Clinical trial NCT01515046: Clinical Trial of High-dose Vitamin C for Advanced Pancreatic Cancer
Official title: Pharmacological Ascorbate for the Control of Metastatic and Node-Positive Pancreatic Cancer (PACMAN): A Phase II Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Pancreatic Neoplasms
Pancreatic Cancer
Keywords: Vitamins
Complementary medicine
Pancreatic cancer
Ascorbate
Ascorbic Acid
Antioxidants
Gemcitabine
Pharmacologic actions
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: Susan L Bader Foundation of Hope
name: Holden Comprehensive Cancer Center
name: National Cancer Institute (NCI)
First posted: 2012-01-23
Enrollment: 1
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Overall Survival
timeFrame: up to 5 years
Secondary outcomes:
measure: Progression Free Survival
timeFrame: up to 5 years
measure: Number of Drug-related Adverse Events Per Cycle
timeFrame: every 28 days up to 5 years
measure: F2-isoprostane Levels
timeFrame: Once every 28 days for up to 5 years
measure: Ascorbate Levels
timeFrame: Once every 28 days up to 5 years
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: The Holden Comprehensive Cancer Center
state: Iowa
Study officials:
affiliation: University of Iowa
name: Joseph J Cullen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Joseph J Cullen, MD
role: STUDY_CHAIR
References:
citation: 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.
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.
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.