Clinical trial NCT03146962: High Dose Vitamin C Intravenous Infusion in Patients With Resectable or Metastatic Solid Tumor Malignancies
Official title: A Phase II Study of High Dose Vitamin C Intravenous Infusion in Patients With Resectable or Metastatic Solid Tumor Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Pancreatic Cancer
Lung Cancer
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: Stand Up To Cancer
First posted: 2017-05-10
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Eligibility 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.

Primary outcomes:
measure: Pathologic Response Based on Tumor Regression Grading in Cohort A Patients
timeFrame: cohort A - 8 weeks
measure: 3-month Disease Control Rate (DCR) Will be Evaluated Using RECIST v 1.1 in Cohort B Patients.
timeFrame: Cohort B - 3 months
measure: Maximal Tolerated Dose of High Dose Vitamin C in Combination With Y90 Radioembolization
timeFrame: Cohort C - 16 weeks
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: cohort B - up to 6 months
measure: Objective Response Rate (ORR)
timeFrame: cohort B - up to 6 months cohort C - 16 weeks
measure: Time to Maximum Concentration and Half-life of Vitamin C (t1/2) in Hours in Cohort B
timeFrame: Up to 24 hours post-infusion
measure: Safety of High Dose Vitamin C Administration Using CTCAE 4.03.
timeFrame: 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.
measure: Maximum Concentration of Vitamin C in Hours in Cohort B
timeFrame: Up to 24 hours post-infusion
Other outcomes:
measure: In Vitro Activity of Vitamin C in Tumor Organoids
timeFrame: cohort A - 8 weeks, cohort B - up to 6 months
measure: Exploratory Biomarker Samples From Tumor Tissue Will be Collected at the Time Points Specified in the Protocol
timeFrame: cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks
measure: Pharmacodynamic Samples From Tumor Tissue Will be Collected at the Time Points Specified in the Protocol.
timeFrame: cohort A - 8 weeks, cohort B - up to 6 months, Cohort C - 16 weeks
Locations:
city: Brooklyn
country: United States
facility: New York-Presbyterian Brooklyn Methodist Hospital
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Manish Shah, MD
role: PRINCIPAL_INVESTIGATOR
References: