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

Primary Purpose

Pancreatic Neoplasms

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Ascorbate

Gemcitabine

Radiation therapy

About this trial

This is an interventional treatment trial for Pancreatic Neoplasms focused on measuring Ascorbate, Vitamin C, Radiation, Gemcitabine, Ascorbic Acid

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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.

Sites / Locations

The Holden Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

50g Ascorbate

75g Ascorbate

100g Ascorbate

25g Ascorbate

Arm Description

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, 5 days a week, for approximately 5 to 6 weeks. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 50 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.

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. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 75 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.

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. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 100 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.

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 on tumor. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks. Gemcitabine: 600 mg/m2, once weekly for 6 weeks. Ascorbate: 25 grams administered intravenously (by IV) during radiation therapy, for approximately 5 to 6 weeks.

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Time to progression

Time from the start of therapy (radiation day 1) to documented disease progression as described by RECIST.

Overall survival

From start of treatment (radiation day 1) until the date of death from any cause.

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).

Full Information

NCT ID

NCT01852890

First Posted

May 3, 2013

Last Updated

October 18, 2023

Sponsor

Joseph J. Cullen

Collaborators

Holden Comprehensive Cancer Center, Gateway for Cancer Research

1. Study Identification

Unique Protocol Identification Number

NCT01852890

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

January 2014 (Actual)

Primary Completion Date

January 22, 2019 (Actual)

Study Completion Date

January 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Joseph J. Cullen

Collaborators

Holden Comprehensive Cancer Center, Gateway for Cancer Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pancreatic Neoplasms

Keywords

Ascorbate, Vitamin C, Radiation, Gemcitabine, Ascorbic Acid

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

16 (Actual)

8. Arms, Groups, and Interventions

Arm Title

50g Ascorbate

Arm Type

Experimental

Arm Description

Arm Title

75g Ascorbate

Arm Type

Experimental

Arm Description

Arm Title

100g Ascorbate

Arm Type

Experimental

Arm Description

Arm Title

25g Ascorbate

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ascorbate

Other Intervention Name(s)

Ascorbic Acid, Vitamin C

Intervention Description

Intravenous infusion of high-dose ascorbate

Intervention Type

Drug

Intervention Name(s)

Gemcitabine

Other Intervention Name(s)

Gemzar

Intervention Description

Intravenous chemotherapeutic

Intervention Type

Radiation

Intervention Name(s)

Radiation therapy

Other Intervention Name(s)

External beam radiation therapy, Intensity modulated radiation therapy, IMRT

Primary Outcome Measure Information:

Title

Number of grade 3, 4, & 5 adverse events during radiation

Description

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).

Time Frame

Weekly during therapy for up to 10 weeks

Secondary Outcome Measure Information:

Title

Time to progression

Description

Time from the start of therapy (radiation day 1) to documented disease progression as described by RECIST.

Time Frame

Monthly, up to 10 years post-treatment

Title

Overall survival

Description

From start of treatment (radiation day 1) until the date of death from any cause.

Time Frame

Monthly, up to 10 years post-treatment

Title

Number of grade 3, 4, & 5 adverse events post-treatment

Description

Time Frame

every 3 months for 2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joseph J Cullen, MD, FACS

Organizational Affiliation

The University of Iowa Hospitals & Clinics

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Holden Comprehensive Cancer Center

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52242

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Data will be shared as per approved IRB application and the subject's opt-in preferences. Data will not be provided from subjects who decline data sharing.

IPD Sharing Time Frame

After completion of primary outcome.

IPD Sharing Access Criteria

Interested researchers should contact the study PI. A non-disclosure may need to be filed dependent upon data requested.

Citations:

PubMed Identifier

23381814

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.

Results Reference

background

PubMed Identifier

22728050

Citation

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.

Results Reference

background

PubMed Identifier

20400857

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.

Results Reference

background

PubMed Identifier

20068072

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.

Results Reference

background

PubMed Identifier

30254147

Citation

Alexander MS, Wilkes JG, Schroeder SR, Buettner GR, Wagner BA, Du J, Gibson-Corley K, O'Leary BR, Spitz DR, Buatti JM, Berg DJ, Bodeker KL, Vollstedt S, Brown HA, Allen BG, Cullen JJ. Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer. Cancer Res. 2018 Dec 15;78(24):6838-6851. doi: 10.1158/0008-5472.CAN-18-1680. Epub 2018 Sep 25.

Results Reference

result

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

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