Clinical Trial of High-dose Vitamin C for Advanced Pancreatic Cancer (PACMAN-II)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pancreatic Neoplasms; Pancreatic Cancer	Drug: Gemcitabine with escalating ascorbic acid	Phase 2

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pharmacological Ascorbate for the Control of Metastatic and Node-Positive Pancreatic Cancer (PACMAN): A Phase II Trial
Study Start Date :	September 2012
Actual Primary Completion Date :	July 2015
Actual Study Completion Date :	December 2016

Arms and Interventions

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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 / infusion for two infusions. Doses are then escalated in 25 gram increments until therapeutic window is achieved (350 mg/dL or above). Dose is then held at that level for the full cycle.

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); Other Names: Gemzar; Ascorbic Acid for Infusion, USP

Outcome Measures

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Primary Outcome Measures :

1. Overall Survival [ Time Frame: up to 5 years ]
   Time to event outcome measure (death), measured in days from cycle 1 day 1.

Secondary Outcome Measures :

1. Progression Free Survival [ Time Frame: up to 5 years ]
   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.
2. Number of Drug-related Adverse Events Per Cycle [ Time Frame: every 28 days up to 5 years ]
   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
3. F2-isoprostane Levels [ Time Frame: Once every 28 days for up to 5 years ]
   F2-isoprostane is a marker of systemic oxidative stress.
4. Ascorbate Levels [ Time Frame: Once every 28 days up to 5 years ]
   Ascorbate levels will be taken at the bottom of each cycle to assess therapeutic dose window.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Contacts and Locations

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Locations

United States, Iowa
The Holden Comprehensive Cancer Center
Iowa City, Iowa, United States, 52242

Sponsors and Collaborators

Joseph J. Cullen

Susan L Bader Foundation of Hope

Holden Comprehensive Cancer Center

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Joseph J Cullen, MD	The University of Iowa
Study Chair:	Joseph J Cullen, MD	The University of Iowa

More Information

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Publications:

Cullen JJ. Ascorbate induces autophagy in pancreatic cancer. Autophagy. 2010 Apr;6(3):421-2. 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.

Responsible Party:	Joseph J. Cullen, Professor of Surgery, University of Iowa
ClinicalTrials.gov Identifier:	NCT01515046 History of Changes
Other Study ID Numbers:	201204737; P30CA086862 ( U.S. NIH Grant/Contract )
First Posted:	January 23, 2012
Results First Posted:	March 29, 2017
Last Update Posted:	June 8, 2017
Last Verified:	May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Joseph J. Cullen, University of Iowa:

Vitamins; Complementary medicine; Pancreatic cancer; Ascorbate	Ascorbic Acid; Antioxidants; Gemcitabine; Pharmacologic actions

Additional relevant MeSH terms:

Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Vitamins; Ascorbic Acid; Gemcitabine; Micronutrients; Growth Substances	Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Antioxidants; Protective Agents