Immunosurveillance for Metastatic Colorectal Cancer (ISMCC)

The Role of Neutrophil Mitochondrial Dysfunction in Medical Rehabilitation During Palliative Chemotherapy for Metastatic Colorectal Cancer

The goal of this clinical trial is to learn if adding sodium nucleinate to FOLFOX chemotherapy helps people with metastatic colorectal cancer (colon or rectal cancer that has spread). Researchers will also look at side effects and how people feel during treatment.

The main questions this study aims to answer are:

1. Does adding sodium nucleinate help treatment work better?
2. Does it improve quality of life (how people feel and function day to day)?
3. Does it affect survival at one year?

Researchers will compare:

1. FOLFOX chemotherapy plus sodium nucleinate versus
2. FOLFOX chemotherapy alone

Participants will:

1. Be randomly assigned (like flipping a coin) to one of the two groups;
2. Receive four cycles of FOLFOX chemotherapy;
3. Take sodium nucleinate daily if assigned to that group;
4. Have checkups and blood tests during the study (including tumor marker blood tests such as CEA and CA 19-9);
5. Complete quality-of-life questionnaires and have other planned tests that look at immune cells and how certain blood cells work;
6. Be followed after treatment to see how they are doing, including up to one year after starting the study.

Study Overview

• Status: Completed
• Conditions: Monitoring, Immunologic
• Intervention / Treatment: Drug: FOLFOX regimen; Dietary supplement: Adenorine; Other: Placebo

Detailed Description

This randomized, single-blinded, parallel-group clinical trial was approved by the Local Ethics Committee of Kazakh National Medical University and conducted at oncology centers affiliated with university clinics in four regions of Kazakhstan. Participants had histologically confirmed metastatic colorectal cancer (T3-4 N1-2 M1). A total of 200 individuals were screened; 187 were enrolled and randomized.

Participants were allocated in a 1:1 ratio using sealed envelopes to receive either (1) FOLFOX chemotherapy plus sodium nucleinate or (2) FOLFOX chemotherapy alone. The intervention group received sodium nucleinate 50 mg per day (25 mg in the morning and 25 mg at lunch), starting 1 week before the first chemotherapy cycle and continued daily for 4 months. Both groups received four cycles of FOLFOX per institutional protocols.

Assessments included monthly clinical evaluation with general and biochemical blood tests during treatment. The following were assessed at baseline and at 1 month after completion of chemotherapy (approximately 5 months after baseline): FDG PET/CT, serum tumor markers (CEA and CA 19-9), peripheral blood immunologic status (CD4+/CD8+ ratio), and neutrophil mitochondrial activity (percentage of neutrophils with preserved mitochondrial function among 200 counted neutrophils). Baseline transthoracic echocardiography was performed to determine left ventricular ejection fraction. Health-related quality of life was assessed using the EORTC QLQ-C30 at baseline, post-treatment, and 1 year post-baseline.

Analyses were performed using Statistica 7.0 (StatSoft, USA). Continuous outcomes were compared between groups using the Mann-Whitney U test as specified in the protocol.

• Study Type: Interventional
• Enrollment (Actual): 187
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Kazakhstan
  • Almaty
    • Almaty, Almaty, Kazakhstan, 050038
      • MIPOClinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically confirmed colorectal cancer.
2. Locally advanced or metastatic disease as treated with palliative FOLFOX per protocol (including metastatic disease [M1]).
3. Able to receive FOLFOX chemotherapy and to comply with study procedures.
4. Provided written informed consent.

Exclusion Criteria:

1. Active pulmonary tuberculosis.
2. Decompensated diabetes mellitus.
3. Decompensated cardiac, vascular, pulmonary, hepatic, or renal failure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Chemotherapy according to the FOLFOX regimen in combination with sodium nucleinate; Patients with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy combined with sodium nucleinate 50 mg/day (25 mg morning, 25 mg lunch) starting 1 week before the first cycle and continued daily for four months.	Drug: FOLFOX regimen; (Day 1-2: Oxaliplatin 100 mg/m2 IV infusion, given as a 120 minutes IV infusion in 500 mL D5W, concurrent with leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2) IV infusion, followed by 5-FU 400 mg/m2 IV bolus, followed by 46-hour 5-FU infusion (2400 mg/m2 for first two cycles, and may be increased to 3000 mg/m2 if tolerated by patient (no toxicity > grade 1 during the first two cycles), days 3-14: Rest days); Dietary supplement: Adenorine; Sodium nucleinate (Adenorine) is an immunomodulatory oligonucleotide preparation. In this trial, it was administered orally at 50 mg per day (25 mg in the morning and 25 mg at lunch before meals) for four months, starting 7 days before the first cycle of FOLFOX chemotherapy.; Other Names: natural oligodeoxynucleotide; sodium nucleinate
Placebo Comparator: Chemotherapy according to the FOLFOX regimen; Patients with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy alone. General and biochemical blood analyses were conducted monthly.	Drug: FOLFOX regimen; (Day 1-2: Oxaliplatin 100 mg/m2 IV infusion, given as a 120 minutes IV infusion in 500 mL D5W, concurrent with leucovorin 400 mg/m2 (or levoleucovorin 200 mg/m2) IV infusion, followed by 5-FU 400 mg/m2 IV bolus, followed by 46-hour 5-FU infusion (2400 mg/m2 for first two cycles, and may be increased to 3000 mg/m2 if tolerated by patient (no toxicity > grade 1 during the first two cycles), days 3-14: Rest days); Other: Placebo; Matching placebo administered orally (25 mg morning, 25 mg lunch) for four months, identical in appearance, taste, and packaging to sodium nucleinate. Contains microcrystalline cellulose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Dose Intensity of FOLFOX	Relative Dose Intensity (RDI) over cycles 1-4 of FOLFOX, calculated as (delivered dose intensity / planned dose intensity) × 100. Dose intensity accounts for both dose reductions and treatment delays for oxaliplatin (mg/m²/week) and infusional 5-fluorouracil (mg/m²/week).	1-4 cycles of FOLFOX

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
EORTC QLQ-C30 Global Health Status/QoL (GHS/QoL)	Global health status/quality of life subscale from the EORTC QLQ-C30. Scores are linearly transformed to a 0-100 scale. Higher scores indicate better global health status/quality of life (better outcome). Minimum = 0, maximum = 100. This is a subscale score, not a total scale score.	Baseline (before start of chemotherapy); 1 month after completion of 4 cycles (approximately 5 months after baseline); 1 year post-baseline
Mitochondrial Activity of Neutrophils	Mitochondrial activity of neutrophils assessed in peripheral blood as the percentage (%) of neutrophils with preserved mitochondrial function among 200 counted neutrophils per participant. Range 0-100%. Higher percentages indicate better preserved neutrophil mitochondrial function. Primary metric: change from baseline to 1 month after completion of chemotherapy.	Baseline (before start of chemotherapy) and post-treatment assessment 1 month after completion of chemotherapy
Positron Emission Tomography/Computed Tomography (PET/CT) Tumour Metabolic Activity	Metabolic response to treatment assessed by [18F]FDG PET/CT using EORTC PET response criteria based on the change in tumor FDG uptake (e.g., SUV metric) between baseline and follow-up. Participants were classified into mutually exclusive categories: partial metabolic response (PMR) (≥25% decrease in tumor FDG uptake), stable metabolic disease (SMD) (does not meet PMR or PMD), or progressive metabolic disease (PMD) (≥25% increase in tumor FDG uptake and/or new FDG-avid lesions). Higher metabolic activity and PMD indicate worse disease activity.	Baseline (before start of chemotherapy) and follow-up FDG-PET/CT 1 month after completion of chemotherapy (approximately 5 months after baseline).
CEA Response (≥50% Decrease From Baseline)	Serum CEA concentration measured in peripheral blood and reported in ng/mL. Higher CEA values generally indicate higher tumor burden and are used to monitor treatment response in conjunction with imaging. CEA response defined as a ≥50% decrease in serum CEA concentration from baseline to 1 month after completion of chemotherapy.	Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline)
CA 19-9(Carbohydrate Antigen 19-9) Response (≥50% Decrease From Baseline)	CA 19-9 response defined as a ≥50% decrease in serum CA 19-9 concentration from baseline to 1 month after completion of chemotherapy. CA 19-9 measured in U/mL. Higher CA 19-9 values indicate higher tumor burden (worse outcome). Normal range approximately 0-27 U/mL.	Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline)
CD4+/CD8+ T-Cell Ratio (Peripheral Blood)	CD4+/CD8+ T-cell ratio measured in peripheral blood (unitless ratio). The prespecified metric is the change in CD4+/CD8+ ratio from baseline to 1 month after completion of chemotherapy.	Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline)
Left Ventricular Ejection Fraction (LVEF) by Echocardiography	Left ventricular ejection fraction (LVEF) ≥50% by echocardiography at baseline was required for study inclusion. Patients with LVEF <50% were excluded.	baseline (before start of chemotherapy)

Collaborators and Investigators

• Sponsor: MIPO Clinic

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2022
• Primary Completion (Actual): July 25, 2023
• Study Completion (Actual): July 30, 2024

Study Registration Dates

• First Submitted: July 6, 2024
• First Submitted That Met QC Criteria: July 14, 2024
• First Posted (Actual): July 19, 2024

Study Record Updates

• Last Update Posted (Actual): June 29, 2026
• Last Update Submitted That Met QC Criteria: June 3, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Rehabilitation; Chemotherapy; Colorectal Cancer; Mitochondria; Sodium Nucleinate
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Immunologic Factors; Gastrointestinal Agents; Adjuvants, Immunologic; Anti-Ulcer Agents; Interferon Inducers; Folfox protocol; sodium nucleinate
• Other Study ID Numbers: 3

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No