<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02969681</url>
  </required_header>
  <id_info>
    <org_study_id>VitC001</org_study_id>
    <nct_id>NCT02969681</nct_id>
  </id_info>
  <brief_title>Vitamin C Intravenously With Chemotherapy in Advanced Colorectal Cancer</brief_title>
  <acronym>Vitality</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sun Yat-sen University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sun Yat-sen University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Preclinical study has shown that human colorectal cancer cells harboring KRAS or BRAF&#xD;
      mutations are selectively killed by high levels of ascorbic acid (AA). High dose of AA aslo&#xD;
      impairs tumor growth in Apc/KRASG12D mutant mice. Previous phase Ⅰ studies have found that&#xD;
      high dose iv AA is well tolerated in cancer patients.This protocol is a phase Ⅲ study of AA&#xD;
      infusions combined with treatment with FOLFOX +/- bevacizumab versus treatment with FOLFOX&#xD;
      +/- bevacizumab alone as first-line therapy in patients with recurrent or advanced colorectal&#xD;
      cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Linus Pauling and Dr Ewan Cameron have published two retrospective studies about using high&#xD;
      dose vitamin C to treat cancer patients forty years ago. Their studies have shown that high&#xD;
      dose vitamin C usage could significantly prolong overall survival of patients with advanced&#xD;
      cancer. Recently, preclinical study has shown that human colorectal cancer cells harboring&#xD;
      KRAS or BRAF mutations are selectively killed by high levels of ascorbic acid (AA). High dose&#xD;
      of AA impairs tumor growth in Apc/KRASG12D mutant mice. Previous phaseⅠ clinical trials have&#xD;
      found that high dose (1.5g/kg or 90g/m2) iv AA is well tolerated in cancer patients. This&#xD;
      protocol is a phase Ⅲ, study of ascorbic acid (AA) infusions combined with treatment with&#xD;
      FOLFOX +/- bevacizumab versus treatment with FOLFOX +/- bevacizumab alone as first-line&#xD;
      therapy in patients with recurrent or advanced colorectal cancer.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2017</start_date>
  <completion_date type="Actual">December 30, 2020</completion_date>
  <primary_completion_date type="Actual">December 30, 2020</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>up to 5 years</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>up to 5 years</time_frame>
    <description>Time to event outcome measure (death), measured in days from cycle 1 day 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Rate</measure>
    <time_frame>up to 5 years</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of treatment-related adverse events</measure>
    <time_frame>up to 5 years</time_frame>
    <description>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</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">442</enrollment>
  <condition>Colorectal Neoplasms</condition>
  <arm_group>
    <arm_group_label>Ascorbic Acid with chemotherapy group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ascorbic Acid with mFOLFOX6 with or without bevacizumab Ascorbic Acid (1.5g/kg/day, D1-3) every 2 weeks&#xD;
mFOLFOX6:&#xD;
Oxaliplatin 85 mg/m² d1 concurrent with&#xD;
Leucovorin 400 mg/m², followed by&#xD;
Bolus 5FU 400 mg/m² , followed by&#xD;
Infusional 5FU 2400 mg/m² over 46 hours, every 2 weeks&#xD;
with or without bevacizumab 5mg/kg, every 2 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Chemotherapy group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>mFOLFOX6:&#xD;
Oxaliplatin 85 mg/m² d1 concurrent with&#xD;
Leucovorin 400 mg/m², followed by&#xD;
Bolus 5FU 400 mg/m² , followed by&#xD;
Infusional 5FU 2400 mg/m² over 46 hours, every 2 weeks&#xD;
with or without bevacizumab 5mg/kg, every 2 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ascorbic acid</intervention_name>
    <description>1.5g/kg/day, D1-3, every 2 weeks</description>
    <arm_group_label>Ascorbic Acid with chemotherapy group</arm_group_label>
    <other_name>Vitamin C</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chemotherapy</intervention_name>
    <description>mFOLFOX6&#xD;
Oxaliplatin 85 mg/m² d1 concurrent with&#xD;
Leucovorin 400 mg/m², followed by&#xD;
Bolus 5FU 400 mg/m² , followed by&#xD;
Infusional 5FU 2400 mg/m² over 46 hours, every 2 weeks&#xD;
with or without bevacizumab 5mg/kg, every 2 weeks</description>
    <arm_group_label>Ascorbic Acid with chemotherapy group</arm_group_label>
    <arm_group_label>Chemotherapy group</arm_group_label>
    <other_name>mFOLFOX6+/- bevacizumab</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Age≥18 years, ≤75 years; Histologically proven metastatic adenocarcinoma of colorectal&#xD;
        cancer (stage Ⅳ disease), unresectable metastatic disease; measurable disease; G6PD status&#xD;
        &gt; lower limit of normal; Eastern Cooperative Oncology Group (ECOG) performance status 0 to&#xD;
        1; Life expectancy of at least 12 weeks; ANC ≥1,500/mm3; Hemoglobin &gt; 8g/dL; platelet ≥&#xD;
        100,000/mm3; Laboratory at baseline evaluation for inclusion in the study: creatinine ≤1.5X&#xD;
        upper limit [if the creatinine is elevated, but ≤1.5X the ULN, a 24 hour creatinine&#xD;
        clearance will be obtained, Creatinine clearance &gt; 50 mL/min (calculated according to&#xD;
        Cockroft and Gault)]; Transaminase (AST/ALT) ≤2.5X upper limit of normal and bilirubin&#xD;
        levels ≤1.5X upper limit of normal without liver metastasis; Transaminase (AST/ALT) ≤5X&#xD;
        upper limit of normal and bilirubin levels ≤1.5X upper limit of normal with liver&#xD;
        metastasis; Women of childbearing potential will confirm a negative pregnancy test and must&#xD;
        practice effective contraception during the study; Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Prior treatment for metastatic disease (adjuvant therapy with fluoropyrimidines&#xD;
        +/-oxaliplatin based regimens allowed if stopped 12 months prior to registration on study);&#xD;
        Surgery (excluding diagnostic biopsy) or irradiation within 3 weeks prior to study entry;&#xD;
        Administration of any investigational drug or agent/procedure, i.e. participation in&#xD;
        another trial within 4 weeks before beginning treatment; Concurrent chronic systemic immune&#xD;
        therapy, chemotherapy, radiation therapy (palliative radiation therapy allowed) or hormone&#xD;
        therapy not indicated in the study protocol; Brain metastasis (known or suspected);&#xD;
        Pregnant or lactating women; Other uncontrolled concomitant illness, including serious&#xD;
        uncontrolled intercurrent infection; Known allergy or any other adverse reaction to any of&#xD;
        the drugs or to any related compound; Previous (within 5 years) or concurrent malignancies&#xD;
        at other sites with the exception of surgically cured or adequately treated carcinoma&#xD;
        in-situ of the cervix and basal cell carcinoma of the skin; Patients who are on strong&#xD;
        inducers of CYP3A4 which include but are not limited to: Aminoglutethimide, Bexarotene,&#xD;
        Bosentan, Carbamazepine, Dexamethasone, Efavirenz, Fosphenytoin, Griseofulvin, Modafinil,&#xD;
        Nafcillin, Nevirapine, Oxcarbazepine, Phenobarbital, Phenytoin, Primidone, Rifabutin,&#xD;
        Rifampin, Rifapentine, St. John's wort; Medical, social or psychological condition which,&#xD;
        in the opinion of the investigator, would not permit the patient to complete the study or&#xD;
        sign meaningful informed consent; Organ allograft requiring immunosuppressive therapy;&#xD;
        Patients with HIV infection&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rui-hua Xu, MD.,PhD.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sun Yat-sen University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Medical Oncology,Sun Yat-sen University Cancer Center</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <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.</citation>
    <PMID>26541605</PMID>
  </reference>
  <reference>
    <citation>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.</citation>
    <PMID>18544557</PMID>
  </reference>
  <reference>
    <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.</citation>
    <PMID>23670640</PMID>
  </reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>May 15, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <last_update_submitted>June 24, 2023</last_update_submitted>
  <last_update_submitted_qc>June 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
    <investigator_full_name>Ruihua Xu</investigator_full_name>
    <investigator_title>Clinical Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ascorbic Acid</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02969681
org study id: VitC001
nct id: NCT02969681
lead sponsor: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival
time frame: up to 5 years
description: 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
measure: Overall Survival
time frame: up to 5 years
description: Time to event outcome measure (death), measured in days from cycle 1 day 1
measure: Response Rate
time frame: up to 5 years
description: 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
measure: Assessment of treatment-related adverse events
time frame: up to 5 years
description: 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
arm group label: Ascorbic Acid with chemotherapy group
arm group type: Experimental
description: Ascorbic Acid with mFOLFOX6 with or without bevacizumab Ascorbic Acid (1.5g/kg/day, D1-3) every 2 weeks
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
arm group label: Chemotherapy group
arm group type: Active Comparator
description: 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
intervention type: Drug
intervention name: ascorbic acid
description: 1.5g/kg/day, D1-3, every 2 weeks
arm group label: Ascorbic Acid with chemotherapy group
other name: Vitamin C
intervention type: Drug
intervention name: Chemotherapy
description: 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
arm group label: Ascorbic Acid with chemotherapy group
arm group label: Chemotherapy group
other name: mFOLFOX6+/- bevacizumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Rui-hua Xu, MD.,PhD.
role: Principal Investigator
affiliation: Sun Yat-sen University
facility: 
country: China
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.
PMID: 26541605
citation: 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.
PMID: 18544557
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.
PMID: 23670640
responsible party type: Principal Investigator
investigator affiliation: Sun Yat-sen University
investigator full name: Ruihua Xu
investigator title: Clinical Professor
mesh term: Colorectal Neoplasms
mesh term: Ascorbic Acid
sharing ipd: Undecided