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: March 2, 2020
• 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 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 1-2 weeks prior to and following Y90 radioembolization of hepatic metastases

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)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• 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: June 30, 2021
• 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). Cohort C will receive high dose vitamin C for 1-2 weeks prior to and following Y90 radioembolization of hepatic metastases	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 1-2 weeks prior to and following Y90 radioembolization of hepatic metastases; Other Name: Ascorbic Acid

Outcome Measures

Primary Outcome Measures :

1. Change in antitumor activity measured by pathologic response based on tumor regression grading in cohort A patients. [ Time Frame: cohort A - 8 weeks ]
   measured by tissue analysis of tumor cell death and fibrotic response in Cohort A subjects
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 ]
   Examination of subjects with stable disease, a partial response, or complete response.
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

Secondary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: cohort B - up to 6 months cohort C - 16 weeks ]
   Defined as the time from registration to cancer progression or death due to any cause
2. Objective response rate (ORR) [ Time Frame: cohort B - up to 6 months cohort C - 16 weeks ]
   Examination of patients with a partial response or complete response based on RECIST 1.1 Criteria.
3. Assessment of pharmacokinetics of high dose vitamin C plasma levels concentrations [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks ]
4. Safety of high dose vitamin C administration using CTCAE 4.03. [ Time Frame: cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks ]

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

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 (cohort A).

3. 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).

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 ≥ 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.
8. Patients with serum electrolytes (including calcium, magnesium, phosphorous, sodium and potassium) within normal limits (supplementation to maintain normal electrolytes is allowed).
9. Patients taking Vitamin C will have stopped taking oral vitamin C more than 1 week before planned study treatment.
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).

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.

Contacts and Locations

Contacts

Contact: Sabrina Machado, RN; 646-962-3378; sam4006@med.cornell.edu

Contact: Carina Puello, RN; 646-962-3541; cap4008@med.cornell.edu

Locations

United States, California

USC Keck School of Medicine, Norris Cancer Center; Recruiting

Los Angeles, California, United States, 90033

Contact: Heinz-Josef Lenz, MD, FACP lenz@med.usc.edu

United States, Connecticut

Smilow Cancer Hospital at Yale New Haven; Recruiting

New Haven, Connecticut, United States, 06520

Contact: Michael Cecchini, MD Michael.cecchini@yale.edu

United States, New York

New York-Presbyterian Brooklyn Methodist Hospital; Recruiting

Brooklyn, New York, United States, 11215

Contact: Uqba Khan, M.D uqk9001@med.cornell.edu

Weill Cornell Medical College; Recruiting

New York, New York, United States, 10065

Contact: Sabrina Machado, RN 212-962-3378 sam4006@med.cornell.edu

Contact: Carina Puello, RN 646-962-3541 cap4008@med.cornell.edu

Principal Investigator: Manish Shah, MD

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
• Other Study ID Numbers: 1610017688
• First Posted: May 10, 2017
• Last Update Posted: March 2, 2020
• Last Verified: February 2020

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; Nutrients; Growth Substances; Physiological Effects of Drugs; Antioxidants; Molecular Mechanisms of Pharmacological Action; Protective Agents