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

• ClinicalTrials.gov Identifier: NCT03146962
• Recruitment Status: Recruiting
• First Posted: May 10, 2017
• Last Update Posted: July 29, 2019
• Sponsor: Weill Medical College of Cornell University
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

Brief Summary:

This is a single arm, 2-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 KRAS or BRAF mutant metastatic cancer who have received prior systemic treatment (cohort B).

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).

Patients enrolled in cohort A will receive high dose Vitamin C infusion for 4 days per week for 2-4 consecutive weeks prior to surgery. Patients enrolled in cohort B will receive high dose Vitamin C infusion for 4 days per week up to 6 months. 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)

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Intervention Model: Single Group 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
• Estimated Primary Completion Date: December 2019
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: All Subjects; 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).	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).; Other Name: Ascorbic Acid

Outcome Measures

Primary Outcome Measures :

1. Preliminary antitumor activity measured by pathologic response based on tumor regression grading in cohort A patients. 3-month disease control rate (DCR) will be evaluated using RECIST v 1.1 in cohort B patients. [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months ]

Secondary Outcome Measures :

1. Progression-free survival (PFS) in cohort B. [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months ]
2. Objective response rate (ORR) in cohort B. [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months ]
3. Assessment of pharmacokinetics of high dose vitamin C plasma levels concentrations [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months ]
4. Safety of high dose vitamin C administration using CTCAE 4.03. [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months ]

Other Outcome Measures:

1. In vitro activity of vitamin C in tumor organoids from cohort A patients [ 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 ]
   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 ]
   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:

1. Male or female ≥ 18 years of age.
2. 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)
3. 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).
4. ECOG performance status 0-1.
5. Life expectancy of at least 6 months.
6. All women of child-bearing potential and all sexually active male patients must agree to use effective contraception.

7. Patient with adequate organ and marrow function as follows:

   • ANC ≥ 1500 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.
8. Patients with serum electrolytes (including calcium, magnesium, phosphorous, sodium and potassium) within normal limits (supplementation to maintain normal electrolytes is allowed).

10. Patients capable of understanding and complying with the protocol and who have signed the informed consent document.

Exclusion Criteria:

1. 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).
2. 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).
3. Patients who have received systemic chemotherapy or targeted therapy for metastatic disease within 2 weeks from start of study drug treatment (cohort B).
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.
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 have a known predisposition for bleeding such as von Willebrand's disease or other such condition.
13. Patients who require therapeutic doses of any anticoagulant, including low molecular weight heparin (LMWH). Concomitant use of warfarin, even at prophylactic doses, is prohibited.
14. Patients who have uncontrolled seizure disorder, ascites, iron overload, edema, or dehydration.
15. Patients who have glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis, or other conditions predisposing patient to hemolysis.
16. Patients who have a history of oxalate renal calculi.

Contacts and Locations

Contacts

Contact: Alice Mercado, RN; 646-962-3080; alm2051@med.cornell.edu

Contact: Scott Sherrin, RN; 646-962-3378; sts2039@med.cornell.edu

Locations

United States, New York

Weill Cornell Medical College; Recruiting

New York, New York, United States, 10065

Contact: Alice Mercado, RN 212-962-3080 alm2051@med.cornell.edu

Contact: Scott Sherrin, RN 646-962-3378 sts2039@med.cornell.edu

Principal Investigator: Manish Shah, MD

Sub-Investigator: Allyson Ocean, MD

Sub-Investigator: Elizabeta Popa, MD

Sub-Investigator: Joseph Ruggiero, MD

Sub-Investigator: Rhonda Yantiss, MD

Sub-Investigator: Meredith Pittman, MD

Sub-Investigator: Lewis Cantley, PhD

Sponsors and Collaborators

Weill Medical College of Cornell University

Investigators

• Principal Investigator: Manish Shah, MD; Weill Cornell Medicine

More Information

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT03146962 History of Changes
• Other Study ID Numbers: 1610017688
• First Posted: May 10, 2017
• Last Update Posted: July 29, 2019
• Last Verified: July 2019

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:

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