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

• ClinicalTrials.gov Identifier: NCT03146962
• Recruitment Status: Completed
• First Posted: May 10, 2017
• Results First Posted: May 2, 2024
• Last Update Posted: May 2, 2024
• Sponsor: Weill Medical College of Cornell University
• Collaborator: Stand Up To Cancer
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Cancer; Pancreatic Cancer; Lung Cancer	Drug: Vitamin C	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of High Dose Vitamin C Intravenous Infusion in Patients With Resectable or Metastatic Solid Tumor Malignancies
• Actual Study Start Date: March 29, 2017
• Actual Primary Completion Date: April 21, 2023
• Actual Study Completion Date: April 21, 2023

Arms and Interventions

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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: Ascorbic Acid

Outcome Measures

Primary Outcome Measures :

1. Pathologic Response Based on Tumor Regression Grading in Cohort A Patients [ Time Frame: cohort A - 8 weeks ]
   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.
2. 3-month Disease Control Rate (DCR) Will be Evaluated Using RECIST v 1.1 in Cohort B Patients. [ Time Frame: Cohort B - 3 months ]
   Percentage of patients with complete response, partial response, or stable disease as a result of their therapy at 3 months
3. Maximal Tolerated Dose of High Dose Vitamin C in Combination With Y90 Radioembolization [ Time Frame: Cohort C - 16 weeks ]
   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.

Secondary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: cohort B - up to 6 months ]
   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.
2. Objective Response Rate (ORR) [ Time Frame: cohort B - up to 6 months cohort C - 16 weeks ]
   Number of patients with a partial response or complete response based on RECIST 1.1 Criteria.
3. Time to Maximum Concentration and Half-life of Vitamin C (t1/2) in Hours in Cohort B [ Time Frame: Up to 24 hours post-infusion ]
   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
4. Safety of High Dose Vitamin C Administration Using CTCAE 4.03. [ Time Frame: 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. ]
   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.
5. Maximum Concentration of Vitamin C in Hours in Cohort B [ Time Frame: Up to 24 hours post-infusion ]
   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.

Other Outcome Measures:

1. In Vitro Activity of Vitamin C in Tumor Organoids [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months ]
   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.
2. Exploratory Biomarker Samples From Tumor Tissue Will be Collected at the Time Points Specified in the Protocol [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks ]
   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.
3. Pharmacodynamic Samples From Tumor Tissue Will be Collected at the Time Points Specified in the Protocol. [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks ]
   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.

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, New York

New York-Presbyterian Brooklyn Methodist Hospital

Brooklyn, New York, United States, 11215

Weill Cornell Medical College

New York, New York, United States, 10065

Sponsors and Collaborators

Weill Medical College of Cornell University

Stand Up To Cancer

Investigators

• Principal Investigator: Manish Shah, MD; Weill Medical College of Cornell University

  Study Documents (Full-Text)

Documents provided by Weill Medical College of Cornell University:

Study Protocol and Statistical Analysis Plan  [PDF] March 8, 2022

More Information

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT03146962
• Other Study ID Numbers: 1610017688
• First Posted: May 10, 2017
• Results First Posted: May 2, 2024
• Last Update Posted: May 2, 2024
• Last Verified: April 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Ascorbic Acid; Vitamins; Micronutrients; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents