Gemcitabine, Ascorbate, Radiation Therapy For Pancreatic Cancer, Phase I

Study Overview

Gemcitabine, Ascorbate, Radiation Therapy for Pancreatic Cancer, Phase I

This is a phase 1 (first in man) study testing the safety of adding high dose ascorbate (vitamin C) to standard radiation and chemotherapy for treatment of pancreatic cancer.

This phase 1 study will test the safety of adding high dose ascorbate (vitamin C) to standard chemoradiation. The ascorbate is infused during external beam radiation therapy treatment. For patients eligible for this trial, standard treatment for their cancer includes radiation therapy combined with weekly gemcitabine (a chemotherapy). Participants will: * receive high doses of intravenous (IV) ascorbate during their daily radiation therapy treatments. Radiation treatments are given once a day, Monday through Friday. * have routine doctor's visits and be asked about any side effects they are experiencing. This is a phase 1 study that will evaluate the side effects of adding ascorbate to standard therapy. The dose given to a participant will be determined by how well other participants have tolerated ascorbate.

Pancreatic Neoplasms

DRUG: Ascorbate
DRUG: Gemcitabine
RADIATION: Radiation therapy

201310772

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 2013-05-03	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-10-25
First Submitted that Met QC Criteria 2013-05-09	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2024-10-29
First Posted (ACTUAL) 2013-05-14	Results First Posted N/A	Last Verified 2024-10

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:
Non Randomized

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: 50g Ascorbate This arm is the initial starting dose. The first study participant will be assigned the 50g ascorbate arm. * Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based on tumor. Radiation is delivered 1 fraction/day,	DRUG: Ascorbate Intravenous infusion of high-dose ascorbate DRUG: Gemcitabine Intravenous chemotherapeutic RADIATION: Radiation therapy
EXPERIMENTAL: 75g Ascorbate If the 50g arm is tolerated, the study opens the 75g arm. * Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based on tumor. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks. *	DRUG: Ascorbate Intravenous infusion of high-dose ascorbate DRUG: Gemcitabine Intravenous chemotherapeutic RADIATION: Radiation therapy
EXPERIMENTAL: 100g Ascorbate If the 75g arm is tolerated, the study opens the 100g arm. * Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based on tumor. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks.	DRUG: Ascorbate Intravenous infusion of high-dose ascorbate DRUG: Gemcitabine Intravenous chemotherapeutic RADIATION: Radiation therapy
EXPERIMENTAL: 25g Ascorbate This study arm will only be used if participants cannot tolerate the 50g arm. If participants cannot tolerate 50 grams of Ascorbate, the 25g arm is opened. * Radiation: Prescribed to either 50 Gy in 25 fractions or at least 50.4 Gy in 28 fractions, based	DRUG: Ascorbate Intravenous infusion of high-dose ascorbate DRUG: Gemcitabine Intravenous chemotherapeutic RADIATION: Radiation therapy

Primary Outcome Measures	Measure Description	Time Frame
Number of grade 3, 4, & 5 adverse events during radiation	Assess grade 3 and higher adverse events. Evaluate the frequency and severity against the published literature to determine the likely causality between ascorbate and the adverse event(s).	Weekly during therapy for up to 10 weeks

Secondary Outcome Measures	Measure Description	Time Frame
Time to progression	Time from the start of therapy (radiation day 1) to documented disease progression as described by RECIST.	Monthly, up to 10 years post-treatment
Overall survival	From start of treatment (radiation day 1) until the date of death from any cause.	Monthly, up to 10 years post-treatment
Number of grade 3, 4, & 5 adverse events post-treatment	Beginning one month after completing radiation therapy, grade 3 and higher adverse events will be assessed. Evaluate the frequency and severity against the published literature to determine the likely causality between ascorbate and the adverse event(s).	every 3 months for 2 years

Contacts and Locations

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

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:

Patients must have histologically or cytologically diagnosed pancreatic adenocarcinoma. Documentation of disease extent by CT scan is required. Radiologically measurable disease is not required.
Age ≥ 18 years
ECOG performance status 0, 1, or 2 (Karnofsky > 50%).
A complete blood count and differential must be obtained within 21 days prior to radiation fraction 1, with adequate bone marrow functions as defined below:

Absolute neutrophil count (ANC) ≥ 1500 cells per mm3
Platelets ≥ 100,000 per mm3
Leukocytes ≥ 3,000 per mm3
Serum blood chemistries within 21 days of radiation fraction 1, as defined below:

Creatinine ≤ 1.5 x UIHC upper limit of normal or creatinine clearance of at least 60 ml/min/1.73 m2 for patients with creatinine levels above institutional normal.
Total bilirubin ≤ 2 x UIHC upper limit of normal
ALT ≤ 2.5 times the UIHC upper limit of normal
AST ≤ 2.5 times the UIHC upper limit of normal
PT/INR within normal limits (UIHC)
Tolerate one test dose (15g) of ascorbate.
Not pregnant.
Ability to understand and willingness to sign a written informed consent document.

G6PD (glucose-6-phosphate dehydrogenase) deficiency.
Prior abdominal radiotherapy that would result in overlap of fields. The treating radiation oncologist should review prior RT fields as available.
Adjuvant therapy (including radiation therapy) within 2 calendar weeks. Toxicities from prior therapy for the malignancy should resolve to grade 1 or less.
Patients actively receiving insulin are excluded.
Patients who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbate may affect urine acidification and, as a result, may affect clearance rates of these drugs.
Second malignancy other than non-melanoma skin cancers within the past 5 years.
Other investigational agents/therapy with the intention to treat the disease under study (observational or imaging trials are acceptable).
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situations, or any other condition that would limit compliance with study requirements as determined by study team members.
Pregnant or lactating women: The risks of radiation and chemotherapy to a fetus are well documented.
Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs. A clinical trial designed to address these interaction issues is more appropriate than this phase 1 study.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Holden Comprehensive Cancer Center
Gateway for Cancer Research

Investigators

PRINCIPAL_INVESTIGATOR: Joseph J Cullen, MD, FACS, The University of Iowa Hospitals & Clinics

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Welsh JL, Wagner BA, van't Erve TJ, Zehr PS, Berg DJ, Halfdanarson TR, Yee NS, Bodeker KL, Du J, Roberts LJ 2nd, Drisko J, Levine M, Buettner GR, Cullen JJ. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013 Mar;71(3):765-75. doi: 10.1007/s00280-013-2070-8. Epub 2013 Feb 5.
Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012 Dec;1826(2):443-57. doi: 10.1016/j.bbcan.2012.06.003. Epub 2012 Jun 20.
Cullen JJ. Ascorbate induces autophagy in pancreatic cancer. Autophagy. 2010 Apr;6(3):421-2. doi: 10.4161/auto.6.3.11527. Epub 2010 Apr 15.
Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, Taghiyev AF, Du C, Knudson CM, Cullen JJ. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010 Jan 15;16(2):509-20. doi: 10.1158/1078-0432.CCR-09-1713. Epub 2010 Jan 12.
Mezey E, Potter JJ, French SW, Tamura T, Halsted CH. Effect of chronic ethanol feeding on hepatic collagen in the monkey. Hepatology. 1983 Jan-Feb;3(1):41-4. doi: 10.1002/hep.1840030106.

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