Adjuvant Chemotherapy in cfHPV-DNA Plasma Positive Patients: A Biomarker In Locally Advanced Cervical Cancer

Study Overview
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Brief Summary
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This study hypothesizes that patients who persist with cell-free human papillomavirus deoxyribonucleic acid (cfHPV-DNA) plasma expression at the end of standard treatment, can derive the benefit of using adjuvant chemotherapy in locally advanced cervical cancer (CC). After standard treatment based on concomitant chemoradiotherapy regime, a qualitative and quantitative research of cfHPV-DNA in plasma of patients will be conducted. Those with a negative qualitative research result will leave the study. Patients who have positive research for plasma 16/18 cfHPV-DNA at the end of chemoradiotherapy treatment will be randomized to receive two additional cycles of adjuvant chemotherapy or observation. Patients will be followed with conduction of computed tomography (CT) scan of the thorax and magnetic resonance (MRI) of abdomen and pelvis and clinical and gynecological examination at every four months.

Detailed Description
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A prospective, randomized, multicenter, national, superiority, parallel, clinical trial, design to evaluate implementation components for conducting a national clinical trial using adjuvant chemotherapy in patients with locally advanced cervical cancer, selected by cfDNA-HPV biomarker. At the end of this pilot study, reaching feasibility goal, it is proposed to amplify size sample, with the same design. Patients will be randomized by stratified randomization process to belong to one of the groups: control (Group B) or intervention (Group C), emphasizing homogeneity of risk factors between them. A randomized list will be generated by using a suitable software, using variable size blocks (2 or 4), with stratification for site and staging. The confidentiality of the randomization list will be maintained through an automated, centralized, Internet-based randomization system, available 24 hours a day (RedCap). Selected patients must receive standard treatment based on concomitant chemoradiotherapy regime, with dose of radiation of 40-50 greys (Gy) (considering additional boost of 10-15 Gy in lymph nodes, radiologically or surgically, compromised) and brachytherapy of 30-40 Gy and cisplatin 40mg/m2 weekly. After four weeks of the end of treatment, a qualitative and quantitative research of cfHPV-DNA in plasma of patients will be conducted. Those with a negative qualitative research result will leave the study. Patients who have positive research for plasma 16/18 cfHPV-DNA at the end of chemoradiotherapy treatment will be randomized to receive two additional cycles of adjuvant chemotherapy or observation. Patients will be followed with conduction of computed tomography (CT) scan of the thorax and magnetic resonance (MRI) of abdomen and pelvis and clinical and gynecological examination at every four months.

Official Title
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Adjuvant Chemotherapy in Cell-free Human Papillomavirus Deoxyribonucleic Acid (cfHPV-DNA) Plasma Positive Patients: A Biomarker In Locally Advanced Cervical Cancer (CC)

Conditions
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Cervical Cancer, Cervix Cancer, Cervix Neoplasm

Intervention / Treatment
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* Drug: cisplatin, gemcitabine
* Other: Follow-up


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IB3 to IVA will be included prospectively. Karnofsky performance status score ≥70, with estimated life expectancy ≥12 weeks, Immunocompetent, Positive research for types 16 or 18 cfHPV-DNA in plasma at diagnosis, Proper hematological, liver and kidney functions. Inclusion criteria will include absolute neutrophils count ≥1.5 x 109/L, platelets ≥100 x 10/L, hemoglobin ≥10,0 g/dL, serum bilirubin ≤ 2.0 x upper limit of normal (ULN), calculated creatinine clearance ≥60 mL/min and alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase ≤ 2.5 x ULN. Patients of child-bearing potential were obligated to use an approved contraceptive method during and for 3 months after the study; Agree with research procedures, by signing the Informed Consent Form (ICF). Exclusion Criteria: Previous cervical cancer or other malignancies, Pregnant women, Previous HPV vaccination with bivalent or superior vaccine, Period between start and end of chemoradiotherapy treatment superior to eight weeks, Inability to perform concurrent cisplatin based-chemoradiotherapy. Tumors containing different HPV genotypes of 16 or 18.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A prospective, randomized, multicenter, national, superiority, parallel, clinical trial, design to evaluate implementation components for conducting a national clinical trial using adjuvant chemotherapy in patients with locally advanced cervical cancer, selected by cfDNA-HPV biomarker. At the end of this pilot study, reaching feasibility goal, it is proposed to amplify size sample, with the same design. The participants will conduct a blood collection for research of cfDNA-HPV and will receive conventional treatment, gold standard currently, characterizing the descriptive phase of the research. In the second operational phase, it will happen the study randomization, designing an experimental study. The pilot study is scheduled to last one year and estimate the possibility to recruit between 30 and 50 patients during 2023.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Control Arm (Standard of Care)<br>Patients will be followed with computed tomography (CT) scan of the thorax and magnetic resonance (MRI) of abdomen and pelvis and clinical and gynecological examination at every four months. | Other: Follow-up<br>* Patients will be followed with computed tomography (CT) scan of the thorax and magnetic resonance (MRI) of abdomen and pelvis and clinical and gynecological examination at every four months.<br>|
| Experimental: Experimental Arm<br>Receive two cycles of cisplatin-based adjuvant chemotherapy 50mg/m2 D1 and gemcitabine 1000mg/m2 D1 and D8 at every 21 days. After that, patients will be followed with conduction of computed tomography (CT) scan of the thorax and magnetic resonance (MRI) of abdomen and pelvis and clinical and gynecological examination at every four months. | Drug: cisplatin, gemcitabine<br>* Two additional cycles of cisplatin-based adjuvant chemotherapy 50mg/m2 D1 and gemcitabine 1000mg/m2 D1 and D8 at every 21 days.<br>Other: Follow-up<br>* Patients will be followed with computed tomography (CT) scan of the thorax and magnetic resonance (MRI) of abdomen and pelvis and clinical and gynecological examination at every four months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activation speed | Accessing regulatory process, hiring and training of investigator sites. | 30 days | 
| Eligibility profile for study of patients with cervical cancer | Analyzing the impact of pandemic on disease diagnosis period. | 120 days | 
| Potential for recruitment | Potential for recruiting 4 to 12 patients/month in each investigator site is sufficient to reach sample goal. | 210 days | 
| Validation of operation structure of the project | Validation of operation structure includes repository, data collection tools, logistics for intervention distribution (chemotherapy) to the participating sites, strategies for recruitment and stimulation of adherence to intervention and follow-ups. | 270 days | 
| Adherence rates to treatment allocated per patient | Objectify 85% or more of adherence rates during intervention. | 270 days | 
| Measure loss of follow-up per study protocol | Aiming at reaching up to 20% during follow-ups and identification of critical factors for loss of follow-up and suggesting mitigation strategies. | 270 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Description of overall rates (non-comparative between treatment groups) of progression-free survival. | 210 days | 
| Overall survival | Description of overall rates (non-comparative between treatment groups) of overall survival. | 210 days | 
| Response rate | Description of response rate via Response Evaluation Criteria In Solid Tumours (RECIST) criteria 1.1 2009. | 210 days | 
| Quality of life questionnaire | Description of quality of life via European Organisation for Research and Treatment of Cancer (EORTC) quality of life core questionnaire (QLC-C30) and a complementary module of the cervical cancer-specific Quality of Life module of the European Organization for Research and Treatment of Cancer (EORTC QLQ-CX24). | 210 days | 
| Adverse Events | Description of tolerance to proposed intervention, by creating a Data and Safety Monitoring Board (DSMB). | 210 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Human papillomavirus, HPV, Cervical cancer, Circulating free DNA, Adjuvant chemotherapy