High Dose Vitamin C Intravenous Infusion in Patients With... | NCT03146962

NCT03146962

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Stand Up To Cancer	OTHER

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort A: Vitamin C + Surgery	Experimental	Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks.	Drug: Vitamin C
Cohort B: Vitamin C Only	Experimental	Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for up to 6 months.	Drug: Vitamin C
Cohort C: Vitamin C + Y-90 Dose Level 1	Experimental	Vitamin C will be administered at a dose of 0.5 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C.	Drug: Vitamin C
Cohort C: Vitamin C + Y-90 Dose Level 2	Experimental	Vitamin C will be administered at a dose of 0.75 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C.	Drug: Vitamin C
Cohort C: Vitamin C + Y-90 Dose Level 3	Experimental	Vitamin C will be administered at a dose of 0.75 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C. A single dose of Vitamin C at 0.5g/kg will also be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Vitamin C	Drug	Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks (cohort A) or up to 6 months (cohort B). Cohort C will receive high dose vitamin C for 1-3 weeks. During week 1 vitamin C infusion and Y90 radioembolization of hepatic metastases will occur same day.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Pathologic Response Based on Tumor Regression Grading in Cohort A Patients	Number of patients with partial or complete pathological response in surgically resected tumor tissue: Pathological response rate is the number of patients with partial or complete pathological response in surgically resected tumor tissue. Pathologic response was assessed by tumor regression grade. This is a pathologic assessment of the amount of residual cancer cells in the specimen and the degree of fibrosis in the sample specimen. A completer response is 0% residual cancer cells. A partial response is 10-50% residual cancer cells, and no response is >50% residual cancer cells within the tumor specimen.	cohort A - 8 weeks
3-month Disease Control Rate (DCR) Will be Evaluated Using RECIST v 1.1 in Cohort B Patients.	Percentage of patients with complete response, partial response, or stable disease as a result of their therapy at 3 months	Cohort B - 3 months
Maximal Tolerated Dose of High Dose Vitamin C in Combination With Y90 Radioembolization	Maximal tolerated dose will be evaluated by assessment of dose limiting toxicities for multiple dose levels. Dose limiting toxicity will be defined as any grade 3-4 adverse event possibly, probably, or definitely attributed to vitamin C therapy in the 21 days of protocol therapy. In any group of 3 patients, if one patient experiences dose limiting toxicity, the group will be expanded by 3 additional patients (eg. 6 for that group). If, at any dose level, 2 or more patients experience a dose limiting toxicity, the maximal tolerated dose will be reached, and further dose escalation will not be pursued. The dose level may then be expanded up to 10 additional patients to confirm the safety and toxicity at that dose level.	Cohort C - 16 weeks

Secondary Outcomes

Measure	Description	Time Frame
Progression-free Survival (PFS)	PFS is defined as the time from registration to cancer progression or death due to any cause for up to 6 months. Cancer progression is defined using the Response Evaluation Criteria in Solid Tumors v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in non-target lesions, or the appearance of new lesions.	cohort B - up to 6 months

Other Outcomes

Measure	Description	Time Frame
In Vitro Activity of Vitamin C in Tumor Organoids	Molecular signature of vitamin C efficacy will be determined using RNA sequencing and compared between KRAS or BRAF mutant vs wild type tumors. Organoids will be prepared from resected tumor samples and treated with vitamin C.	cohort A - 8 weeks, cohort B - up to 6 months

Eligibility Module

Eligibility Criteria

Inclusion Criteria

Male or female ≥ 18 years of age.
Patients with histologically proven early stage or locally advanced colorectal adenocarcinoma, lung cancer or pancreatic cancer, who are eligible for resection (cohort A).
Patients with inoperable, metastatic extended RAS (e.g. KRAS or NRAS) or BRAF mutant colorectal adenocarcinoma, lung cancer and pancreatic cancer, or other solid tumor, who have received at least 1 line of treatment for metastatic disease (cohort B).
Patients with metastatic cancer with an extended RAS (e.g. KRAS or NRAS) or BRAF mutation with liver metastases amenable to Y90 radioembolization (cohort C).
ECOG performance status 0-1.
Life expectancy of at least 6 months.
All women of child-bearing potential and all sexually active male patients must agree to use effective contraception.

Exclusion Criteria:

Patients with uncontrolled intercurrent illness including, but not limited to uncontrolled infection, symptomatic congestive heart failure (NYHA class III and IV), uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements (Appendix B: New York Heart Association (NYHA) Classifications).
Patients with active heart disease including myocardial infarction within previous 3 months, symptomatic coronary artery disease, arrhythmias not controlled by medication, unstable angina pectoris, or uncontrolled congestive heart failure (NYHA class III and IV) (Appendix B: New York Heart Association (NYHA) Classifications).
Patients who have received an investigational drug within 21 days of the first dose of study drug.
Patients who are pregnant or lactating.
Patients who are known to be positive for the human immunodeficiency virus (HIV). The effect of Vitamin C on HIV medications is unknown. Note: HIV testing is not required for eligibility, but if performed previously and was positive, the patient is ineligible for the study.
Patient who are receiving drugs which are known to interact with Vitamin C, potential risk and eligibility will be evaluated individually by the investigator. a. Most of the known interactions with vitamin C are from oral use and acidification of the stomach lining. There are few known interactions with high dose intravenous vitamin C. We recommend not using deferoxamine as there may be an association with ventricular dysfunction (unknown mechanism).
Patients who have uncontrolled or severe hyponatremia, hypernatremia, SIADH, hypokalemia, hyperkalemia, hypomagnesemia, or hypermagnesemia
Patients who have uncontrolled or severe coagulopathies or a history of clinically significant bleeding within the past 6 months, such as hemoptysis, epistaxis, hematochezia, hematuria, or gastrointestinal bleeding.
Patients who require therapeutic doses of warfarin
Patients who have uncontrolled seizure disorder, ascites, iron overload, edema, or dehydration.
Patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis, or other conditions predisposing patient to hemolysis.
Patients who have a known history of recurrent oxalate renal calculi or multiple oxalate.

Name	Affiliation	Role
Manish Shah, MD	Weill Medical College of Cornell University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
New York-Presbyterian Brooklyn Methodist Hospital		Brooklyn	New York	11215	United States
Weill Cornell Medical College

Arm/Group Information

ID	Title	Description
FG000	Cohort A: Vitamin C + Surgery	Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks. Vitamin C: Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks (cohort A) or up to 6 months (cohort B). Cohort C will receive high dose vitamin C for 1-3 weeks. During week 1 vitamin C infusion and Y90 radioembolization of hepatic metastases will occur same day.
FG001	Cohort B: Vitamin C Only	Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for up to 6 months. Vitamin C: Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks (cohort A) or up to 6 months (cohort B). Cohort C will receive high dose vitamin C for 1-3 weeks. During week 1 vitamin C infusion and Y90 radioembolization of hepatic metastases will occur same day.
FG002	Cohort C: Vitamin C + Y-90 Dose Level 1	Vitamin C will be administered at a dose of 0.5 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C.
FG003	Cohort C: Vitamin C + Y-90 Dose Level 2	Vitamin C will be administered at a dose of 0.75 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C.
FG004	Cohort C: Vitamin C + Y-90 Dose Level 3	Vitamin C will be administered at a dose of 0.75 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C. A single dose of Vitamin C at 0.5g/kg will also be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment.
FG005	Cohort C: Vitamin C + Y-90 Dose Level 4	Vitamin C will be administered at a dose of 1 g/kg intravenously for 4 days /week for 1-2 weeks prior to and following Y90 therapy for a total of 4 weeks of vitamin C. A single dose of Vitamin C at 0.5g/kg will also be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment.
FG006	Cohort C: Vitamin C + Y-90 Dose Level 5	A single dose of Vitamin C at 0.75g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy.
FG007	Cohort C: Vitamin C + Y-90 Dose Level 6	A single dose of Vitamin C at 0.75g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1.25 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy.
FG008	Cohort C: Vitamin C + Y-90 Dose Level 7	A single dose of Vitamin C at 1g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1.25 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy.
FG009	Cohort C: Vitamin C + Y-90 Dose Level 8	A single dose of Vitamin C at 1.25g/kg will be administered on the day of Y90 radioembolization, administered prior to or within 24 hours of a Y90 treatment. Vitamin C will also be administered at a dose of 1.25 g/kg intravenously for 4 days/week for 1-2 weeks following Y90 therapy.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Cohort A: Vitamin C + Surgery	Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks. Vitamin C: Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks (cohort A) or up to 6 months (cohort B). Cohort C will receive high dose vitamin C for 1-3 weeks. During week 1 vitamin C infusion and Y90 radioembolization of hepatic metastases will occur same day.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Pathologic Response Based on Tumor Regression Grading in Cohort A Patients

Number of patients with partial or complete pathological response in surgically resected tumor tissue: Pathological response rate is the number of patients with partial or complete pathological response in surgically resected tumor tissue. Pathologic response was assessed by tumor regression grade. This is a pathologic assessment of the amount of residual cancer cells in the specimen and the degree of fibrosis in the sample specimen. A completer response is 0% residual cancer cells. A partial response is 10-50% residual cancer cells, and no response is >50% residual cancer cells within the tumor specimen.

Only the 6 patients who had surgery from Cohort A, and thus had evaluable tissue, were analyzed for this measure. Participants in Cohort B and C did not undergo surgery, and were thus not evaluable.

Posted

Count of Participants

Participants

cohort A - 8 weeks

ID	Title	Description
OG000	Cohort A: Vitamin C + Surgery

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Cohort A: Vitamin C + Surgery	Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks. Vitamin C: Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks (cohort A) or up to 6 months (cohort B). Cohort C will receive high dose vitamin C for 1-3 weeks. During week 1 vitamin C infusion and Y90 radioembolization of hepatic metastases will occur same day.

ID	Term
D015179	Colorectal Neoplasms
D010190	Pancreatic Neoplasms
D008175	Lung Neoplasms

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site

ID	Term
D013400	Sugar Acids
D000144	Acids, Acyclic
D002264	Carboxylic Acids
D009930	Organic Chemicals