Clinical Trial Of High-dose Vitamin C For Advanced Pancreatic Cancer

Study Overview

Clinical Trial of High-dose Vitamin C for Advanced Pancreatic Cancer

This is a phase II study. It is designed to provide information about if high-dose ascorbate (vitamin C) increases survival for pancreatic cancer patients. The hypothesis is that vitamin C is well tolerated and increases cancer treatment effectiveness, lengthening survival time for patients with advanced pancreatic cancer.

Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence; the prognosis remains dismal. We propose to investigate an entirely new approach, using pharmacological ascorbate, combined with Gemcitabine, to treat this cancer. Intravenous ascorbate (i.e., ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations, which are in the range that can be cytotoxic to tumor cells. Though ascorbate has been utilized in cancer therapy, few studies have investigated intravenous deliver of ascorbate. Preliminary studies from our group have demonstrated that ascorbate induces oxidative stress and cytotoxicity in pancreatic cancer cells; this cytotoxicity appears to be greater in tumor vs. normal cells. We hypothesize that production of H2O2 mediates the increased susceptibility of pancreatic cancer cells to ascorbate-induced metabolic oxidative stress. Gemcitabine is the standard chemotherapy drug used to treat pancreatic cancer.

Pancreatic Neoplasms
Pancreatic Cancer

DRUG: Gemcitabine with escalating ascorbic acid

201204737
P30CA086862 (U.S. NIH Grant/Contract)

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 2012-01-18	Results First Submitted 2017-02-10	Last Update Submitted that met QC Criteria 2017-05-11
First Submitted that Met QC Criteria 2012-01-18	Results First Submitted that Met QC Criteria 2017-02-10	Last Update Posted (ACTUAL) 2017-06-08
First Posted (ACTUAL) 2012-01-23	Results First Posted 2017-03-29	Last Verified 2017-05

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:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Gemcitabine with escalating IV ascorbate Gemcitabine (1000 mg/m2) weekly for three weeks and then one week off. Ascorbic Gemcitabine (1000 mg/m2) weekly for three weeks and then one week off. Ascorbate (vitamin C) given twice weekly, escalating doses weekly. Week 1: 15 grams ascorbate / infusio	DRUG: Gemcitabine with escalating ascorbic acid Gemcitabine 1000 mg/m2 weekly for 3 weeks with one week off (this is 1 cycle) Ascorbate dose is targeted to achieve plasma level of 350 mg/dL. Infusions are given twice weekly, each week of a cycle (4 weeks to a cycle)

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Gemcitabine with escalating IV ascorbate

Gemcitabine (1000 mg/m2) weekly for three weeks and then one week off. Ascorbic Gemcitabine (1000 mg/m2) weekly for three weeks and then one week off. Ascorbate (vitamin C) given twice weekly, escalating doses weekly. Week 1: 15 grams ascorbate / infusio

DRUG: Gemcitabine with escalating ascorbic acid

Gemcitabine 1000 mg/m2 weekly for 3 weeks with one week off (this is 1 cycle) Ascorbate dose is targeted to achieve plasma level of 350 mg/dL. Infusions are given twice weekly, each week of a cycle (4 weeks to a cycle)

Primary Outcome Measures	Measure Description	Time Frame
Overall Survival	Time to event outcome measure (death), measured in days from cycle 1 day 1.	up to 5 years

Secondary Outcome Measures	Measure Description	Time Frame
Progression Free Survival	Time-to-event outcome measure (initial disease progression) measured in days from cycle 1 day 1 to day of first progression as defined by RECIST criteria from NCI.	up to 5 years
Number of Drug-related Adverse Events Per Cycle	Adverse events linked to ascorbate will be categorized and quantified using CTCAE v4 at the bottom of each cycle. Incidence and frequency will be compared to scientific literature	every 28 days up to 5 years
F2-isoprostane Levels	F2-isoprostane is a marker of systemic oxidative stress.	Once every 28 days for up to 5 years
Ascorbate Levels	Ascorbate levels will be taken at the bottom of each cycle to assess therapeutic dose window.	Once every 28 days up to 5 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 a cytological or histological diagnosis of adenocarcinoma arising in the pancreas. Diagnosis from metastatic sampling is acceptable.
Disease must be measured radiologically.
Failed initial therapy or ineligible for definitive curative therapy.
If prior treatment included radiation therapy, recurrent disease must be outside of the targeted volume.
Age ≥ 18 years
ECOG performance status 0-2 (Karnofsky > 50%, see Appendix A).
Patients must have normal organ and marrow function as defined below:

leukocytes ≥ 3,000/mm3
absolute neutrophil count ≥ 1,500/mm3
platelets ≥ 100,000/mm3
total bilirubin < 2x institutional upper limit of normal
AST(SGOT) < 3x institutional upper limit of normal OR < 5x institutional upper limit of normal for patients presenting with liver metastases
ALT (SGPT) < 3x institutional upper limit of normal OR < 5x institutional upper limit of normal for patients presenting with liver metastases
PT/INR within normal institutional limits, unless patient is on warfarin or other antithrombotic agents
creatinine < 1.5 X institutional upper limit of normal OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
Not pregnant. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
Ability to understand and the willingness to sign a written informed consent document.

Prior chemotherapy to treat metastatic disease.
Adjuvant therapy (including radiation therapy) within 4 calendar weeks.
Unresolved toxicities from prior therapy for the malignancy.
G6PD (glucose-6-phosphate dehydrogenase) deficiency.
Second malignancy other than non-melanoma skin cancers within the past 5 years.
Excess consumption of alcohol where an excess of alcohol is defined as more than four of any one of the following per day: 30 mL distilled spirits, 340 mL beer, or 120 mL wine.
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 chemotherapy to a fetus/infant are well documented.

Collaborators and Investigators

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

Susan L Bader Foundation of Hope
Holden Comprehensive Cancer Center
National Cancer Institute (NCI)

Investigators

PRINCIPAL_INVESTIGATOR: Joseph J Cullen, MD, University of Iowa

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

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.
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.

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