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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:
Researchers will compare:
Participants will:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Chemotherapy according to the FOLFOX regimen in combination with sodium nucleinate | Active Comparator | 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. |
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| Chemotherapy according to the FOLFOX regimen | Placebo Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Adenorine | Dietary Supplement | 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. |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| MIPOClinic | Almaty | Almaty | 050038 | Kazakhstan |
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Of 200 patients screened, 187 met eligibility criteria, provided informed consent, and were enrolled (randomized). Thirteen patients were screening failures: 8 did not meet inclusion/exclusion criteria, 5 withdrew consent before randomization.
Patients with histologically confirmed metastatic colorectal cancer (stage M1 only) were recruited at oncology centers affiliated with university clinics in 4 regions of Kazakhstan. Active enrollment began on July 15, 2022 and was completed in July 2024.
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| ID | Title | Description |
|---|---|---|
| FG000 | Main Group: FOLFOX With Sodium Nucleinate | Patients received 4 cycles of palliative FOLFOX chemotherapy plus sodium nucleinate 50 mg/day (25 mg morning, 25 mg at lunch) starting 1 week before the first cycle and continued daily for 4 months. |
| FG001 | Control Group: FOLFOX Alone | Patients received 4 cycles of palliative FOLFOX chemotherapy alone. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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The analysis included all 187 randomized participants.
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| ID | Title | Description |
|---|---|---|
| BG000 | Main Group: FOLFOX With Sodium Nucleinate | Participants with metastatic colorectal cancer (stage T3-4 N1-2 M) received four courses of FOLFOX chemotherapy combined with mitochondrial immunotherapy using sodium nucleinate. Sodium nucleinate was administered at 50 mg per day (25 mg in the morning and 25 mg at lunch before meals) daily for four months. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Age was recorded at the time of enrollment in years. Data are presented as mean ± standard deviation. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Secondary | 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. | All randomized participants who started chemotherapy were included in this analysis (89 in the main group and 98 in the control group) | Posted | Mean | Standard Deviation | EORTC QLQ-C30 score (0-100) | Baseline (before start of chemotherapy); 1 month after completion of 4 cycles (approximately 5 months after baseline); 1 year post-baseline |
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From the start of treatment through 30 days after completion of the last chemotherapy cycle, up to 5 months.
Adverse events were assessed monthly during the treatment period using clinical evaluation and laboratory monitoring. Adverse events were graded according to CTCAE version 5.0. The analysis population included the Safety Set: all randomized participants who received at least one dose of study treatment (89 in main group, 98 in control group).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Main Group: FOLFOX With Sodium Nucleinate | Participants with metastatic colorectal cancer (stage T3-4 N1-2 M) received four courses of FOLFOX chemotherapy combined with mitochondrial immunotherapy using sodium nucleinate. Sodium nucleinate was administered at 50 mg per day (25 mg in the morning and 25 mg at lunch before meals) daily for four months. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Neutropenia (Grade 3-4) | Blood and lymphatic system disorders | CTCAE v5.0 | Systematic Assessment | Grade 3-4 neutropenia assessed according to CTCAE version 5.0. Grade 3 defined as absolute neutrophil count 500 to <1000 cells/mm³; Grade 4 defined as absolute neutrophil count <500 cells/mm³. Event was considered related to chemotherapy. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Treatment interruptions (due to any adverse event) | General disorders | CTCAE v5.0 | Systematic Assessment | Treatment interruptions were defined as delay or discontinuation of chemotherapy due to adverse events including leukopenia, neutropenia, and infectious complications. Events were assessed monthly through clinical evaluation and laboratory monitoring |
Single-center study. Participants blinded (placebo-controlled), treating clinicians not blinded. Chemotherapy dose modifications governed by objective criteria with blinded adjudication. Follow-up limited to 12 months. Age restricted to 40-65 years.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Stanislav Alexandrovich Panov, MD | Military Clinical Hospital of the Ministry of Defense of the Republic of Kazakhstan | +7-747-682-6613 | panov_stanislav@mail.ru |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 20, 2022 | Jun 3, 2026 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jun 30, 2022 | May 28, 2026 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
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| ID | Term |
|---|---|
| C013683 | sodium nucleinate |
| C410216 | Folfox protocol |
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The primary purpose of this treatment trial is to determine whether adding sodium nucleinate mitochondrial immunotherapy to FOLFOX chemotherapy improves quality of life and reduces one-year mortality in metastatic colorectal cancer.
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Randomization 1:1 using computer-generated block randomization with variable block sizes, stratified by ECOG status, metastatic sites, and prior adjuvant chemotherapy. Allocation concealment: sequentially numbered, opaque, sealed envelopes (SNOSE); randomization table not disclosed to researchers.
Blinded outcome assessors: intake nurse, lab technician, researcher performing measurements, social worker processing QoL questionnaires, and statistician (Group A/B until database lock). Treating clinicians were not blinded.
All chemotherapy dose modifications (delays, reductions, cancellations) were governed by protocol-defined objective criteria (e.g., ANC <1000/mm³, platelets <50,000/mm³, CTCAE grade ≥3) with no investigator discretion. A blinded Endpoint Adjudication Committee reviewed 100% of modifications to verify adherence to objective criteria.
Treating physician had no access to functional blood tests or QoL results during treatment; outcomes entered after treatment course compl
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| Placebo | Other | 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. |
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| FOLFOX regimen | Drug | (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) |
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| 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) |
| BG001 |
| Control Group: FOLFOX Alone |
Participants with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy alone. |
| BG002 | Total | Total of all reporting groups |
All 187 randomized participants were included in the age analysis. No participants were excluded. The number of participants analyzed matches the overall number of baseline participants for each arm. |
| Mean |
| Standard Deviation |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
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| Region of Enrollment | Participants were enrolled from oncology centers in 4 regions of Kazakhstan where University Clinics were located. | Number | Participants |
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| Primary tumour site (colon vs rectum) | Distribution of primary tumour localization in the colon versus rectum at baseline. | Count of Participants | Participants |
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| OG001 | Control Group: FOLFOX Alone | Participants with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy alone. |
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| Secondary | 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. | All randomized participants with available mitochondrial activity measurements at the specified time point were included. | Posted | Mean | Standard Deviation | cell percentage | Baseline (before start of chemotherapy) and post-treatment assessment 1 month after completion of chemotherapy |
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| Secondary | 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. | All randomized participants with an evaluable baseline and follow-up FDG-PET/CT were included in this analysis (89 in the main group; 98 in the control group). The response categories (PMR, SMD, PMD) are mutually exclusive and sum to the number analyzed in each arm. | Posted | Count of Participants | Participants | Baseline (before start of chemotherapy) and follow-up FDG-PET/CT 1 month after completion of chemotherapy (approximately 5 months after baseline). |
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| Secondary | 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. | All randomized participants with available serum CEA measurements at the specified time point were included; participants without an available sample/result were excluded from that time point's analysis (missing data reflected in N analyzed for that row). | Posted | Count of Participants | Participants | Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline) |
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| Secondary | 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. | All 89 participants in the main group and 98 participants in the control group had CA 19-9 measurements at both baseline and 1 month after completion of chemotherapy. No participants were excluded from this analysis. | Posted | Count of Participants | Participants | Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline) |
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| Secondary | 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. | All randomized participants with available CD4+/CD8+ ratio measurements at the specified time points were included (89 in the main group; 98 in the control group). No participants were excluded from this analysis. | Posted | Mean | Standard Deviation | Ratio | Baseline (before start of chemotherapy) and 1 month after completion of chemotherapy (approximately 5 months after baseline) |
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| Secondary | 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. | All 89 participants in the main group and 98 participants in the control group underwent baseline echocardiography. No participants were excluded from this analysis. | Posted | Mean | Standard Deviation | Percentage | baseline (before start of chemotherapy) |
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| Primary | 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). | 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). | Posted | Mean | Standard Deviation | percentage | 1-4 cycles of FOLFOX |
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| 6 |
| 89 |
| 13 |
| 89 |
| 6 |
| 89 |
| EG001 | Control Group: FOLFOX Alone | Participants with metastatic colorectal cancer (stages T3-4 N1-2 M1) received four courses of FOLFOX chemotherapy alone. | 27 | 98 | 52 | 98 | 52 | 98 |
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| Febrile Neutropenia (Grade 3-4) | Blood and lymphatic system disorders | CTCAE v5.0 | Systematic Assessment | Grade 3-4 febrile neutropenia assessed according to CTCAE version 5.0. Defined as fever (temperature ≥38.3°C) with absolute neutrophil count <500 cells/mm³. Event was considered related to chemotherapy. |
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| Leukopenia (Grade 1-2) | Blood and lymphatic system disorders | CTCAE v5.0 | Systematic Assessment | Grade 1-2 leukopenia defined as white blood cell count 3,000 to <4,000/mm³ (Grade 1) or 2,000 to <3,000/mm³ (Grade 2) per CTCAE v5.0. Event considered related to chemotherapy. |
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| Neutropenia (Grade 1-2) | Blood and lymphatic system disorders | CTCAE v5.0 | Systematic Assessment | Grade 1-2 neutropenia defined as absolute neutrophil count 1,000 to <1,500/mm³ (Grade 1) or 500 to <1,000/mm³ (Grade 2) per CTCAE v5.0. Event considered related to chemotherapy. |
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| Anemia (Grade 1-2) | Blood and lymphatic system disorders | CTCAE v5.0 | Systematic Assessment | Grade 1-2 anemia defined as hemoglobin 100 to <120 g/L (Grade 1) or 80 to <100 g/L (Grade 2) per CTCAE v5.0. Event considered related to chemotherapy. |
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| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| Progressive metabolic disease (PMD) |
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