Vitamin C Intravenously With Chemotherapy in Advanced Colorectal Cancer

Colorectal Neoplasms Clinical Trial

— Vitality  

Official title:

A Randomized Phase Ⅲ Study of IV Ascorbic Acid in Combination With FOLFOX+/- Bevacizumab vs Treatment With FOLFOX+/- Bevacizumab Alone as First-line Therapy for Advanced Colorectal Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02969681
• Other study ID #: VitC001
• Status: Completed
• Phase: Phase 3
• Start date: January 2017
• Est. completion date: December 30, 2020

Study information

• Verified date: June 2023
• Source: Sun Yat-sen University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Preclinical study has shown that human colorectal cancer cells harboring KRAS or BRAF mutations are selectively killed by high levels of ascorbic acid (AA). High dose of AA aslo impairs tumor growth in Apc/KRASG12D mutant mice. Previous phase Ⅰ studies have found that high dose iv AA is well tolerated in cancer patients.This protocol is a phase Ⅲ study of AA infusions combined with treatment with FOLFOX +/- bevacizumab versus treatment with FOLFOX +/- bevacizumab alone as first-line therapy in patients with recurrent or advanced colorectal cancer.

Description:

Linus Pauling and Dr Ewan Cameron have published two retrospective studies about using high dose vitamin C to treat cancer patients forty years ago. Their studies have shown that high dose vitamin C usage could significantly prolong overall survival of patients with advanced cancer. Recently, preclinical study has shown that human colorectal cancer cells harboring KRAS or BRAF mutations are selectively killed by high levels of ascorbic acid (AA). High dose of AA impairs tumor growth in Apc/KRASG12D mutant mice. Previous phaseⅠ clinical trials have found that high dose (1.5g/kg or 90g/m2) iv AA is well tolerated in cancer patients. This protocol is a phase Ⅲ, study of ascorbic acid (AA) infusions combined with treatment with FOLFOX +/- bevacizumab versus treatment with FOLFOX +/- bevacizumab alone as first-line therapy in patients with recurrent or advanced colorectal cancer.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 442
• Est. completion date: December 30, 2020
• Est. primary completion date: December 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

Age=18 years, =75 years; Histologically proven metastatic adenocarcinoma of colorectal cancer (stage ? disease), unresectable metastatic disease; measurable disease; G6PD status > lower limit of normal; Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1; Life expectancy of at least 12 weeks; ANC =1,500/mm3; Hemoglobin > 8g/dL; platelet = 100,000/mm3; Laboratory at baseline evaluation for inclusion in the study: creatinine =1.5X upper limit [if the creatinine is elevated, but =1.5X the ULN, a 24 hour creatinine clearance will be obtained, Creatinine clearance > 50 mL/min (calculated according to Cockroft and Gault)]; Transaminase (AST/ALT) =2.5X upper limit of normal and bilirubin levels =1.5X upper limit of normal without liver metastasis; Transaminase (AST/ALT) =5X upper limit of normal and bilirubin levels =1.5X upper limit of normal with liver metastasis; Women of childbearing potential will confirm a negative pregnancy test and must practice effective contraception during the study; Written informed consent

Exclusion Criteria:

Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines +/-oxaliplatin based regimens allowed if stopped 12 months prior to registration on study); Surgery (excluding diagnostic biopsy) or irradiation within 3 weeks prior to study entry; Administration of any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment; Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy (palliative radiation therapy allowed) or hormone therapy not indicated in the study protocol; Brain metastasis (known or suspected); Pregnant or lactating women; Other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection; Known allergy or any other adverse reaction to any of the drugs or to any related compound; Previous (within 5 years) or concurrent malignancies at other sites with the exception of surgically cured or adequately treated carcinoma in-situ of the cervix and basal cell carcinoma of the skin; Patients who are on strong inducers of CYP3A4 which include but are not limited to: Aminoglutethimide, Bexarotene, Bosentan, Carbamazepine, Dexamethasone, Efavirenz, Fosphenytoin, Griseofulvin, Modafinil, Nafcillin, Nevirapine, Oxcarbazepine, Phenobarbital, Phenytoin, Primidone, Rifabutin, Rifampin, Rifapentine, St. John's wort; Medical, social or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or sign meaningful informed consent; Organ allograft requiring immunosuppressive therapy; Patients with HIV infection

Related Conditions & MeSH terms

• Colorectal Neoplasms

Intervention

Drug:
• ascorbic acid
1.5g/kg/day, D1-3, every 2 weeks
• Chemotherapy
mFOLFOX6 Oxaliplatin 85 mg/m² d1 concurrent with Leucovorin 400 mg/m², followed by Bolus 5FU 400 mg/m² , followed by Infusional 5FU 2400 mg/m² over 46 hours, every 2 weeks with or without bevacizumab 5mg/kg, every 2 weeks

Locations

Country	Name	City	State
China	Medical Oncology,Sun Yat-sen University Cancer Center	Guangzhou	Guangdong

Sponsors (1)

Lead Sponsor	Collaborator
Sun Yat-sen University

Country where clinical trial is conducted

China, 

References & Publications (3)

Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, Rousseau C, Robitaille L, Miller WH Jr. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008 Nov;19(11):1969-74. doi: 10.1093/annonc/mdn377. Epub 2008 Jun 9. Erratum In: Ann Oncol. 2008 Dec;19(12):2095. — View Citation

Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139-46. doi: 10.1007/s00280-013-2179-9. Epub 2013 May 14. — View Citation

Yun J, Mullarky E, Lu C, Bosch KN, Kavalier A, Rivera K, Roper J, Chio II, Giannopoulou EG, Rago C, Muley A, Asara JM, Paik J, Elemento O, Chen Z, Pappin DJ, Dow LE, Papadopoulos N, Gross SS, Cantley LC. Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH. Science. 2015 Dec 11;350(6266):1391-6. doi: 10.1126/science.aaa5004. Epub 2015 Nov 5. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival	Time-to-event outcome measure (initial disease progression) measured in days from cycle 1 day 1 to day of first progression as defined by RECIST1.1 criteria from NCI	up to 5 years
Secondary	Overall Survival	Time to event outcome measure (death), measured in days from cycle 1 day 1	up to 5 years
Secondary	Response Rate	To utilize CT or PET/CT scans to assess overall tumor response rate (complete and partial response) and evaluate disease progression in subjects with advanced or recurrent RAS mutant colorectal cancer treated with the combination of ascorbic acid and FOLOX/FORFIRI +/- bevacizumab versus treatment with FOLFOX/FORFIRI +/- bevacizumab alone	up to 5 years
Secondary	Assessment of treatment-related adverse events	Assessment of the percentage of participants with adverse events and serious adverse events observed throughout the study, and for 30 days after cessation of study treatment	up to 5 years