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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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Colorectal Cancer, Pancreatic Cancer, Lung Cancer

Intervention / Treatment
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* Drug: Vitamin C


Participation Criteria
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Eligibility Criteria
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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). Note: If subject refuses chemotherapy and therefore has no prior chemotherapy, they can be eligible for the trial with approval from the primary investigator. 3.1 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. Patient with adequate organ and marrow function as follows: ANC ≥ 1000 mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9 g/dL, serum creatinine ≤1.8 mg/dL or creatinine clearance > 50 mL/min (Appendix C: Estimating Creatinine Clearance); bilirubin ≤ 1.5 mg/dL; alanine aminotransferase (ALT), aspartate transaminase (AST) ≤ 2.5 times the upper limit of normal if no liver involvement or ≤ 5 times the upper limit of normal with liver involvement. Patients with serum electrolytes (including calcium, magnesium, phosphorous, sodium and potassium) within normal limits (supplementation to maintain normal electrolytes is allowed). Patients taking Vitamin C will have stopped taking oral vitamin C more than 1 week before planned study treatment. Patients capable of understanding and complying with the protocol and who have signed the informed consent document. 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). 4. Patients who have received an investigational drug within 21 days of the first dose of study drug. 5. Patient who have not recovered to grade ≤ 1 from adverse events (AEs) due to investigational drugs or other medications, which were administered more than 4 weeks prior to the first dose of study drug. 6. Patients who are pregnant or lactating. 7. 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. 8. Patients who have the inability or unwillingness to abide by the study protocol or cooperate fully with the investigator or designee. 9. 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). 10. Patients who have uncontrolled or severe hyponatremia, hypernatremia, SIADH, hypokalemia, hyperkalemia, hypomagnesemia, or hypermagnesemia 11. 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. 12. Patients who require therapeutic doses of warfarin is prohibited. 13. Patients who have uncontrolled seizure disorder, ascites, iron overload, edema, or dehydration. 14. Patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis, or other conditions predisposing patient to hemolysis. 15. Patients who have a known history of recurrent oxalate renal calculi or multiple oxalate.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: All Subjects<br>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. | Drug: Vitamin C<br>* 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.<br>* Other names: Ascorbic Acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in antitumor activity measured by pathologic response based on tumor regression grading in cohort A patients. | measured by tissue analysis of tumor cell death and fibrotic response in Cohort A subjects | cohort A - 8 weeks | 
| 3-month disease control rate (DCR) will be evaluated using RECIST v 1.1 in cohort B patients. | Examination of subjects with stable disease, a partial response, or complete response. | 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 | Cohort C - 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Defined as the time from registration to cancer progression or death due to any cause | cohort B - up to 6 months cohort C - 16 weeks | 
| Objective response rate (ORR) | Examination 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 | 
| Assessment of pharmacokinetics of high dose vitamin C plasma levels concentrations |  | cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks | 
| Safety of high dose vitamin C administration using CTCAE 4.03. |  | cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks |