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

NCT07164534NOT_YET_RECRUITINGPHASE3INTERVENTIONAL

Summary

Cervical cancer is the second most common cancer in Indian women, and most patients are diagnosed at advanced stages. The standard treatment for these stages is concurrent chemoradiotherapy, but this can cause long-term side effects such as bladder inflammation, strictures, ulcers, and tissue damage, which negatively impact patients' quality of life. Previous studies have shown that oral sodium-copper-chlorophyllin can help reduce radiation-related side effects in rectal, prostate, and cervical cancer patients. However, no study has compared side effects between patients receiving standard follow-up care and those taking sodium-copper-chlorophyllin during follow-up. We hypothesize that the use of sodium-copper-chlorophyllin as a short-duration adjuvant is associated with reduced incidence of late grade 2 or higher gastrointestinal and genitourinary toxicities compared to patients receiving standard-of-care follow-up.

Key Facts

Lead Sponsor

Tata Memorial Hospital

Enrollment

316

Start Date

2026-03-01

Completion Date

2030-03-01

Study Type

INTERVENTIONAL

Official Title

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

Interventions

Sodium-copper-chlorophyllina semi-synthetic derivative of chlorophyllis made up of a mixture of sodium copper salts.

Conditions

Uterine Cervical Neoplasm

Eligibility

Age Range

18 Years+

Sex

FEMALE

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 D 2cm³ EQD2 ³ by more than 70 Gy, or
  * Bladder D 2cm³ EQD2 ³ more than 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 willingness to sign an informed consent document

Exclusion Criteria:

* Subjects with known hypersensitivity or contraindication to the study drug or to any known component of the 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

Outcome Measures

Primary Outcomes

Proportion of patients with cumulative late grade 2 or higher radiotherapy-related gastrointestinal and genitourinary toxicity incidence

Proportion of patients with cumulative late grade 2 or higher radiotherapy-related gastrointestinal and genitourinary toxicity incidence, reported using the time-to-event method, taken from the date of random assignment to the occurrence of late toxicity, or death because of late toxicity, at 24 months after completion of RT, by addition of sodium-copper-chlorophyllin for 3 months post RT (starting within 2 weeks of treatment completion), as compared to standard-of-care follow-up.

Time frame: 24 months

Secondary Outcomes

Local Control at 24 months

Local Control: defined as the time interval between the date of random assignment and first evidence of local relapse.

Time frame: 24 months

Pelvic Control at 24 months

Pelvic Control: defined as the time interval between the dates of random assignment and first evidence of local and pelvic relapse

Time frame: 24 months

Nodal Relapse at 24 months

Nodal Control: defined as the time interval between the dates of random assignment and first evidence of any regional nodal relapse

Time frame: 24 months

Cumulative C-MOSES score

Cumulative time and severity incidence of toxicity scores (Months and Severity Score (MOSES) C-MOSES) for each patient, which is a toxicity summarising method that incorporates time

Time frame: 24 months

Proportion of patients with radiotherapy-related urinary stress incontinence

Proportion of patients with RT-related urinary stress incontinence, as measured by the Oxford scale at treatment completion, 3 months, 6 months and 9 months after completion of RT

Time frame: At treatment completion, 3 months, 6 months, 9 months

Disease-Free Survival at 24 months

Disease-Free Survival: defined as the time interval between date of random assignment and first relapse or death because of any cause.

Time frame: 24 months

Overall Survival at 24 months

Overall Survival: defined as the time interval between the date of random assignment and death due to any cause.

Time frame: 24 months

Proportion of patients with any acute toxicity

Proportion of patients with any acute toxicity at treatment completion, 4 weeks, 8 weeks and 12 weeks after treatment completion.

Time frame: 4 weeks, 8 weeks and 12 weeks post radiotherapy completion

Proportion of patients with any haematological abnormalities

Proportion of patients with any haematological abnormalities (anaemia, neutropenia, thrombocytopenia) at 3 months and 6 months after completion of RT

Time frame: 3 months and 6 months post radiotherapy completion

Patient-reported quality of life (QoL)

Patient-reported quality of life (QoL) using EORTC-QLQ-C30 at baseline and all follow-ups

Time frame: 3, 6, 9, 12, 15, 18, 21 and 24 months after radiotherapy completion

Cost of management of radiotherapy-related toxicity

Cost (in INR) of management of treatment-related toxicity in both arms

Time frame: 24 months

Linked Papers

2021-10-20

Severity and Persistency of Late Gastrointestinal Morbidity in Locally Advanced Cervical Cancer: Lessons Learned From EMBRACE-I and Implications for the Future

The purpose was to evaluate patient- and treatment-related risk factors for physician-assessed and patient-reported gastrointestinal (GI) symptoms after radio(chemo)therapy and image guided adaptive brachytherapy in locally advanced cervical cancer. Of 1416 patients from the EMBRACE-I study, 1199 and 1002 were prospectively evaluated using physician-assessed (Common Terminology Criteria for Adverse Events [CTCAE]) and patient-reported (European Organization for Research and Treatment of Cancer [EORTC]) GI symptoms, respectively. CTCAE severe grade (grade [G] ≥3) events were pooled according to the location in the GI tract (anus/rectum, sigmoid, and colon/small bowel). CTCAE G ≥2 and EORTC "very much" and "quite a bit" plus "very much" scores (≥ "quite a bit") were analyzed for individual symptoms with Cox regression. Logistic regression was used for persistent G ≥1 and EORTC ≥ "quite a bit" symptoms, defined if present in at least half of follow-ups. The incidence of G ≥3 events was 2.8%, 1.8%, and 2.3% for G ≥3 anus/rectum, sigmoid, and colon/small bowel events, respectively. Among G ≥2 symptoms, diarrhea and flatulence were the most prevalent (8.5% and 9.9%, respectively). Among patient-related factors, baseline morbidity, increasing age, smoking status, and low body mass index were associated with GI symptoms to varying degrees. Among treatment-related factors, rectum D The analysis showed that both EBRT and image guided adaptive brachytherapy contribute to GI symptoms after locally advanced cervical cancer treatment. Rectum D

2021-09-10

Late Toxicity After Adjuvant Conventional Radiation Versus Image-Guided Intensity-Modulated Radiotherapy for Cervical Cancer (PARCER): A Randomized Controlled Trial

PURPOSE Postoperative Adjuvant Radiation in Cervical Cancer (PARCER), a phase III randomized trial, compared late toxicity after image-guided intensity-modulated radiotherapy (IG-IMRT) with three-dimensional conformal radiation therapy (3D-CRT) in women with cervical cancer undergoing postoperative radiation. METHODS Patients were randomly assigned to receive either IG-IMRT or 3D-CRT after stratification for the type of hysterectomy and use of concurrent chemotherapy. The primary end point was 3-year grade ≥ 2 late GI toxicity assessed using Common Toxicity Criteria for Adverse Events v 3.0 and estimated using time-to-event, intention-to-treat analysis, with a study level type I error of 0.05 and a nominal α of .047 after accounting for one interim analysis. Secondary end points included acute toxicity, health-related quality of life, and pelvic relapse-free, disease-free, and overall survival. RESULTS Between 2011 and 2019, 300 patients were randomly assigned (IG-IMRT 151 and 3D-CRT 149). At a median follow-up of 46 (interquartile range, 20-72) months, the 3-year cumulative incidence of grade ≥ 2 late GI toxicity in the IG-IMRT and 3D-CRT arms were 21.1% versus 42.4% (hazard ratio [HR] 0.46; 95% CI, 0.29 to 0.73; P < .001). The cumulative incidence of grade ≥ 2 any late toxicity was 28.1% versus 48.9% (HR 0.50; 95% CI, 0.33 to 0.76; P < .001), respectively. Patients reported reduced diarrhea ( P = .04), improved appetite ( P = .008), and lesser bowel symptoms ( P = .002) with IG-IMRT. However, no difference was observed in the time by treatment interaction. The 3-year pelvic relapse-free survival and disease-free survival in the IG-IMRT versus the 3D-CRT arm were 81.8% versus 84% (HR 1.17; 95% CI, 0.68 to 1.99; P = .55) and 76.9% versus 81.2% (HR 1.03; 95% CI, 0.62 to 1.71; P = .89), respectively. CONCLUSION IG-IMRT results in reduced toxicity with no difference in disease outcomes.

2021-02-03

Risk factors and dose-effects for bladder fistula, bleeding and cystitis after radiotherapy with imaged-guided adaptive brachytherapy for cervical cancer: An EMBRACE analysis

To identify patient- and treatment-related risk factors for fistula, bleeding, cystitis, pain and difficulty in voiding in locally advanced cervical cancer patients treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Morbidity within the EMBRACE-I study was prospectively reported for physician-assessed (CTCAE) fistula, bleeding and cystitis and patient-reported (EORTC) pain and difficulty in voiding. Analysis of risk factors was performed in patients without bladder infiltration. Risk factors were tested with Cox regression for grade (G) ≥ 3 cystitis, for G ≥ 2 fistula, bleeding and cystitis, and for EORTC "very much" and "quite a bit" or worse. Of 1416 patients enrolled, 1153 and 884 patients without bladder infiltration were evaluable for the analysis of CTCAE and EORTC items, respectively. Median follow-up was 48[3-120] months. Crude incidence rates for G ≥ 2 fistula, bleeding and cystitis were 0.7%, 2.7% and 8.8%, respectively, and 16% and 14% for "quite a bit" or worse pain and difficulty in voiding, respectively. Baseline urinary morbidity and overweight/obesity were significant risk factors for most endpoints. Bladder D Clinical and treatment-related risk factors for bladder fistula, bleeding and cystitis were identified within a prospective and multi-institutional setting. A dose-effect was established with bladder D

2020-10-14

Importance of the ICRU bladder point dose on incidence and persistence of urinary frequency and incontinence in locally advanced cervical cancer: An EMBRACE analysis

To identify patient- and treatment-related risk factors and dose-effects for urinary frequency and incontinence in locally advanced cervical cancer (LACC) treated with radio(chemo)therapy and image-guided adaptive brachytherapy (IGABT). Physician-assessed (CTCAE) and patient-reported (EORTC) frequency and incontinence recorded in the EMBRACE-I study were analysed. Risk factors analysis was performed in patients without bladder infiltration and with baseline morbidity available. Cox regression was used for CTCAE grade (G) ≥ 3 and G ≥ 2 and for EORTC "very much" and "quite a bit" or worse. Logistic regression was used for late persistent morbidity defined when CTCAE G ≥ 1 or EORTC ≥ "quite a bit" were scored in at least half of follow-ups. Longitudinal data on 1153 and 884 patients were available for CTCAE and EORTC analysis, respectively. Median follow-up was 48[3-120] months. Crude incidence rates of G≥2 were 13% and 11% for frequency and incontinence, respectively. Baseline morbidity and overweight-obesity were risk factors for both symptoms. Elderly patients were at higher risk for incontinence. Patients receiving conformal-radiotherapy were at higher risk for frequency. ICRU bladder point (ICRU-BP) dose was a stronger predictor for incontinence than bladder D ICRU-BP dose, in addition to clinical parameters, is a risk factor for urinary incontinence and shows a dose-effect after radio(chemo)therapy and IGABT. ICRU-BP dose should be monitored during treatment planning alongside volumetric parameters. Frequency seems associated with larger irradiated volumes.

2020-08-25

Persistence of Late Substantial Patient-Reported Symptoms (LAPERS) After Radiochemotherapy Including Image Guided Adaptive Brachytherapy for Locally Advanced Cervical Cancer: A Report From the EMBRACE Study

This report describes the persistence of late substantial treatment-related patient-reported symptoms (LAPERS) in the multi-institutional EMBRACE study on magnetic resonance image guided adaptive brachytherapy in locally advanced cervical cancer (LACC). Patient-reported symptoms (European Organization for Research and Treatment of Cancer [EORTC]-C30/CX24) and physician-assessed morbidity (Common Terminology Criteria for Adverse Events [CTCAE], version 3.0) were assessed at baseline and regular timepoints during follow-up. Patients with sufficient EORTC follow-up (baseline and ≥3 late follow-up visits) were analyzed. LAPERS events were defined as the presence of substantial EORTC symptoms (quite a bit/very much) for at least half of the assessments (persistence) and progression beyond baseline condition (treatment-related). For each EORTC symptom, the ratio between LAPERS rates and crude incidence rates of substantial symptoms was calculated to represent the proportion of symptomatic patients with persisting symptoms. For 9 symptoms with a corresponding EORTC/CTCAE assessment, the overlap of LAPERS and severe morbidity events (grades 3-5) was evaluated. Of 1047 patients with EORTC available, 741 had sufficient follow-up for the LAPERS analyses. The median follow-up was 59 months (interquartile range, 42-70 months). Across all symptoms, the proportion of patients with LAPERS events (LAPERS rates) was in median 4.6% (range, 0.0% vaginal bleeding to 20.4% tiredness). Urinary frequency, neuropathy, fatigue, insomnia, and menopausal symptoms revealed LAPERS rates of >10%. Vomiting, blood in stool, urinary pain/burning, and abnormal vaginal bleeding displayed LAPERS rates of <1%. A median of 19% of symptomatic patients (interquartile range, 8.0%-28.5%) showed persistent long-term symptoms (LAPERS events). In symptoms with a corresponding EORTC/CTCAE assessment, 12% of LAPERS events were accompanied by a severe CTCAE event. Within this large cohort of survivors of LACC, a subgroup of patients with persistent symptoms (LAPERS events) was identified. For symptoms with a corresponding EORTC/CTCAE assessment, the vast majority of LAPERS events occurred in patients without corresponding severe physician-assessed morbidity. These findings emphasize the importance of distinguishing between transient and persisting symptoms in the aftercare of LACC survivors.

Temporal course of late rectal toxicity &amp; impact of intervention in patients undergoing radiation for cervical cancer

Background &amp; objectives: There is limited information available on the temporal course of late stage radiotherapy adverse effects. The present study reports on the temporal course of late toxicities after chemoradiation and brachytherapy. Methods: Women with cervical cancer who presented with late toxicity after (chemo) radiation were included in the study. Grade of toxicity (Clinical Toxicity Criteria for Adverse Events version 4.03) and type of intervention were recorded at three-monthly interval for the first year and then six monthly until 24 months. Direct cost for the management of toxicity was calculated. Univariate analysis was performed to understand the impact of various factors on persistence of toxicity. Results: Ninety two patients were included in this study. Grades I, II, III and IV toxicities were observed in 50 (54%), 33 (36%), 7 (8%) and 2 (2%) patients, respectively, at first reporting. Patients spent a median of 12 (3-27) months with toxicity. At 12 months, 48/92 (52.2%) patients had a complete resolution of toxicity, whereas 27/92 (29.3%) patients had low grade (I-II) persistent toxicity. Only 6/92 (6.5%) patients who had grade III−IV toxicity had resolution to a lower grade. Four (4.3%) patients died due to toxicity. At 24 months, 9 (10%) patients continued to have grade ≥ III toxicity. On an average, 7 (2-24) interventions were required for the clinical management of late toxicity and median direct cost incurred was JOURNAL/ijmer/04.03/02223309-202108000-00023/math_23MM1/v/2022-09-30T185846Z/r/image-tiff 50,625 (1,125-303,750). Interpretation &amp; conclusions: In this study late radiation toxicity resolved within 12 months in more than half of patients. However, others are likely to have had persistent lower grade toxicity or progression to higher grade. Structured strategies are hence needed for the effective management of late toxicities.

MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study

The concept of the use of MRI for image-guided adaptive brachytherapy (IGABT) in locally advanced cervical cancer was introduced 20 years ago. Here, we report on EMBRACE-I, which aimed to evaluate local tumour control and morbidity after chemoradiotherapy and MRI-based IGABT. EMBRACE-I was a prospective, observational, multicentre cohort study. Data from patients from 24 centres in Europe, Asia, and North America were prospectively collected. The inclusion criteria were patients older than 18 years, with biopsy-proven squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix, The International Federation of Gynecology and Obstetrics (FIGO) stage IB-IVA disease or FIGO stage IVB disease restricted to paraaortic lymph metastasis below the L1-L2 interspace, suitable for curative treatment. Treatment consisted of chemoradiotherapy (weekly intravenous cisplatin 40 mg/m Patient accrual began on July 30, 2008, and closed on Dec 29, 2015. A total of 1416 patients were registered in the database. After exclusion for not meeting patient selection criteria before treatment, being registered but not entered in the database, meeting the exclusion criteria, and being falsely excluded, data from 1341 patients were available for analysis of disease and data from 1251 patients were available for assessment of morbidity outcome. MRI-based IGABT including dose optimisation was done in 1317 (98·2%) of 1341 patients. Median high-risk clinical target volume was 28 cm Chemoradiotherapy and MRI-based IGABT result in effective and stable long-term local control across all stages of locally advanced cervical cancer, with a limited severe morbidity per organ. These results represent a positive breakthrough in the treatment of locally advanced cervical cancer, which might be used as a benchmark for clinical practice and all future studies. Medical University of Vienna, Aarhus University Hospital, Elekta AB, and Varian Medical Systems.

Linked Investigators

Akshay Mangaj

Amita Maheshwari

Barbara Segedin

F. Huang

Ina Jürgemlienk-Schulz

Jacob Christian Lindegaard

Jaya Ghosh

Kari Tanderup

Kedar Deodhar

Sofia Spampinato

Sudeep Gupta

Supriya Chopra