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A Clinical Trial Evaluating the Effect of Pharmacological Ascorbate on Radiation Therapy for Pancreatic Cancer Patients (XACT-PANC-2)

Primary Purpose

Pancreatic Neoplasm

Status

Not yet recruiting

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Ascorbate

Gemcitabine

radiation therapy

About this trial

This is an interventional treatment trial for Pancreatic Neoplasm focused on measuring ascorbic acid, ascorbate, sodium ascorbate, radiotherapy, radiotherapy, image-guided, gemcitabine, adverse event, quality of life, radiation enteropathy

Eligibility Criteria

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

Inclusion Criteria:

To be eligible to participate in this study, an individual must meet ALL of the following criteria:

Ability and willingness to provide informed consent (power of attorney and legally authorized representatives are not accepted for informed consent)
Stated willingness to comply with all study procedures and availability for duration of the study
At least 18 years of age
Histologic or cytologic diagnosis of pancreatic adenocarcinoma
Referral for gemcitabine-based chemoradiation
Good performance status (ECOG of 0, 1, or 2; KPS of > 50)
No other active malignancy that requires immediate treatment. Slow growing concurrent cancers (such as prostate cancer) are acceptable with appropriate documentation from their treating oncologists for that primary.
Not experiencing an uncontrolled illness such as infection requiring inpatient admission, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other condition that would limit compliance with the study requirements or unacceptably increase risk to the participant (as determined by study team members).
Agree to abstain from alcohol and specified over the counter supplements during study treatment

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participating in this study:

Glucose-6-phosphate dehydrogenase (G6PD) deficiency
HIV positive individuals requiring anti-retroviral drug therapy (high-dose ascorbate is known to interact with many of these drugs)
Platelet count of <100,000 k/mm3
Prior radiation that would result in field overlap (this will be determined by the study's radiation oncologist)
Presence of metastatic disease beyond regional lymphatics
Actively receiving insulin
Other therapy (including radiation therapy) within 2 calendar weeks of study therapy
On any of the following drugs and cannot or will not accept a drug substitution: warfarin, flecainide, methadone, amphetamines, quinidine, and chlorpropamide
Other investigational agents (PET or SPECT imaging agents are acceptable)
Other investigational therapy with the intention to treat the disease under study
Pregnancy
Individuals declining to use acceptable birth control during the duration of the study
Lactating women who decline to discontinue breastfeeding their child (women may withhold breast feeding and resume under the direction of their medical oncologist after completion of study)

Sites / Locations

The University of Iowa

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Investigational Therapy (ASC)

Standard Therapy (ChemoRT)

Arm Description

75 grams of pharmacological ascorbate, daily (M-F) 600 mg/m2 of gemcitabine, once a week for up to 6 weeks 50 to 50.4 Gray of radiation therapy delivered using a volumetric arc therapy (VMAT) technique

600 mg/m2 of gemcitabine, once a week for up to 6 weeks 50 to 50.4 Gray of radiation therapy delivered using a volumetric arc therapy (VMAT) technique

Outcomes

Primary Outcome Measures

Overall survival (OS)

The study will determine the time (calculated in months) between study day 1 and death from any cause. After 10 years post-treatment, dates will be censored to date of last follow-up

Secondary Outcome Measures

Progression free survival (PFS)

From radiation day 1 to documented disease progression in CT imaging as described by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Measured in months.

Toxicity over time (ToxT)

Toxicity over time will be assessed by summarizing treatment emergent adverse events by system organ class and/or preferred term, type of adverse event, and severity. Elapsed days of toxicity will be summarized.

Metastasis free survival (MFS)

time from treatment initiation (day 1) to the date of first documentation of disease progression outside of the pelvis (per RECIST 1.1)

Resection rate

Rate of patients who undergo resection of tumor

Adverse event frequency and categorization

Categorize and quantify adverse events using the Common Terminology Criteria for Adverse Events (CTCAE, v 5)

Patient reported outcome measure: Vaizey Incontinence questionnaire

Patient reported outcome measure of bowel side effects collected at pre-specified timepoints.

Quality of life: Modified Inflammatory Bowel Disease questionnaire

Patient completed quality of life form collected at pre-specified timepoints.

Pathologic characteristics

• Mucosal ulcerations, inflammatory cell infiltration, collage deposition, and microvascular changes will be assessed

Full Information

NCT ID

NCT03541486

First Posted

April 29, 2018

Last Updated

February 16, 2023

Sponsor

Joseph J. Cullen, MD, FACS

Collaborators

Holden Comprehensive Cancer Center

1. Study Identification

Unique Protocol Identification Number

NCT03541486

Brief Title

A Clinical Trial Evaluating the Effect of Pharmacological Ascorbate on Radiation Therapy for Pancreatic Cancer Patients

Acronym

XACT-PANC-2

Official Title

XACT-Pancreas 2: Pharmacological Ascorbate, Gemcitabine, and Radiation Therapy for Pancreatic Cancer, Phase 2

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Not yet recruiting

Study Start Date

December 31, 2025 (Anticipated)

Primary Completion Date

December 31, 2029 (Anticipated)

Study Completion Date

December 31, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Joseph J. Cullen, MD, FACS

Collaborators

Holden Comprehensive Cancer Center

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

Radiation therapy improves cancer cure rates by killing cancer cells but it also contributes to long-term side effects in cancer survivors by unintentionally damaging normal organs such as the intestine. This research will what side effects patients with cancer experience, if high dose vitamin C helps reduce these side effects, and if high dose vitamin C increases the survival of patients with pancreatic cancer. We will meet with patients during the study to better understand their experience during their cancer treatment. In the long term, our research could provide a new way help cancer survivors avoid many permanent side effects of cancer treatments.

Detailed Description

This is a randomized phase 2 study is designed to determine initial efficacy and assess adverse events, and quantify pathologic evidence of intestinal radiation injury. The ascorbate is infused before, during, and after the external beam radiation therapy treatment. Each ascorbate infusion is 75 grams (roughly the same amount of vitamin C from 1,000 oranges). For patients eligible for this trial, standard treatment for their cancer includes radiation therapy combined with weekly gemcitabine (a chemotherapy). Participants will: be randomized (like flipping a coin) to receive the investigational treatment (pharmacological ascorbate plus gemcitabine plus radiation) or standard treatment only (gemcitabine plus radiation) receive gemcitabine (a chemotherapy) once a week for up to 6 weeks of therapy (all participants) receive radiation treatments are given once a day, Monday through Friday (all participants). have routine doctor's visits and be asked about any side effects they are experiencing (all participants). be interviewed to discuss their side effects, how it impacts their life, and describe their recent activities. receive pharmacological ascorbate intravenously ascorbate during their daily radiation therapy treatments (if randomized to receive the investigational treatment). Once the patient completes radiation, the ascorbate infusions are also completed. However, the patient will need to return for regular follow-up care at University of Iowa. We are interested in the long-term side effects of radiation - which may not develop for years - so it is important the participant return to radiation oncology for follow-up. We will also conduct interviews at that time to review the side effects and how they impact the participant's quality of life.

6. Conditions and Keywords

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

Pancreatic Neoplasm

Keywords

ascorbic acid, ascorbate, sodium ascorbate, radiotherapy, radiotherapy, image-guided, gemcitabine, adverse event, quality of life, radiation enteropathy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Randomized trial (standard vs. experimental) in a one-to-one ratio.

Masking

Outcomes Assessor

Masking Description

Radiologic measurements will be completed by a reviewer blinded to treatment assignment

Allocation

Randomized

Enrollment

60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Investigational Therapy (ASC)

Arm Type

Experimental

Arm Description

Arm Title

Standard Therapy (ChemoRT)

Arm Type

Active Comparator

Arm Description

600 mg/m2 of gemcitabine, once a week for up to 6 weeks 50 to 50.4 Gray of radiation therapy delivered using a volumetric arc therapy (VMAT) technique

Intervention Type

Drug

Intervention Name(s)

Ascorbate

Other Intervention Name(s)

Ascor L 500, Pharmacological ascorbate, Vitamin C

Intervention Description

75 gram infusion daily (M-F) on days when radiation therapy is administered. The infusion occurs during the 'beam on' of the radiation therapy.

Intervention Type

Drug

Intervention Name(s)

Gemcitabine

Other Intervention Name(s)

Gemzar

Intervention Description

600 mg/m2 once weekly for up to weeks

Intervention Type

Radiation

Intervention Name(s)

radiation therapy

Other Intervention Name(s)

Volumetric Arc Therapy (VMAT), External beam radiation therapy

Intervention Description

Prescribed to 50 Gy in 25 fractions. Radiation is delivered 1 fraction/day, 5 days a week, for approximately 5 to 6 weeks.

Primary Outcome Measure Information:

Title

Overall survival (OS)

Description

The study will determine the time (calculated in months) between study day 1 and death from any cause. After 10 years post-treatment, dates will be censored to date of last follow-up

Time Frame

Up to 5 years post treatment

Secondary Outcome Measure Information:

Title

Progression free survival (PFS)

Description

From radiation day 1 to documented disease progression in CT imaging as described by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Measured in months.

Time Frame

Up to 5 years post-treatment

Title

Toxicity over time (ToxT)

Description

Time Frame

Treatment day 1 to 30 days post-treatment

Title

Metastasis free survival (MFS)

Description

time from treatment initiation (day 1) to the date of first documentation of disease progression outside of the pelvis (per RECIST 1.1)

Time Frame

Up to 5 years post-treatment

Title

Resection rate

Description

Rate of patients who undergo resection of tumor

Time Frame

Within 2 month post-radiation

Title

Adverse event frequency and categorization

Description

Categorize and quantify adverse events using the Common Terminology Criteria for Adverse Events (CTCAE, v 5)

Time Frame

Weekly for the first 6 weeks and then at follow-up through 5 years post-treatment

Title

Patient reported outcome measure: Vaizey Incontinence questionnaire

Description

Patient reported outcome measure of bowel side effects collected at pre-specified timepoints.

Time Frame

Treatment day 1 to 5 years post-treatment

Title

Quality of life: Modified Inflammatory Bowel Disease questionnaire

Description

Patient completed quality of life form collected at pre-specified timepoints.

Time Frame

Treatment day 1 to 5 years post-treatment

Title

Pathologic characteristics

Description

• Mucosal ulcerations, inflammatory cell infiltration, collage deposition, and microvascular changes will be assessed

Time Frame

At surgery

Other Pre-specified Outcome Measures:

Title

Exploration of patient reported outcomes during combined therapy [qualitative string]

Description

Semi-structured one-on-one interviews for thematic analysis

Time Frame

During treatment phase and up to 5 years post-treatment

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: To be eligible to participate in this study, an individual must meet ALL of the following criteria: Ability and willingness to provide informed consent (power of attorney and legally authorized representatives are not accepted for informed consent) Stated willingness to comply with all study procedures and availability for duration of the study At least 18 years of age Histologic or cytologic diagnosis of pancreatic adenocarcinoma Referral for gemcitabine-based chemoradiation Good performance status (ECOG of 0, 1, or 2; KPS of > 50) No other active malignancy that requires immediate treatment. Slow growing concurrent cancers (such as prostate cancer) are acceptable with appropriate documentation from their treating oncologists for that primary. Not experiencing an uncontrolled illness such as infection requiring inpatient admission, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other condition that would limit compliance with the study requirements or unacceptably increase risk to the participant (as determined by study team members). Agree to abstain from alcohol and specified over the counter supplements during study treatment Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participating in this study: Glucose-6-phosphate dehydrogenase (G6PD) deficiency HIV positive individuals requiring anti-retroviral drug therapy (high-dose ascorbate is known to interact with many of these drugs) Platelet count of <100,000 k/mm3 Prior radiation that would result in field overlap (this will be determined by the study's radiation oncologist) Presence of metastatic disease beyond regional lymphatics Actively receiving insulin Other therapy (including radiation therapy) within 2 calendar weeks of study therapy On any of the following drugs and cannot or will not accept a drug substitution: warfarin, flecainide, methadone, amphetamines, quinidine, and chlorpropamide Other investigational agents (PET or SPECT imaging agents are acceptable) Other investigational therapy with the intention to treat the disease under study Pregnancy Individuals declining to use acceptable birth control during the duration of the study Lactating women who decline to discontinue breastfeeding their child (women may withhold breast feeding and resume under the direction of their medical oncologist after completion of study)

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Joseph Caster, MD, PhD

Phone

319-353-8836

joseph-caster@uiowa.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Joseph J. Cullen, MD, FACS

Phone

(319) 353-8297

joseph-cullen@uiowa.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Joseph Caster, MD, PhD

Organizational Affiliation

University of Iowa

Official's Role

Principal Investigator

Facility Information:

Facility Name

The University of Iowa

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52242

Country

United States

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Sandy Vollstedt, RN, BSN, OCN

Phone

319-353-7143

sandy-vollstedt@uiowa.edu

First Name & Middle Initial & Last Name & Degree

Heather Brown, RN, BAN, OCN

Phone

319-384-7912

heather-brown@uiowa.edu

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

All collected IPD, including endpoints (OS, PFS, MFS, AE, and PROs), treatment information, coding, code book, and demographics.

IPD Sharing Time Frame

Study protocol and consent will be shared after primary completion. Statistical analysis plan will be shared with results reporting. Data are available upon request and will be available for 2 years after the withdraw of the IND.

IPD Sharing Access Criteria

An IRB-stamped signed usage agreement will be required in addition to a data sharing agreement between the academic centers. Interested researchers should contact Dr. Caster or Dr. Cullen

Citations:

PubMed Identifier

28366679

Citation

Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, Sandhu S, Carlisle TL, Smith MC, Abu Hejleh T, Berg DJ, Zhang J, Keech J, Parekh KR, Bhatia S, Monga V, Bodeker KL, Ahmann L, Vollstedt S, Brown H, Shanahan Kauffman EP, Schall ME, Hohl RJ, Clamon GH, Greenlee JD, Howard MA, Schultz MK, Smith BJ, Riley DP, Domann FE, Cullen JJ, Buettner GR, Buatti JM, Spitz DR, Allen BG. O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 2017 Apr 10;31(4):487-500.e8. doi: 10.1016/j.ccell.2017.02.018. Epub 2017 Mar 30. Erratum In: Cancer Cell. 2017 Aug 14;32(2):268.

Results Reference

background

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

27833040

Citation

Doskey CM, Buranasudja V, Wagner BA, Wilkes JG, Du J, Cullen JJ, Buettner GR. Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy. Redox Biol. 2016 Dec;10:274-284. doi: 10.1016/j.redox.2016.10.010. Epub 2016 Oct 28.

Results Reference

background

PubMed Identifier

26201606

Citation

Cieslak JA, Cullen JJ. Treatment of Pancreatic Cancer with Pharmacological Ascorbate. Curr Pharm Biotechnol. 2015;16(9):759-70. doi: 10.2174/138920101609150715135921.

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

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A Clinical Trial Evaluating the Effect of Pharmacological Ascorbate on Radiation Therapy for Pancreatic Cancer Patients

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