ICMJE
 (submitted: March 2, 2017)
  • Local control [ Time Frame: At 4 months ]
    RECIST guidelines will be followed for the criteria for radiographic response evaluation
  • Local control [ Time Frame: At 8 months ]
    RECIST guidelines will be followed for the criteria for radiographic response evaluation
  • Local control [ Time Frame: At 12 months ]
    RECIST guidelines will be followed for the criteria for radiographic response evaluation
Change History Complete list of historical versions of study NCT03073785 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2019)
  • Maximum tolerated dose of zoledronic acid determined by dose limiting toxicities evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after surgery ]
    Safety variables to be analyzed are adverse events. Adverse events will be tallied for overall frequency (number and percentage of subjects), worst reported severity, and relationship to study drugs. Serious adverse events will be summarized similarly.
  • Local failure-free survival will be compared between patients with and without Zometa [ Time Frame: From date of administration of study drug to the date of first appearance of local disease progression or recurrence by imaging, or death, assessed up to 5 years ]
    Time to local failure will be analyzed using Kaplan-Meier method
  • Overall survival will be compared between patients with and without Zometa [ Time Frame: From the first date of study drug to the date of death, assessed up to 5 years ]
    Time to death will be analyzed using Kaplan-Meier method
  • Surgical complete resection (negative margin) rate will be compared between patients with and without Zometa [ Time Frame: Immediate after the surgery ]
    The number and proportion of patients undergoing complete resection will be reported.
  • Pathologic response for patients who undergo resection will be compared between patients with and without Zometa [ Time Frame: Immediate after surgery ]
    The pathologic response will be scored from 0-9 by a pathologist, 0 is no response and 9 is complete response.
  • The change of tumor size after SBRT will be compared between patients with and without Zometa [ Time Frame: within 1 months prior to SBRT and 4-5 weeks after SBRT ]
    The size of tumor will be measured on CT/MRI before and after SBRT
  • The change of max and average SUV after SBRT will be compared between patients with and without Zometa. [ Time Frame: within 1 months prior to SBRT and 4-5 weeks after SBRT ]
    The max and average SUV will be measured on PET before and after SBRT
  • Tumor and organ motion [ Time Frame: Immediate prior to SBRT ]
    The amplitude of 3D tumor/organ motion will be measured using 4D CT scans
Original Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2017)
  • Local failure-free survival [ Time Frame: From date of administration of study drug to the date of first appearance of tumor lesions by imaging, or death, assessed up to 5 years ]
    Will be analyzed using Kaplan-Meier plots, medians, and ranges.
  • Maximum tolerated dose of zoledronic acid determined by dose limiting toxicities evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 30 days after surgery ]
    Safety variables to be analyzed are adverse events. Adverse events will be tallied for overall frequency (number and percentage of subjects), worst reported severity, and relationship to study drugs. Serious adverse events will be summarized similarly.
  • Overall survival [ Time Frame: From the first date of study drug to the date of death, assessed up to 5 years ]
    Will be analyzed using Kaplan-Meier plots, medians, and ranges.
  • Surgical complete resection (negative margin) rate [ Time Frame: At the time of surgery ]
    The number of patients experiencing local progressive disease (LPD) will be reported. An exact one-sided 90% confidence interval will be constructed round the local progressive disease rate.
  • Surgical complete resection (negative margin) rate [ Time Frame: Week 6-9 At the time of surgery ]
    The proportion of patients experiencing local progressive disease (LPD) will be reported. An exact one-sided 90% confidence interval will be constructed round the local progressive disease rate.
  • Tumor and organ motion using 4D CT and respiratory gating system [ Time Frame: Week 6-9 Prior to surgery ]
    Will assess the effect of tumor/organ motion on the dosimetry, local control, and survival.
  • Tumor response rate using pathology specimen [ Time Frame: Week 6-9 Prior to surgery ]
    The number patients experiencing LPD will be reported. An exact one-sided 90% confidence interval will be constructed round the local progressive disease rate.
  • Proportional tumor response rate using pathology specimen [ Time Frame: Week 6-9 Prior to surgery ]
    The proportion of patients experiencing LPD will be reported. An exact one-sided 90% confidence interval will be constructed round the local progressive disease rate.
  • Tumor response rate using positron emission tomography/CT/magnetic resonance imaging [ Time Frame: Week 6-9 Prior to surgery ]
    The number of patients experiencing LPD will be reported. An exact one-sided 90% confidence interval will be constructed round the local progressive disease rate.
  • Proportional tumor response rate using positron emission tomography/CT/magnetic resonance imaging [ Time Frame: Week 6-9 Prior to surgery ]
    The proportion of patients experiencing LPD will be reported. An exact one-sided 90% confidence interval will be constructed round the local progressive disease rate.
  • Tumor/organ motion [ Time Frame: Week 6-9 Prior to surgery ]
    Will assess the effect of tumor/organ motion on the dosimetry, local control, and survival.
Current Other Pre-specified Outcome Measures
 (submitted: March 8, 2019)
  • RNA seq will be used to assess gene expression involved in cholesterol biosynthesis in patients who had resection with or without Zometa [ Time Frame: up to 5 years ]
    Change in expression of genes involved in cholesterol biosynthesis in patients who undergo resection will be assessed.
  • Pharmacokinetics parameters of zoledronic acid [ Time Frame: At 0 and 1 hours post zoledronic acid dose, and before radiation treatments on days 2, 3, 4, and 5 ]
    The concentration of plasma zoledronic acid will be measured.in patients who received zoledronic acid
Original Other Pre-specified Outcome Measures
 (submitted: March 2, 2017)
  • 4D CT and respiratory gating value [ Time Frame: Week 6-9 Prior to surgery ]
    Will assess the effect of tumor/organ motion on the dosimetry, local control, and survival.
  • Change in expression of genes involved in cholesterol biosynthesis in tissue [ Time Frame: Baseline to 5 weeks ]
    Immunohistochemistry staining of Farnesyl diphosphate synthase (FDPS) of pancreatic cancer tissue samples will be done to examine the change in expression of genes involved in cholesterol biosynthesis in tissue
  • Pharmacokinetics parameters of zoledronic acid [ Time Frame: At 0, 1, 24, 60, 84, and 108 hours post zoledronic acid dose ]
    Blood samples will be collected to measure the drug level of zoledronic acid at selected time points.
 
Descriptive Information
Brief Title  ICMJE Hypofractionated Stereotactic Body Radiation Therapy and Fluorouracil or Capecitabine With or Without Zoledronic Acid in Treating Patients With Locally Advanced Pancreatic Cancer
Official Title  ICMJE 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
Brief Summary This randomized phase II trial studies how well hypofractionated stereotactic body radiation therapy and fluorouracil or capecitabine with or without zoledronic acid work in treating patients with pancreatic cancer that has spread from where it started 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 and 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 patients with pancreatic cancer.
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of hypofractionated radiation therapy concurrently with zoledronic acid (Zometa) and fluorouracil (5Fu) or capecitabine.

SECONDARY OBJECTIVES:

I. To examine the toxicity of Zometa while it is used concurrently with hypofractionated radiation therapy.

II. To evaluate local failure-free survival and overall survival, surgical resection rate and tumor response rate.

TERTIARY OBJECTIVES:

I. To quantify the amplitude of the expression of genes that are involved in cholesterol biosynthesis (ACAT2, DHCR7, ELFN2, FASN, SC4MOL, and SQLE) in pancreatic tumor tissue prior to and following the Zometa and radiation therapy if the pancreatic cancer tissue is available.

II. To measure Zometa pharmacokinetics at steady-state. III. To evaluate tumor and organ motion with 4 dimension(D) computed tomography (CT) and respiratory gating system and to evaluate the effect of tumor/organ motion on the dosimetry, local control and survival.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients undergo hypofractionated stereotactic body radiation therapy in 5 fractions on days 1-5. Patients receive fluorouracil intravenously (IV) over 24 hours on day 1 weekly for 4 weeks or capecitabine orally (PO) every 12 hours starting the evening before day 1 of radiation therapy for 4 weeks as per standard of care. Patients then undergo surgery 6-8 weeks after completion of radiation therapy.

ARM B: Patients receive zoledronic acid IV over no less than 15 minutes 1 week prior to radiation therapy. Patients undergo hypofractionated stereotactic body radiation therapy and receive treatment with fluorouracil IV or capecitabine PO as in Arm A. Patients then undergo surgery 6-8 weeks after completion of radiation therapy.

After completion of study treatment, patients are followed up for 30 days, every 3 months for the first year, every 4 months for the second year, and then every 6 months thereafter.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Pancreatic Adenocarcinoma
  • Recurrent Pancreatic Carcinoma
  • 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
  • Stage III Pancreatic Cancer AJCC v6 and v7
  • Stage IV Pancreatic Cancer AJCC v6 and v7
Intervention  ICMJE
  • Drug: Capecitabine
    Given PO
    Other Names:
    • Ro 09-1978/000
    • Xeloda
  • Drug: Fluorouracil
    Given IV
    Other Names:
    • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
    • 5-Fluorouracil
    • 5-Fluracil
    • 5-FU
    • AccuSite
    • Carac
    • Fluoro Uracil
    • Fluouracil
    • Flurablastin
    • Fluracedyl
    • Fluracil
    • Fluril
    • Fluroblastin
    • Ribofluor
    • Ro 2-9757
    • Ro-2-9757
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Pharmacological Study
    Correlative studies
  • Radiation: Stereotactic Body Radiation Therapy
    Undergo hypofractionated stereotactic radiotherapy
    Other Names:
    • SABR
    • SBRT
    • Stereotactic Ablative Body Radiation Therapy
  • Drug: Zoledronic Acid
    Given IV
    Other Names:
    • [1-Hydroxy-2-(1H-imidazol-1-yl)ethylidene]bisphosphonic Acid
    • CGP 42446
    • CGP42446A
    • NDC-Zoledronate
    • Reclast
    • ZOL 446
    • Zometa
Study Arms  ICMJE
  • Active Comparator: Arm A (chemotherapy, radiation therapy)
    Patients undergo hypofractionated stereotactic body radiation therapy in 5 fractions on days 1-5. Patients receive fluorouracil IV over 24 hours on day 1 weekly for 4 weeks or capecitabine PO every 12 hours starting the evening before day 1 of radiation therapy for 4 weeks as per standard of care. Patients then undergo surgery 6-8 weeks after completion of radiation therapy.
    Interventions:
    • Drug: Capecitabine
    • Drug: Fluorouracil
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Radiation: Stereotactic Body Radiation Therapy
  • Experimental: Arm B (zoledronic acid, chemotherapy, radiation therapy)
    Patients receive zoledronic acid IV over no less than 15 minutes 1 week prior to radiation therapy. Patients undergo hypofractionated stereotactic body radiation therapy and receive treatment with fluorouracil IV or capecitabine PO as in Arm A. Patients then undergo surgery 6-8 weeks after completion of radiation therapy.
    Interventions:
    • Drug: Capecitabine
    • Drug: Fluorouracil
    • Other: Laboratory Biomarker Analysis
    • Other: Pharmacological Study
    • Radiation: Stereotactic Body Radiation Therapy
    • Drug: Zoledronic Acid
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 8, 2019)
44
Original Estimated Enrollment  ICMJE
 (submitted: March 2, 2017)
40
Estimated Study Completion Date  ICMJE May 2021
Estimated Primary Completion Date May 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pathologically confirmed adenocarcinoma of the pancreas; patients with 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
  • Patients with inoperable conditions with resectable disease (T1-2NoMo)
  • Karnofsky performance status of 60% or better
  • Patients who received recent chemotherapy for pancreatic cancer are eligible; patients who received chemotherapy > 5 years ago for malignancies other than pancreatic cancer are also eligible, provided that chemotherapy was completed > 5 years ago and that there is no evidence of the second malignancy at the time of study entry
  • Patients who received radiation therapy > 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 are eligible, provided that radiation therapy was completed > 5 years ago and that there is no evidence of the second malignancy at the time of study entry
  • All malignant disease must be able to be encompassed within a single irradiation field
  • Patients must have an absolute neutrophil count (ANC) greater than or equal to 1500/uL
  • All patients must have radiographically assessable disease
  • Platelet count greater than or equal to 100,000/uL
  • Patients must have a 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 the patient has biliary obstruction, biliary decompression will be required; either endoscopic placement of a biliary stent or percutaneous transhepatic drainage is acceptable; once biliary drainage has been established, institution of protocol therapy may proceed when the total bilirubin falls to 4.0 mg/dL or lower)
  • Patients must have a calculated creatinine clearance of >= 35
  • The patient must be aware 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:

  • Patients with a known allergy to Zometa or to antiemetics appropriate for administration in conjunction with protocol-directed therapy
  • Uncontrolled inter-current illness including, but not limited to ongoing or active infection requiring intravenous antibiotics, symptomatic congestive heart failure, unstable angina pectoris, or serious, uncontrolled cardiac arrhythmia, that might jeopardize the ability of the patient to receive the therapy program outlined in this protocol with reasonable safety
  • Pregnant and nursing women are excluded from this study
  • Patients with prior malignancy will be excluded except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas, or other cancers from which the patient has been disease-free for at least 5 years
  • Patients with 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)
  • Patients with known human immunodeficiency virus (HIV) infection, or hepatic insufficiency
  • Patients may not be receiving or have received Zometa during/or within 3 weeks prior to treatment with Zometa
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03073785
Other Study ID Numbers  ICMJE 552-16
NCI-2016-01360 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
552-16 ( Other Identifier: University of Nebraska Medical Center )
P30CA036727 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Chi Lin, MD, University of Nebraska
Study Sponsor  ICMJE Chi Lin, MD
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Chi Lin University of Nebraska
PRS Account University of Nebraska
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP