Testing Higher Dose Radiation Therapy For Locally Advanced Pancreatic Cancer

Study Overview

Testing Higher Dose Radiation Therapy for Locally Advanced Pancreatic Cancer

This phase III trial compares the effect of dose-escalated radiation therapy to usual care in patients with locally advanced unresectable pancreatic ductal adenocarcinoma who have received an initial 4-6 months of chemotherapy. Usual care options include additional chemotherapy, observation, or standard lower-dose radiation therapy. These treatments may delay tumor growth but have not been shown to improve survival. Radiation therapy uses high energy X-rays to kill cancer cells and shrink tumors. Dose-escalated radiation therapy involves the precise delivery of higher doses to the tumor, often over a shorter period of time. This trial assesses whether using dose-escalated radiation therapy can prolong survival.

PRIMARY OBJECTIVE: I. To evaluate whether dose-escalated radiation therapy (RT) improves 3-year overall survival (OS) compared to standard treatments without dose-escalated RT, in locally advanced pancreatic cancer patients without radiographic progression and with biochemical response after an initial interval of chemotherapy. SECONDARY OBJECTIVES: I. To evaluate and compare local progression between the two treatment arms. II. To evaluate and compare progression-free survival (PFS) between the two treatment arms. III. To evaluate and compare chemotherapy-free interval between the two treatment arms. IV. To evaluate and compare toxicity within and between the two treatment arms. HEALTH-RELATED QUALITY-OF-LIFE (HRQOL) OBJECTIVES: I. Primary: To compare Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) Total Score at 6 months between the two treatment arms. II. Secondary: To compare nadir of HRQoL scores over course of study participation between the two treatment arms. III. Secondary: To evaluate HRQoL scores over time between the two treatment arms. EXPLORATORY OBJECTIVE: I. Biospecimen collection for future correlative analyses. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I (STANDARD OF CARE): Patients are assigned to 1 of 3 treatment options per physician's decision. OPTION 1: Patients continue to receive fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin (FOLFIRINOX or modified FOLFIRINOX [mFOLFIRINOX]) or fluorouracil, liposomal irinotecan, leucovorin calcium, and oxaliplatin (NALIRIFOX) or gemcitabine/nab-paclitaxel per standard of care for a total of 6 months of treatment. Patients may continue treatment beyond 6 months at physician's discretion. OPTION 2: Patients undergo standard dose radiation therapy once daily for 28 fractions and receive fluorouracil or capecitabine per standard of care during radiation therapy. After completing concurrent chemoradiation, patients who received less than 6 months of chemotherapy at study entry are encouraged to receive the remaining chemotherapy to total 6 months of chemotherapy. Patients may continue chemotherapy treatment beyond 6 months at physician's discretion. OPTION 3: Patients undergo observation per standard of care. (It is recommended [but not required] that this option only be for patients that have already completed total 6 months chemotherapy pre-randomization.) Additionally, patients undergo blood sample collection, computed tomography (CT), magnetic resonance imaging (MRI) and tumor tissue biopsy throughout the study. ARM II (DOSE-ESCALATED RADIATION THERAPY): Patients undergo dose-escalated RT daily, every other day, or twice weekly for 5 fractions or daily for 25 fractions (with or without concurrent fluoropyrimidine). After completing dose-escalated RT, patients who received less than 6 months of chemotherapy at study entry are encouraged to receive the remaining chemotherapy to total 6 months of chemotherapy. Patients may continue chemotherapy treatment beyond 6 months at physician's discretion. Additionally, patients undergo blood sample collection, CT, MRI and tumor tissue biopsy throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years then annually for 3 years.

Pancreas Cancer

DRUG: Fluorouracil
DRUG: Irinotecan Hydrochloride
DRUG: leucovorin calcium
DRUG: Oxaliplatin
DRUG: Irinotecan Sucrosofate
DRUG: Gemcitabine
DRUG: Nab paclitaxel
RADIATION: Radiation Therapy
DRUG: Capecitabine
OTHER: Observation Activity
PROCEDURE: Biospecimen Collection
PROCEDURE: Biopsy Procedure
PROCEDURE: Computed Tomography
PROCEDURE: Magnetic Resonance Imaging
OTHER: Questionnaire Administration
RADIATION: Dose-escalated Radiation Therapy
PROCEDURE: Biospecimen Collection
PROCEDURE: Biopsy Procedure
PROCEDURE: Computed Tomography
PROCEDURE: Magnetic Resonance Imaging
OTHER: Questionnaire Administration

NRG-GI011

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2025-04-25	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-07-22
First Submitted that Met QC Criteria 2025-04-25	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-07-23
First Posted (ACTUAL) 2025-05-06	Results First Posted N/A	Last Verified 2025-07

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
ACTIVE_COMPARATOR: Arm I (standard of care) 1: Patients continue to receive fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin or fluorouracil, liposomal irinotecan, leucovorin calcium, and oxaliplatin or gemcitabine/nab-paclitaxel per standard of care for a total of 6 mont	DRUG: Fluorouracil Given fluorouracil DRUG: Irinotecan Hydrochloride Given irinotecan hydrochloride DRUG: leucovorin calcium Given leucovorin calcium DRUG: Oxaliplatin Given oxaliplatin DRUG: Irinotecan Sucrosofate Given liposomal irinotecan DRUG: Gemcitabine Given Gemcitabine DRUG: Nab paclitaxel Given Nab-paclitaxel RADIATION: Radiation Therapy Undergo standard radiation therapy DRUG: Capecitabine Given capecitabine OTHER: Observation Activity Undergo Observation PROCEDURE: Biospecimen Collection Undergo blood sample collection PROCEDURE: Biopsy Procedure Undergo tumor tissue biopsy PROCEDURE: Computed Tomography Undergo CT PROCEDURE: Magnetic Resonance Imaging Undergo MRI OTHER: Questionnaire Administration Ancillary studies
EXPERIMENTAL: ARM II (DOSE-ESCALATED RADIATION THERAPY): ): Patients undergo dose-escalated RT daily, every other day, or twice weekly for 5 fractions or daily for 25 fractions (with or without concurrent fluoropyrimidine). After completing dose-escalated RT, patients who received less than 6 months of chemothe	RADIATION: Dose-escalated Radiation Therapy Undergo dose-escalated radiation using intensity-modulated radiation therapy treatment planning PROCEDURE: Biospecimen Collection Undergo blood sample collection PROCEDURE: Biopsy Procedure Biopsy, BIOPSY, Biopsy, Biopsy, Biopsy, biopsy, Biopsy, Biopsy, Biopsy, Biopsy, Biopsy, BIOPSY\_TYPE, BIOPSY\_TYPE, BIOPSY\_TYPE, Bx PROCEDURE: Computed Tomography Undergo CT PROCEDURE: Magnetic Resonance Imaging Undergo MRI OTHER: Questionnaire Administration Ancillary studies

Participant Group/Arm

Intervention/Treatment

ACTIVE_COMPARATOR: Arm I (standard of care)

1: Patients continue to receive fluorouracil, irinotecan hydrochloride, leucovorin calcium, and oxaliplatin or fluorouracil, liposomal irinotecan, leucovorin calcium, and oxaliplatin or gemcitabine/nab-paclitaxel per standard of care for a total of 6 mont

DRUG: Fluorouracil

Given fluorouracil

DRUG: Irinotecan Hydrochloride

Given irinotecan hydrochloride

DRUG: leucovorin calcium

Given leucovorin calcium

DRUG: Oxaliplatin

Given oxaliplatin

DRUG: Irinotecan Sucrosofate

Given liposomal irinotecan

DRUG: Gemcitabine

Given Gemcitabine

DRUG: Nab paclitaxel

Given Nab-paclitaxel

RADIATION: Radiation Therapy

Undergo standard radiation therapy

DRUG: Capecitabine

Given capecitabine

OTHER: Observation Activity

Undergo Observation

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

PROCEDURE: Biopsy Procedure

Undergo tumor tissue biopsy

PROCEDURE: Computed Tomography

Undergo CT

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

OTHER: Questionnaire Administration

Ancillary studies

EXPERIMENTAL: ARM II (DOSE-ESCALATED RADIATION THERAPY):

): Patients undergo dose-escalated RT daily, every other day, or twice weekly for 5 fractions or daily for 25 fractions (with or without concurrent fluoropyrimidine). After completing dose-escalated RT, patients who received less than 6 months of chemothe

RADIATION: Dose-escalated Radiation Therapy

Undergo dose-escalated radiation using intensity-modulated radiation therapy treatment planning

PROCEDURE: Biospecimen Collection

Undergo blood sample collection

PROCEDURE: Biopsy Procedure

Biopsy, BIOPSY, Biopsy, Biopsy, Biopsy, biopsy, Biopsy, Biopsy, Biopsy, Biopsy, Biopsy, BIOPSY\_TYPE, BIOPSY\_TYPE, BIOPSY\_TYPE, Bx

PROCEDURE: Computed Tomography

Undergo CT

PROCEDURE: Magnetic Resonance Imaging

Undergo MRI

OTHER: Questionnaire Administration

Ancillary studies

Primary Outcome Measures	Measure Description	Time Frame
Overall survival (OS)	OS will be estimated by the Kaplan-Meier method (Kaplan 1958). The 3-year OS estimates between the two arms will be compared using a Z-test. A logistic regression model will be used to analyze the effects of factors, in addition to treatment, including, but not limited to the stratification factor, which may be associated with 3-year OS. The primary hypothesis of improved 3-year OS will be tested with a 1-sided significance level of 0.023.	assessed up to 3 years

Secondary Outcome Measures	Measure Description	Time Frame
Local progression (LP)	Defined as progression of the primary tumor/nodes as determined by Response Evaluation Criteria in Solid Tumors criteria. LP will be estimated by the cumulative incidence method (Kalbfleish 1980), with death as a competing risk, and compared between treatment arms using Gray's test (Gray 1988). The Fine-Gray regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with LP (Fine 1999).	From randomization to date of failure, date of death (competing event), or last known follow-up date, assessed up to 5 years
Progression-free survival (PFS)	Defined as local progression, distant failure, or death due to any cause. PFS will be estimated by the Kaplan-Meier method (Kaplan 1958) and estimates between treatment arms will be compared using the log-rank test (Mantel 1966). The Cox proportional hazard regression model will be used to analyze the effects of factors, in addition to treatment, which may be associated with PFS (Cox 1972).	From the date of randomization to the date of first PFS failure or last follow-up for patients without a reported PFS event, assessed up to 5 years
Chemotherapy-free interval (CFI)	Defined as the time in months without chemotherapy for locally advanced pancreatic cancer post the initial chemotherapy treatment. Mean CFI will be compared between treatment arms using a Z-test. Regression modeling will be used to analyze the effects of factors, in addition to treatment, which may be associated with CFI.	From the date of last dose of initial chemotherapy to the date of first dose of second line chemotherapy for progression, assessed up to 5 years
Long-term radiation-related ≥ grade 3 adverse events	The percentage of patients on the dose-escalated radiation therapy arm will be reported	Up to 1 year
Incidence of ≥ grade 3 adverse events	The percentage of patients will be compared between the treatment arms using a Z-test.	Up to 90 days after randomization

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Nina Sanford

Phone Number:

Email: Nina.Sanford@UTSouthwestern.edu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

• At time of enrollment, the patient must have received 4-6 months of active chemotherapy with FOLFIRINOX (8-12 cycles) or NALIRIFOX (8-12 cycles) or gemcitabine/nab-paclitaxel (4-6 cycles) (1 regimen, no sequential chemotherapy). "Active chemotherapy" refers to time on chemotherapy not counting treatment breaks (i.e. if a patient had 1 month of chemotherapy followed by 1 month break, this would count as 1 month chemotherapy). Study registration must occur within 45 days of last day of chemotherapy cycle

BASELINE PRE-ENTRY CHEMOTHERAPY REQUIREMENTS:
Pathologically (histologically or cytologically) proven diagnosis of pancreatic ductal adenocarcinoma
Locally advanced unresectable disease (as defined per the National Comprehensive Cancer Network [NCCN] guidelines and institutional tumor board review)
Patients must have baseline pre-chemotherapy scans for staging. Options include: CT chest/abdomen/pelvis, CT chest/MRI abdomen/pelvis, or CT chest/CT pelvis/MRI abdomen performed prior to enrollment
Age ≥ 18 years
Performance status Eastern Cooperative Oncology Group (ECOG) 0-2
Baseline CA19-9 with a normal bilirubin level (defined as ≤ 1.2 mg/dl)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN)
POST PRE-ENTRY CHEMOTHERAPY REQUIREMENTS:
If baseline CA19-9 is elevated (defined as > 37 u/mL) the post-pre-entry chemotherapy CA19-9 must be less than 37 u/mL or a 50% decline from pre-chemotherapy level with absolute value less than 100u/mL
If baseline CA19-9 is not elevated (defined as ≤ 37 u/mL) the post-pre-entry chemotherapy CA19-9 must remain ≤ 37 u/mL
No active duodenal or gastric ulcers
No direct tumor invasion of the bowel or stomach
Restaging scans showing at least stable disease (no progression). Options for scans include: CT chest/abdomen/pelvis, CT chest/MRI abdomen/pelvis, or CT chest/CT pelvis/MRI abdomen performed prior to enrollment, with restaging CT showing at least stable disease
Not pregnant and not nursing
No cardiac condition that was the primary reason for hospitalization in the last 6 months
New York Heart Association Functional Classification II or better (NYHA Functional Classification III/IV are not eligible) (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.)
HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Collaborators and Investigators

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