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

Pancreatic Cancer Clinical Trial

— PACMAN-II  

Official title:

Pharmacological Ascorbate for the Control of Metastatic and Node-Positive Pancreatic Cancer (PACMAN): A Phase II Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01515046
• Other study ID #: 201204737
• Secondary ID: P30CA086862
• Status: Terminated
• Phase: Phase 2
• First received: January 18, 2012
• Last updated: November 30, 2015
• Start date: September 2012
• Est. completion date: July 2016

Study information

• Verified date: November 2015
• Source: University of Iowa
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: July 2016
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Pancreatic Cancer
• Pancreatic Neoplasms

Intervention

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)

Locations

Country	Name	City	State
United States	The Holden Comprehensive Cancer Center	Iowa City	Iowa

Sponsors (4)

Lead Sponsor	Collaborator
Joseph J. Cullen	Holden Comprehensive Cancer Center, National Cancer Institute (NCI), Susan L Bader Foundation of Hope

Country where clinical trial is conducted

United States, 

References & Publications (3)

Cullen JJ. Ascorbate induces autophagy in pancreatic cancer. Autophagy. 2010 Apr;6(3):421-2. Epub 2010 Apr 15. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall survival	Time to event outcome measure (death), measured in days from cycle 1 day 1.	up to 5 years	No
Secondary	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	No
Secondary	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	Yes
Secondary	F2-isoprostane levels	F2-isoprostane is a marker of systemic oxidative stress.	Once every 28 days for up to 5 years	Yes
Secondary	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	No