A Clinical Trial Evaluating the Effect of Pharmacological Ascorbate on Radiation Therapy for Pancreatic Cancer Patients

Study Overview
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Brief Summary
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Radiation therapy improves cancer cure rates by killing cancer cells but it also contributes to long-term side effects in cancer survivors by unintentionally damaging normal organs such as the intestine. This research will what side effects patients with cancer experience, if high dose vitamin C helps reduce these side effects, and if high dose vitamin C increases the survival of patients with pancreatic cancer. We will meet with patients during the study to better understand their experience during their cancer treatment. In the long term, our research could provide a new way help cancer survivors avoid many permanent side effects of cancer treatments.

Detailed Description
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This is a randomized phase 2 study is designed to determine initial efficacy and assess adverse events, and quantify pathologic evidence of intestinal radiation injury. The ascorbate is infused before, during, and after the external beam radiation therapy treatment. Each ascorbate infusion is 75 grams (roughly the same amount of vitamin C from 1,000 oranges). For patients eligible for this trial, standard treatment for their cancer includes radiation therapy combined with weekly gemcitabine (a chemotherapy). Participants will: be randomized (like flipping a coin) to receive the investigational treatment (pharmacological ascorbate plus gemcitabine plus radiation) or standard treatment only (gemcitabine plus radiation) receive gemcitabine (a chemotherapy) once a week for up to 6 weeks of therapy (all participants) receive radiation treatments are given once a day, Monday through Friday (all participants). have routine doctor's visits and be asked about any side effects they are experiencing (all participants). be interviewed to discuss their side effects, how it impacts their life, and describe their recent activities. receive pharmacological ascorbate intravenously ascorbate during their daily radiation therapy treatments (if randomized to receive the investigational treatment). Once the patient completes radiation, the ascorbate infusions are also completed. However, the patient will need to return for regular follow-up care at University of Iowa. We are interested in the long-term side effects of radiation - which may not develop for years - so it is important the participant return to radiation oncology for follow-up. We will also conduct interviews at that time to review the side effects and how they impact the participant's quality of life.

Official Title
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XACT-Pancreas 2: Pharmacological Ascorbate, Gemcitabine, and Radiation Therapy for Pancreatic Cancer, Phase 2

Conditions
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Pancreatic Neoplasm

Intervention / Treatment
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* Drug: Ascorbate
* Drug: Gemcitabine
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible to participate in this study, an individual must meet ALL of the following criteria: Ability and willingness to provide informed consent (power of attorney and legally authorized representatives are not accepted for informed consent) Stated willingness to comply with all study procedures and availability for duration of the study At least 18 years of age Histologic or cytologic diagnosis of pancreatic adenocarcinoma Referral for gemcitabine-based chemoradiation Good performance status (ECOG of 0, 1, or 2; KPS of > 50) No other active malignancy that requires immediate treatment. Slow growing concurrent cancers (such as prostate cancer) are acceptable with appropriate documentation from their treating oncologists for that primary. Not experiencing an uncontrolled illness such as infection requiring inpatient admission, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other condition that would limit compliance with the study requirements or unacceptably increase risk to the participant (as determined by study team members). Agree to abstain from alcohol and specified over the counter supplements during study treatment Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participating in this study: Glucose-6-phosphate dehydrogenase (G6PD) deficiency HIV positive individuals requiring anti-retroviral drug therapy (high-dose ascorbate is known to interact with many of these drugs) Platelet count of <100,000 k/mm3 Prior radiation that would result in field overlap (this will be determined by the study's radiation oncologist) Presence of metastatic disease beyond regional lymphatics Actively receiving insulin Other therapy (including radiation therapy) within 2 calendar weeks of study therapy On any of the following drugs and cannot or will not accept a drug substitution: warfarin, flecainide, methadone, amphetamines, quinidine, and chlorpropamide Other investigational agents (PET or SPECT imaging agents are acceptable) Other investigational therapy with the intention to treat the disease under study Pregnancy Individuals declining to use acceptable birth control during the duration of the study Lactating women who decline to discontinue breastfeeding their child (women may withhold breast feeding and resume under the direction of their medical oncologist after completion of study)

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized trial (standard vs. experimental) in a one-to-one ratio.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Therapy (ASC)<br>75 grams of pharmacological ascorbate, daily (M-F) 600 mg/m2 of gemcitabine, once a week for up to 6 weeks 50 to 50.4 Gray of radiation therapy delivered using a volumetric arc therapy (VMAT) technique | Drug: Ascorbate<br>* 75 gram infusion daily (M-F) on days when radiation therapy is administered. The infusion occurs during the 'beam on' of the radiation therapy.<br>* Other names: Vitamin C;Drug: Gemcitabine<br>* 600 mg/m2 once weekly for up to weeks<br>* Other names: Gemzar;Radiation: radiation therapy<br>* Prescribed to 50 Gy in 25 fractions. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks.<br>* Other names: External beam radiation therapy;|
| Active Comparator: Standard Therapy (ChemoRT)<br>600 mg/m2 of gemcitabine, once a week for up to 6 weeks 50 to 50.4 Gray of radiation therapy delivered using a volumetric arc therapy (VMAT) technique | Drug: Gemcitabine<br>* 600 mg/m2 once weekly for up to weeks<br>* Other names: Gemzar;Radiation: radiation therapy<br>* Prescribed to 50 Gy in 25 fractions. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks.<br>* Other names: External beam radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | The study will determine the time (calculated in months) between study day 1 and death from any cause. After 10 years post-treatment, dates will be censored to date of last follow-up | Up to 5 years post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) | From radiation day 1 to documented disease progression in CT imaging as described by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Measured in months. | Up to 5 years post-treatment | 
| Toxicity over time (ToxT) | Toxicity over time will be assessed by summarizing treatment emergent adverse events by system organ class and/or preferred term, type of adverse event, and severity. Elapsed days of toxicity will be summarized. | Treatment day 1 to 30 days post-treatment | 
| Metastasis free survival (MFS) | time from treatment initiation (day 1) to the date of first documentation of disease progression outside of the pelvis (per RECIST 1.1) | Up to 5 years post-treatment | 
| Resection rate | Rate of patients who undergo resection of tumor | Within 2 month post-radiation | 
| Adverse event frequency and categorization | Categorize and quantify adverse events using the Common Terminology Criteria for Adverse Events (CTCAE, v 5) | Weekly for the first 6 weeks and then at follow-up through 5 years post-treatment | 
| Patient reported outcome measure: Vaizey Incontinence questionnaire | Patient reported outcome measure of bowel side effects collected at pre-specified timepoints. | Treatment day 1 to 5 years post-treatment | 
| Quality of life: Modified Inflammatory Bowel Disease questionnaire | Patient completed quality of life form collected at pre-specified timepoints. | Treatment day 1 to 5 years post-treatment | 
| Pathologic characteristics | • Mucosal ulcerations, inflammatory cell infiltration, collage deposition, and microvascular changes will be assessed | At surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ascorbic acid, ascorbate, sodium ascorbate, radiotherapy, radiotherapy, image-guided, gemcitabine, adverse event, quality of life, radiation enteropathy