High Dose Vitamin C Intravenous Infusion in Patients With Resectable or Metastatic Solid Tumor Malignancies

A Phase II Study of High Dose Vitamin C Intravenous Infusion in Patients With Resectable or Metastatic Solid Tumor Malignancies

This is a multicenter, single arm, 3-cohort, open-label trial of high dose Vitamin C intravenous infusion in subjects with solid tumor malignancies who are eligible for resection (cohort A) or with extended RAS (e.g.KRAS or NRAS) or BRAF mutation metastatic cancer who have received prior systemic treatment (cohort B). Cohort C will involve patients with colorectal cancer having an extended RAS or BRAF mutation who are amenable for localregional therapy of hepatic metastases with Yttrium-90 radioembolization.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Pancreatic Cancer; Lung Cancer
• Intervention / Treatment: Drug: Vitamin C

Detailed Description

This clinical trial is for men and women with resectable or metastatic solid tumor malignancies. The objective of the study is to investigate whether high dose vitamin C infusion leads to pathological tumor response in resectable colorectal, pancreatic, and lung cancer (cohort A) or objective tumor response in KRAS or BRAF mutant solid tumors (cohort B). For Cohort C, the primary objective is to determine that maximal tolerated dose of the combination of high dose vitamin C with Y90 radioembolization for patients solid tumor malignancies and liver metastases amenable to local-regional therapy

Patients in cohort A receive a high dose vitamin C infusion for 4 days per week for 2-4 consecutive weeks prior to surgery. Patients in cohort B receive high dose vitamin C infusion for 4 days per week for up to 6 months or disease progression. 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.

A tumor sample will be resected after completion of study drug (high dose vitamin C infusion) treatment to examine the effects of study drug (Cohort A only). In addition, organoids will be grown in vitro and continue to be treated with vitamin C added in culture medium to examine tumor response. The resected tumor in this study will

Key eligibility:

• Men and women age 18 and older
• Patients with histologically proven early stage or locally advanced colorectal adenocarcinoma, lung cancer or pancreatic cancer, who are eligible for resection, and have not received chemotherapy or radiotherapy (cohort A) Patients with inoperable, metastatic, KRAS or BRAF mutant colorectal adenocarcinoma, lung cancer and pancreatic cancer, 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).

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Brooklyn, New York, United States, 11215
      • New York-Presbyterian Brooklyn Methodist Hospital
    • New York, New York, United States, 10065
      • Weill Cornell Medical College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid
Experimental: 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.	Drug: 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.; Other Names: Ascorbic Acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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 Outcome Measures

Outcome Measure	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
Objective Response Rate (ORR)	Number of patients with a partial response or complete response based on RECIST 1.1 Criteria.	cohort B - up to 6 months cohort C - 16 weeks
Time to Maximum Concentration and Half-life of Vitamin C (t1/2) in Hours in Cohort B	The serum concentration of vitamin C was serially measured following vitamin C infusion at 1.25 g/kg at various timepoints up to 24 hours post infusion to determine the Tmax and t(1/2) in hours	Up to 24 hours post-infusion
Safety of High Dose Vitamin C Administration Using CTCAE 4.03.	The number of participants per cohort who experienced a Grade 3 or 4 adverse event (as defined by CTCAE v4.03) that was deemed possibly, probably, or definitely related to Vitamin C.	Adverse events were assessed from the start of study treatment to 30 days after the last infusion of vitamin C. For Cohort A and C, this was approximately 2 months. For Cohort B this was about a 6 month duration.
Maximum Concentration of Vitamin C in Hours in Cohort B	The serum concentration of vitamin C was serially measured following vitamin C infusion at 1.25 g/kg at various timepoints up to 24 hours post infusion to determine the maximum concentration (Cmax) in mM.	Up to 24 hours post-infusion

Other Outcome Measures

Outcome Measure	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
Exploratory Biomarker Samples From Tumor Tissue Will be Collected at the Time Points Specified in the Protocol	To explore potential correlation of gene expression pattern with anti-tumor activity of vitamin C, we plan to perform RNA sequencing using surgical sample in cohort A patients who will receive vitamin C infusion pre-operatively.	cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks
Pharmacodynamic Samples From Tumor Tissue Will be Collected at the Time Points Specified in the Protocol.	Immunohistochemical (IHC) staining for GLUT1 protein expression will be performed on Formalin Fixed Paraffin Embedded (FFPE) tumor tissues. Immunohistochemical (IHC) staining for phosphor-AMPK will be performed on Formalin Fixed Paraffin Embedded (FFPE) tumor tissues to assess AMPK activation.	cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Collaborators: Stand Up To Cancer
• Investigators: Principal Investigator: Manish Shah, MD, Weill Medical College of Cornell University

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2017
• Primary Completion (Actual): April 21, 2023
• Study Completion (Actual): April 21, 2023

Study Registration Dates

• First Submitted: April 27, 2017
• First Submitted That Met QC Criteria: May 9, 2017
• First Posted (Actual): May 10, 2017

Study Record Updates

• Last Update Posted (Estimated): May 2, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Protective Agents; Micronutrients; Vitamins; Antioxidants; Ascorbic Acid
• Other Study ID Numbers: 1610017688

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No