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Efficacy, Tolerability and Safety of Intravenous D-VC With ATO in Patients With Advanced/Metastatic Colorectal Cancer

Primary Purpose

Colorectal Cancer, Metastatic Colorectal Cancer

Status
Recruiting
Phase
Phase 1
Locations
Kazakhstan
Study Type
Interventional
Intervention
D-isoascorbic Acid (D-VC) With Arsenic Trioxide (ATO)
FOLFOX/FOLFIRI regimen
Sponsored by
Nazarbayev University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Colorectal Cancer

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Phase 1: INCLUSION CRITERIA: informed consent to participate in the study patients of the second clinical group with malignant neoplasms of a common/metastatic form that have exhausted standard therapy. patients who have received at least 3 lines of standard therapy, including those with the use of targeted drugs, patients who have exhausted the possibilities of using specialized drugs, as part of the recommendations of treatment protocols the presence of "+" KRAS / NRAS status of the primary tumor or metastatic focus (determined in LEKzone 2, codons 12, 13, 61) ≥1 measurable lesion defined by RECIST v1.1 ECOG PS 0.1 or 2 EXCLUSION CRITERIA: age up to 18 years pregnancy and lactation patients with an autoimmune disease or with a medical diagnosis requiring systemic immunosuppression decompensated diabetes mellitus renal failure, urolithiasis diabetes thrombophlebitis, tendency to thrombosis severe lung disease, dyspnea at rest, pleural effusion cardiovascular insufficiency, ejection fraction of the heart <40% sensory neuropathy of the 1st degree of any etiology uncontrolled infections persons from the category of "vulnerable patients" (homeless, military personnel, incapacitated, patients in emergency conditions, other persons who may be subjected to pressure); Allergy in history and during screening (drug, pollen, etc.); participation in any other clinical trial; hypersensitivity to arsenic; individual intolerance to ascorbic acid; thrombophlebitis and thrombosis, a tendency to thrombosis in history; increased blood clotting and pathologies associated with this deviation; diabetes; nephrolithiasis or nephrolithiasis; the patient does not agree to perform the procedures required by the protocol and is unable to adhere to the schedule of procedures. if the patients have any other laboratory or other abnormalities, in the opinion of the Investigator, that can harm the patients and the results of the study. Phase II: INCLUSION CRITERIA: for both groups (30 patients, considering 20% decrease from the study): informed consent to participate in the study patients of the second clinical group with advanced/metastatic colorectal cancer Patients must have previously received at least 3 lines of standard drug therapy, including those with the use of targeted drugs, who have exhausted the possibilities of using specialized drugs, as part of the recommendations of colorectal cancer treatment protocols - the presence of "+" KRAS / NRAS status of the primary tumor, or metastatic focus (determined in exon 2, codons 12, 13, 61) ≥1 measurable lesion defined by RECIST v1.1 ECOG PS 0.1 or 2 EXCLUSION CRITERIA: age up to 18 years patients with an autoimmune disease or with a medical diagnosis requiring systemic immunosuppression decompensated diabetes mellitus renal failure, urolithiasis thrombophlebitis, tendency to thrombosis severe lung disease, dyspnea at rest, pleural effusion cardiovascular insufficiency, ejection fraction of the heart <40% sensory neuropathy of the 1st degree of any etiology uncontrolled infections persons from the category of "vulnerable patients" (homeless, military personnel, incapacitated, patients in emergency conditions, other persons who may be subjected to pressure); Allergy in history and during screening (drug, pollen, etc.); participation in any other clinical trial; hypersensitivity to arsenic; individual intolerance to ascorbic acid; thrombophlebitis and thrombosis, a tendency to thrombosis in history; increased blood clotting and pathologies associated with this deviation; diabetes; nephrolithiasis or nephrolithiasis; the patient does not agree to perform the procedures required by the protocol and is unable to adhere to the schedule of procedures. if the patients have any other laboratory or other abnormalities, in the opinion of the Investigator, that can harm the patients and the results of the study.

Sites / Locations

  • Kazakh Institute of Oncology and RadiologyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Active Comparator

Arm Label

Combination of D-isoascorbic acid (D-VC) with arsenic trioxide (ATO)-Phase 1

Combination of D-isoascorbic acid (D-VC) with arsenic trioxide (ATO)-Phase 2

Standard therapy (FOLFOX/FOLFIRI)-Phase 2

Arm Description

Participants will receive single intravenous administration as monotherapy of D-isoascorbic acid (D-VC) with dose escalation (0.05, 0.1, 0.2 g/kg/day) and with arsenic trioxide (ATO). Patients who have satisfactorily tolerated the study drug in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.

After 2 hours of intravenous administration of arsenic trioxide (ATO) (at a dose of 0.15 mg / kg / day) participants will further receive D-isoascorbic acid (D-VC) intravenously once a day at the maximum tolerated dose, determined at the end of phase I.

Drug: FOLFOX/FOLFIRI regimen FOLFOX - oxaliplatin 85mg/m2 1 day, Leucovorin 200mg/m2 IV 2h, 1, 2 days, 5 - Fluorouracil 400mg/m2 IV bolus, 1, 2 days, 5 - Fluorouracil 600mg/m2 IV 22h, 1, 2 days FOLFIRI - Irinotecan 180 mg/m2 IV, Leucovorin 400 mg/m2 IV, Fluorouracil bolus 400 mg/m2 IV, Fluorouracil infusional 2400 mg/m2 IV. Courses are held every 2 weeks

Outcomes

Primary Outcome Measures

Change from baseline DV-C levels at 1 hour
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Change from baseline DV-C levels at 3 hours
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Change from baseline DV-C levels at 6 hours
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Change from baseline DV-C levels at 24 hours
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Response to D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO)
Objective partial or complete response by RECIST 1.1, confirmed on a second CT scan at least 4 weeks apart

Secondary Outcome Measures

Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 1 hour
Adverse events in patients will be assessed by CTCAE v4.0
Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 3 hours
Adverse events in patients will be assessed by CTCAE v4.0
Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 6 hours
Adverse events in patients will be assessed by CTCAE v4.0
Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 24 hours
Adverse events in patients will be assessed by CTCAE v4.0

Full Information

First Posted
January 18, 2023
Last Updated
February 8, 2023
Sponsor
Nazarbayev University
Collaborators
National Laboratory Astana
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1. Study Identification

Unique Protocol Identification Number
NCT05721872
Brief Title
Efficacy, Tolerability and Safety of Intravenous D-VC With ATO in Patients With Advanced/Metastatic Colorectal Cancer
Official Title
An Exploratory Phase I/II Single-center Clinical Trial of the Efficacy, Tolerability and Safety of Intravenous D-isoascorbic Acid With Arsenic Trioxide in Patients With Advanced/Metastatic Colorectal Cancer Who Have Exhausted Standard Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 15, 2023 (Anticipated)
Primary Completion Date
August 2023 (Anticipated)
Study Completion Date
November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nazarbayev University
Collaborators
National Laboratory Astana

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this exploratory phase I/II single-center clinical trial is to evaluate effectiveness, tolerability, and safety of Intravenous D-isoascorbic Acid (D-VC) With Arsenic Trioxide in Patients With Advanced/Metastatic Colorectal Cancer Who Have Exhausted Standard Therapy The main questions are to learn about effectiveness, tolerability, and safety of Intravenous D-isoascorbic Acid (D-VC) With Arsenic Trioxide. The study aims to: Assess the tolerability and pharmacokinetics of D-isoascorbic acid (D-VC) with a single intravenous injection in the monotherapy regimen and in the sequential administration regimen with arsenic trioxide (ATO) in patients on standard therapy for advanced/metastatic malignancies (Phase I) Evaluate the efficacy and safety of D-isoascorbic acid (D-VC) with repeated intravenous administration in the mode of sequential administration with arsenic trioxide (ATO) in patients who have exhausted standard therapy for advanced/metastatic colorectal cancer (Phase II) In phase I participants will receive single intravenous administration as monotherapy of D-isoascorbic acid (D-VC) with dose escalation (0.05, 0.1, 0.2 g/kg/day) and with arsenic trioxide (ATO). Patients who have satisfactorily tolerated the study drug in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial. To study the safety and efficacy of the study drug in phase II, D-VC after the administration of ATO will be implemented in 2 groups: Study group 1: ATO (at a dose of 0.15 mg / kg / day) after intravenous administration after 2 hours D-VC intravenously once a day at the maximum tolerated dose, determined at the end of phase I for at least 15 patients. Group 2 standard therapy: 15 patients. For the phase I researchers will compare laboratory tests (including clinical biochemistry and hematology), vital signs, clinical adverse events (diseases, symptoms and complaints) and other specific safety tests (for example, an electrocardiogram, ophthalmic examination) between groups. They will also measure the degree to which overt adverse reactions can be subjectively tolerated by the subject of the study. For the phase II researchers will compare degrees of tumor volume reduction on CT; objective response rate (ORR) based on BICR according to RECIST v1.1 between test and standard therapy groups. They will also continue evaluation of safety and tolerability of ATO + D-VC combination therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Cancer, Metastatic Colorectal Cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
38 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Combination of D-isoascorbic acid (D-VC) with arsenic trioxide (ATO)-Phase 1
Arm Type
Experimental
Arm Description
Participants will receive single intravenous administration as monotherapy of D-isoascorbic acid (D-VC) with dose escalation (0.05, 0.1, 0.2 g/kg/day) and with arsenic trioxide (ATO). Patients who have satisfactorily tolerated the study drug in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Arm Title
Combination of D-isoascorbic acid (D-VC) with arsenic trioxide (ATO)-Phase 2
Arm Type
Experimental
Arm Description
After 2 hours of intravenous administration of arsenic trioxide (ATO) (at a dose of 0.15 mg / kg / day) participants will further receive D-isoascorbic acid (D-VC) intravenously once a day at the maximum tolerated dose, determined at the end of phase I.
Arm Title
Standard therapy (FOLFOX/FOLFIRI)-Phase 2
Arm Type
Active Comparator
Arm Description
Drug: FOLFOX/FOLFIRI regimen FOLFOX - oxaliplatin 85mg/m2 1 day, Leucovorin 200mg/m2 IV 2h, 1, 2 days, 5 - Fluorouracil 400mg/m2 IV bolus, 1, 2 days, 5 - Fluorouracil 600mg/m2 IV 22h, 1, 2 days FOLFIRI - Irinotecan 180 mg/m2 IV, Leucovorin 400 mg/m2 IV, Fluorouracil bolus 400 mg/m2 IV, Fluorouracil infusional 2400 mg/m2 IV. Courses are held every 2 weeks
Intervention Type
Combination Product
Intervention Name(s)
D-isoascorbic Acid (D-VC) With Arsenic Trioxide (ATO)
Intervention Description
After 2 hours of intravenous administration of arsenic trioxide (ATO) (at a dose of 0.15 mg / kg / day) participants will further receive D-isoascorbic acid (D-VC) intravenously once a day at the maximum tolerated dose, determined at the end of phase I. Phase 1 - Scheme 1 - single intravenous administration in monotherapy with dose escalation (0.05, 0.1, 0.15 g/kg/day); Scheme 2 - single intravenous administration in the mode of sequential administration with arsenic trioxide with dose escalation of D-isoascorbic acid (0.05, 0.1, 0.15 g/kg/day). Phase 2 - Study group 1: After 2 hours of intravenous administration of arsenic trioxide (ATO) (at a dose of 0.15 mg / kg / day) participants will further receive D-isoascorbic acid (D-VC) intravenously once a day at the maximum tolerated dose, determined at the end of phase I for at least 15 patients.
Intervention Type
Drug
Intervention Name(s)
FOLFOX/FOLFIRI regimen
Intervention Description
FOLFOX - oxaliplatin 85mg/m2 1 day Leucovorin 200mg/m2 IV 2h, 1, 2 days 5 - Fluorouracil 400mg/m2 IV bolus, 1, 2 days 5 - Fluorouracil 600mg/m2 IV 22h, 1, 2 days FOLFIRI Irinotecan 180 mg/m2 IV Leucovorin 400 mg/m2 IV Fluorouracil bolus 400 mg/m2 IV Fluorouracil infusional 2400 mg/m2 IV Courses are held every 2 weeks
Primary Outcome Measure Information:
Title
Change from baseline DV-C levels at 1 hour
Description
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Time Frame
Baseline, 1 hour
Title
Change from baseline DV-C levels at 3 hours
Description
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Time Frame
Baseline, 3 hours
Title
Change from baseline DV-C levels at 6 hours
Description
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Time Frame
Baseline, 6 hours
Title
Change from baseline DV-C levels at 24 hours
Description
Patients who have satisfactorily tolerated D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO) in a phase I study are transferred to a phase II clinical trial.
Time Frame
Baseline, 24 hours
Title
Response to D-isoascorbic Acid (D-VC) in combination with arsenic trioxide (ATO)
Description
Objective partial or complete response by RECIST 1.1, confirmed on a second CT scan at least 4 weeks apart
Time Frame
Baseline, 4 weeks
Secondary Outcome Measure Information:
Title
Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 1 hour
Description
Adverse events in patients will be assessed by CTCAE v4.0
Time Frame
Baseline, 1 hour
Title
Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 3 hours
Description
Adverse events in patients will be assessed by CTCAE v4.0
Time Frame
Baseline, 3 hours
Title
Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 6 hours
Description
Adverse events in patients will be assessed by CTCAE v4.0
Time Frame
Baseline, 6 hours
Title
Change from baseline number of participants with treatment-related adverse events as assessed by CTCAE v4.0 at 24 hours
Description
Adverse events in patients will be assessed by CTCAE v4.0
Time Frame
Baseline, 24 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Phase 1: INCLUSION CRITERIA: informed consent to participate in the study patients of the second clinical group with malignant neoplasms of a common/metastatic form that have exhausted standard therapy. patients who have received at least 3 lines of standard therapy, including those with the use of targeted drugs, patients who have exhausted the possibilities of using specialized drugs, as part of the recommendations of treatment protocols the presence of "+" KRAS / NRAS status of the primary tumor or metastatic focus (determined in LEKzone 2, codons 12, 13, 61) ≥1 measurable lesion defined by RECIST v1.1 ECOG PS 0.1 or 2 EXCLUSION CRITERIA: age up to 18 years pregnancy and lactation patients with an autoimmune disease or with a medical diagnosis requiring systemic immunosuppression decompensated diabetes mellitus renal failure, urolithiasis diabetes thrombophlebitis, tendency to thrombosis severe lung disease, dyspnea at rest, pleural effusion cardiovascular insufficiency, ejection fraction of the heart <40% sensory neuropathy of the 1st degree of any etiology uncontrolled infections persons from the category of "vulnerable patients" (homeless, military personnel, incapacitated, patients in emergency conditions, other persons who may be subjected to pressure); Allergy in history and during screening (drug, pollen, etc.); participation in any other clinical trial; hypersensitivity to arsenic; individual intolerance to ascorbic acid; thrombophlebitis and thrombosis, a tendency to thrombosis in history; increased blood clotting and pathologies associated with this deviation; diabetes; nephrolithiasis or nephrolithiasis; the patient does not agree to perform the procedures required by the protocol and is unable to adhere to the schedule of procedures. if the patients have any other laboratory or other abnormalities, in the opinion of the Investigator, that can harm the patients and the results of the study. Phase II: INCLUSION CRITERIA: for both groups (30 patients, considering 20% decrease from the study): informed consent to participate in the study patients of the second clinical group with advanced/metastatic colorectal cancer Patients must have previously received at least 3 lines of standard drug therapy, including those with the use of targeted drugs, who have exhausted the possibilities of using specialized drugs, as part of the recommendations of colorectal cancer treatment protocols - the presence of "+" KRAS / NRAS status of the primary tumor, or metastatic focus (determined in exon 2, codons 12, 13, 61) ≥1 measurable lesion defined by RECIST v1.1 ECOG PS 0.1 or 2 EXCLUSION CRITERIA: age up to 18 years patients with an autoimmune disease or with a medical diagnosis requiring systemic immunosuppression decompensated diabetes mellitus renal failure, urolithiasis thrombophlebitis, tendency to thrombosis severe lung disease, dyspnea at rest, pleural effusion cardiovascular insufficiency, ejection fraction of the heart <40% sensory neuropathy of the 1st degree of any etiology uncontrolled infections persons from the category of "vulnerable patients" (homeless, military personnel, incapacitated, patients in emergency conditions, other persons who may be subjected to pressure); Allergy in history and during screening (drug, pollen, etc.); participation in any other clinical trial; hypersensitivity to arsenic; individual intolerance to ascorbic acid; thrombophlebitis and thrombosis, a tendency to thrombosis in history; increased blood clotting and pathologies associated with this deviation; diabetes; nephrolithiasis or nephrolithiasis; the patient does not agree to perform the procedures required by the protocol and is unable to adhere to the schedule of procedures. if the patients have any other laboratory or other abnormalities, in the opinion of the Investigator, that can harm the patients and the results of the study.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dos Sarbassov, PhD
Phone
+77172705873
Email
nlagen.dir@nu.edu.kz
Facility Information:
Facility Name
Kazakh Institute of Oncology and Radiology
City
Almaty
ZIP/Postal Code
050000
Country
Kazakhstan
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kaldygul Smagulova, MD, PhD
Phone
+7-727-292-77-55
Email
kazior@onco.kz

12. IPD Sharing Statement

Plan to Share IPD
No

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Efficacy, Tolerability and Safety of Intravenous D-VC With ATO in Patients With Advanced/Metastatic Colorectal Cancer

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