A Clinical Trial to Assess the Effectiveness of NRF2 Activator (Oral Sodium-copper- Chlophyllin ) in Locally Advanced Cervical Cancer to Reduce Late Radiotherapy Toxicity.

Descriptive summary

Objectives

Primary objective

• To assess the effectiveness of adjuvant sodium-copper-chlorophyllin in reducing the cumulative incidence of late grade 2 or higher RT-related gastrointestinal and genitourinary toxicity in cervix cancer patients, measured using the time-to-event method

Secondary objectives

• To evaluate the effect of sodium-copper-chlorophyllin tablet administration on 24-month local control, pelvic control, nodal relapse, disease-free survival, overall survival
• To compare the effect of sodium-copper-chlorophyllin on haematological parameters (persistent anaemia, neutropenia, thrombocytopenia)
• To compare the number of patients with RT-related urinary stress incontinence
• To examine the effect of diabetes mellitus, hypertension, bone health and vitamin deficiencies on the occurrence and recovery from RT-related toxicity
• To calculate cumulative time- and severity-related toxicity scores (C-MOSES scores)
• To compare prevalence of cystoscopic and sigmopidoscopy changes in test and standard arms and clinical symptoms in relation to the findings.
• To evaluate the quality of life in both arms
• To compare time spent in toxicity
• To calculate direct financial costs of adverse event management and impact on health care system.
• To investigate the effect of sodium-copper-chlorophyllin on the immune cell profile and oxidative stress markers of patients

Trial Design

This is a parallel-arm, randomized Phase III trial designed to test whether oral sodium-copper-chlorophyllin can reduce late (grade 2 or higher) gastrointestinal and genitourinary toxicities 24 months after completion of radiotherapy (RT) in cervical cancer patients.

Sample Size

Total of 316 patients will need to be randomized to the two arms in a 2:1 ratio (210 in the treatment group and 106 in the control group), accounting for an estimated 10%loss to follow-up. This sample size calculation was conducted using RPACT Package of R software.

Arm 1 (Test arm): Oral adjuvant sodium-copper-chlorophyllin 750mg given once daily, on an empty stomach for 3 months, starting within 2 weeks of RT completion

Arm 2 (Standard arm): Standard-of-care follow-up (no intervention) post RT

Patient will be selected as per Inclusion \& Exclusion Criteria.

Inclusion criteria

• Female subjects aged 18 years or above with histologically proven locally advanced
• squamous cell or adenocarcinoma of the cervix
• Subjects eligible for RT and planned for definitive RT +/- chemotherapy with
• brachytherapy.
• Subjects who exceed the dose constraints of:
• Rectum/sigmoid D2cm3 EQD23 by >70 Gy, or
• Bladder D2cm3 EQD23 >80 Gy
• Subjects with adequate haematological, renal, hepatic and coagulation profiles and laboratory parameters within the following ranges:
• Haemoglobin: ≥ 8 g/dl
• ANC ≥ 1,500/mm^3
• Platelet count 100,000/mm^3
• Creatinine Clearance: ≥ 50 ml/min (as per Cockcroft-Gault formula)
• Bilirubin: ≤ 2 x Upper limit of normal (ULN)
• AST and ALT: ≤ 1.5 x ULN
• Subjects willing and able to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments
• Ability to understand and willing to sign an informed consent document

Exclusion criteria

• Subjects with known hypersensitivity or contraindication to study drug or to any known component of study drug formulation
• Subjects with clinically significant decreased hematologic reserves, with major organ failure, severe electrolyte or metabolic abnormalities, any active infection or any other medical condition that may interfere with the ability to receive study treatment
• HIV positive patients
• Subjects with a history of blood dyscrasias
• Subjects consuming any other concurrent investigational agents
• Subjects with any other previous or current malignancy or RT that is likely to interfere with the protocol treatment or any other condition which according to the principal investigator might make an individual unsuitable for this study
• Subjects participating in any other clinical study within 90 days before enrolment in the study
• Subjects on active anti-coagulant treatment

Study Procedure

• All patients will have a baseline MRI or CT of the abdomen and pelvis.
• Concurrent chemoradiation and image-guided brachytherapy will be administered as per standard of care.
• Similarly, follow-up will be as per standard of care.
• During RT, patients will be evaluated weekly by investigators, and toxicities will be recorded using CTCAE v5.0 guidelines.
• Patients in the test arm will receive sodium-copper-chlorophyllin tablets (750 mg) once daily for 3 months, starting within 2 weeks of RT completion. Thus, a patient will take a total of 90 tablets. Sufficient tablets will be dispensed to the patient at each follow-up to last until the subsequent follow-up.
• Compliance to sodium-copper-chlorophyllin will be checked weekly by the study PI and study staff and through a patient drug logbook.
• The number of patients who do not complete the sodium-copper-chlorophyllin regimen will be noted, along with the reason for non-compliance.
• At the first follow-up, all patients will undergo clinical examination, blood collection and weight documentation.
• Radiological Examination will be done as per protocol.
• Patients will be followed post-completion of RT at 1 week for assessment of toxicity.
• Patients will be assessed at 3-month intervals for 2 years.
• for late grade ≥2 RT-related gastrointestinal and genitourinary toxicities and any other changes,
• Cystoscopies and sigmoidoscopies will be done.
• Cystoscopy and sigmoidoscopy will be performed twice a year for all patients.

Criteria for Adverse events

If there is suspicion of disease relapse, treatment will be given at the investigator's discretion.

Any grade 2 or higher nausea, vomiting or other sodium-copper-chlorophyllin-related adverse events will be reported in the case report forms. If any of the above adverse events lead to admission, serious adverse events (SAEs) will be reported to the IEC.

Statistical Plan

In this study, exploratory descriptive analyses and statistical analyses tests such as Kaplan-Meier, Chi-Square, Fisher's analysis and ANOVA will be conducted.

Baseline characteristics of patients in both study arms will be summarized using means and standard deviations for continuous variables and counts and percentages for categorical variables.

The primary efficacy endpoint will be assessed using Kaplan Meier Analysis using two-sided log rank test.

Secondary analyses will include logistic regression to adjust for confounders such as age and cancer stage with subgroup analyses based on HR-CTV and other relevant factors.

Time-to-toxicity will be evaluated using Kaplan-Meier survival analysis and log-rank tests for 2- and 3-year outcomes. Haematological parameters will be compared using Chi-Square or Fisher's exact tests.

Changes in Quality of Life (QOL) scores over a 2-year follow-up will be assessed using linear mixed modelling.

Average costs per grade of toxicity and according to arm of the study will be calculated. An Analysis of Variance (ANOVA) test will be considered to determine if there is a difference in costs between grades of toxicity, and an independent sample t-test will be used to determine if the average cost according to study arm is significantly different. The costs of study related additional cystoscopy and sigmoidoscopy are not included.

All analyses will be conducted using SPSS version 28, with a significance level set at 0.05.

Interim and full analyses will be performed.

Anticipated benefits of this study

If the trial results are positive, using adjuvant sodium-copper-chlorophyllin could potentially lower the incidence of late-grade toxicity associated with RT by 10% for cervical cancer.

This has the potential to improve the long-term quality of life for patients and reduce the costs associated with managing treatment-related side effects for both the healthcare system and patients.