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

Brief summary public domain (ClinicalTrials.gov)

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 public domain (ClinicalTrials.gov)

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).

Intervention public domain (ClinicalTrials.gov)

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.

Arm public domain (ClinicalTrials.gov)

Cohort A: Vitamin C + Surgery (experimental): Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for 2-4 consecutive weeks.

Arm public domain (ClinicalTrials.gov)

Cohort B: Vitamin C Only (experimental): Vitamin C infusion will be administered intravenously at 1.25 g/kg for 4 days per week for up to 6 months.

Arm public domain (ClinicalTrials.gov)

Cohort C: Vitamin C + Y-90 Dose Level 1 (experimental): 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.

Arm public domain (ClinicalTrials.gov)

Cohort C: Vitamin C + Y-90 Dose Level 2 (experimental): 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.

Arm public domain (ClinicalTrials.gov)

Cohort C: Vitamin C + Y-90 Dose Level 3 (experimental): 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.

Arm public domain (ClinicalTrials.gov)

Cohort C: Vitamin C + Y-90 Dose Level 4 (experimental): 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.

Primary outcome public domain (ClinicalTrials.gov)

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. Time frame: cohort A - 8 weeks.

Primary outcome public domain (ClinicalTrials.gov)

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 Time frame: Cohort B - 3 months.

Primary outcome public domain (ClinicalTrials.gov)

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. Time frame: Cohort C - 16 weeks.

Secondary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (PFS). Time frame: cohort B - up to 6 months.

Secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR). Time frame: cohort B - up to 6 months cohort C - 16 weeks.

Secondary outcome public domain (ClinicalTrials.gov)

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.

Secondary outcome public domain (ClinicalTrials.gov)

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..

Secondary outcome public domain (ClinicalTrials.gov)

Maximum Concentration of Vitamin C in Hours in Cohort B. Time frame: Up to 24 hours post-infusion.

Eligibility public domain (ClinicalTrials.gov)

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, …

Enrollment public domain (ClinicalTrials.gov)

Enrollment: 61 participants (actual).

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Pathologic Response Based on Tumor Regression Grading in Cohort A Patients [cohort A - 8 weeks]. Count Of Participants, Participants. Cohort A: Vitamin C + Surgery (n=6): 1.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

3-month Disease Control Rate (DCR) Will be Evaluated Using RECIST v 1.1 in Cohort B Patients. [Cohort B - 3 months]. Count Of Participants, Participants. Cohort B: Vitamin C Only (n=16): 1.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Maximal Tolerated Dose of High Dose Vitamin C in Combination With Y90 Radioembolization [Cohort C - 16 weeks]. Number, g/kg. Vitamin C Weekly Infusion Dose: Cohort C: Vitamin C + Y-90 (All Dose Levels) (n=30): 1.25. Vitamin C Infusion Dose the Day of Y-90 Radioembolization: Cohort C: Vitamin C + Y-90 (All Dose Levels) (n=30): 1.25.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Progression-free Survival (PFS) [cohort B - up to 6 months]. Median, days (Full Range). Cohort B: Vitamin C Only (n=16): 36 (14 to 151).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Objective Response Rate (ORR) [cohort B - up to 6 months cohort C - 16 weeks]. Count Of Participants, Participants. Cohort B: Vitamin C Only (n=16): 0; Cohort C: Vitamin C + Y-90 Dose Level 1 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 2 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 3 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 4 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 5 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 6 (n=4): 1; Cohort C: Vitamin C + Y-90 Dose Level 7 (n=3): 1; Cohort C: Vitamin C + Y-90 Dose Level 8 (n=5): 0.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Time to Maximum Concentration and Half-life of Vitamin C (t1/2) in Hours in Cohort B [Up to 24 hours post-infusion]. Mean, hours (Standard Deviation). T(max): Cohort B: Vitamin C Only (n=16): 2.28 (0.38). t(1/2): Cohort B: Vitamin C Only (n=16): 6.46 (1.44).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Safety of High Dose Vitamin C Administration Using CTCAE 4.03. [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.]. Count Of Participants, Participants. Alkaline Phosphatase Increase: Cohort A: Vitamin C + Surgery (n=7): 0; Cohort B: Vitamin C Only (n=19): 2; Cohort C: Vitamin C + Y-90 Dose Level 1 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 2 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 3 (n=4): 0; Cohort C: Vitamin C + Y-90 Dose Level 4 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 5 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 6 (n=7): 1; Cohort C: Vitamin C + Y-90 Dose Level 7 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 8 (n=6): 0. Aspartate Aminotransferase Increase: Cohort A: Vitamin C + Surgery (n=7): 0; Cohort B: Vitamin C Only (n=19): 2; Cohort C: Vitamin C + Y-90 Dose Level 1 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 2 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 3 (n=4): 0; Cohort C: Vitamin C + Y-90 Dose Level 4 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 5 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 6 (n=7): 3; Cohort C: Vitamin C + Y-90 Dose Level 7 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 8 (n=6): 0. Alanine Aminotransferase Increase: Cohort A: Vitamin C + Surgery (n=7): 0; Cohort B: Vitamin C Only (n=19): 3; Cohort C: Vitamin C + Y-90 Dose Level 1 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 2 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 3 (n=4): 0; Cohort C: Vitamin C + Y-90 Dose Level 4 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 5 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 6 (n=7): 1; Cohort C: Vitamin C + Y-90 Dose Level 7 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 8 (n=6): 0. Anemia: Cohort A: Vitamin C + Surgery (n=7): 0; Cohort B: Vitamin C Only (n=19): 1; Cohort C: Vitamin C + Y-90 Dose Level 1 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 2 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 3 (n=4): 0; Cohort C: Vitamin C + Y-90 Dose Level 4 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 5 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 6 (n=7): 1; Cohort C: Vitamin C + Y-90 Dose Level 7 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 8 (n=6): 1. Hypokalemia: Cohort A: Vitamin C + Surgery (n=7): 0; Cohort B: Vitamin C Only (n=19): 0; Cohort C: Vitamin C + Y-90 Dose Level 1 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 2 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 3 (n=4): 0; Cohort C: Vitamin C + Y-90 Dose Level 4 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 5 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 6 (n=7): 0; Cohort C: Vitamin C + Y-90 Dose Level 7 (n=3): 0; Cohort C: Vitamin C + Y-90 Dose Level 8 (n=6): 1. Blood Bilirubin Increased: Cohort A: Vitamin C + Surgery (n=7): 0; Cohort B: Vitamin C Only (n=19): 0; Cohort C: Vitamin C + Y-90 Dose Level 1 (n=3): 0; Cohort C: Vitamin C + Y-90

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Maximum Concentration of Vitamin C in Hours in Cohort B [Up to 24 hours post-infusion]. Mean, mM (Standard Deviation). Cohort B: Vitamin C Only (n=16): 41.19 (10.89).