Nivolumab-ipilimumab and Chemoradiation for Cervical Cancer

Study Overview
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Brief Summary
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A total of 112 patients with locally advanced cervical cancer will be randomized 1:1 to standard therapy with cisplatin-based chemoradiation or nivolumab-ipilimumab induction followed by cisplatin-based chemoradiation. The primary outcome will be 3-year disease-free survival.

Detailed Description
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Patients with adenocarcinoma or squamous cell carcinoma of the cervix, FIGO Stage IB2-IB3 node positive or Stage IIB-IVA will be randomized to conventional cisplatin-based chemo-radiation or to 4 cycles of induction immunotherapy with nivolumab 1mg/kg and ipilimumab 3mg/kg every 3 weeks, followed by cisplatin chemo-radiation with concurrent nivolumab 240mg every 2 weeks. Primary outcome will be 3-year progression-free survival.

Official Title
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Randomized Phase II Study to Evaluate Induction Nivolumab-Ipilimumab, Followed by Nivolumab With Chemoradiotherapy Versus Chemoradiotherapy for Advanced Cervical Cancer

Conditions
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Uterine Cervical Neoplasms

Intervention / Treatment
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* Drug: Nivolumab 40 mg in 4 ml Injection
* Drug: Ipilimumab 200 MG in 40 ML Injection
* Radiation: Chemoradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female participants older than 18 years Documented evidence of cervical adenocarcinoma or squamous carcinoma FIGO Stage IB2-IB3 node positive or Stage IIB-IVA No prior chemotherapy, immune checkpoint inhibitors or radiotherapy for cervical cancer WHO/ECOG performance status of 0-1 At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 Target Lesion at baseline. Exclusion Criteria: Diagnosis of small cell (neuroendocrine) histology cervical cancer Intent to administer a fertility-sparing treatment regimen Undergone a previous hysterectomy Evidence of metastatic disease per RECIST 1.1 including lymph nodes ≥15 mm (short axis) above the L1 cephalad body or outside the planned radiation field. History of allogeneic organ transplantation Active or prior documented autoimmune or inflammatory disorders Uncontrolled intercurrent illness History of another primary malignancy and active primary immunodeficiency Patients with active infection Laboratory values that fall into: WBC count (WBC) < 2000/μL ; Neutrophil count < 1500/μL; Platelet count < 100 x 103/μL; Hemoglobin level < 9.0 g/dL; Serum creatinine > 1.5 x upper limit of normal (ULN) unless creatinine clearance is ≥ 40 mL/min (measured or calculated using the Cockcroft-Gault formula); Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): > 3.0 x ULN; Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN); Any positive test result for hepatitis B virus or hepatitis C virus that indicates the presence of the virus, for example, positive Hepatitis B surface antigen (HBsAg, Australia antigen) or Hepatitis C antibodies (anti- HCV) positive (unless the HCV-RNA is negative). Participants with a condition requiring systemic treatment or with corticosteroids (>10 mg daily of a prednisone equivalent) or other immunosuppressive drugs within 14 days of initiating study treatment. Pregnant or breastfeeding woman

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 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: Prospective randomized trial, stratified by center, disease stage and type of radiation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Chemoradiation<br>Traditional radiation therapy with a target of 45 Gy in 25 1.8Gy fractions with concurrent weekly cisplatin 40mg/m2/week or carboplatin AUC 2/week | Radiation: Chemoradiation<br>* Radiation to a dose of 45Gy over 25 1.8Gyfractions and brachytherapy with concurrent weekly cisplatin 40mg/m2/w or carboplatin AUC 2/w<br>* Other names: Cisplatin-based chemoradiation;|
| Experimental: Immunotherapy<br>4 cycles of induction therapy with nivolumab 1mg/kg and ipilimumab 3mg/kg every 3 weeks followed by traditional radiation therapy with a target of 45 Gy in 25 1.8Gy fractions with concurrent weekly cisplatin 40mg/m2/week (or carboplatin AUC 2/week) with concurrent nivolumab 240mg every 2 weeks. | Drug: Nivolumab 40 mg in 4 ml Injection<br>* Nivolumab 1mg/kg every 3 weeks for 4 cycles prior to radiation and 240mg every 2 weeks with concurrent radiation<br>* Other names: Opdivo;Drug: Ipilimumab 200 MG in 40 ML Injection<br>* Ipilimumab 3mg/kg every 3 weeks for 4 cycles prior to radiation<br>* Other names: Yervoy;Radiation: Chemoradiation<br>* Radiation to a dose of 45Gy over 25 1.8Gyfractions and brachytherapy with concurrent weekly cisplatin 40mg/m2/w or carboplatin AUC 2/w<br>* Other names: Cisplatin-based chemoradiation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year progression-free survival | No evidence of disease recurrence/regrowth after 3 years of follow-up | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year overall survival | Rate of survival 3 years after the end of chemoradiation | 3 years | 
| Objective response rate | RECIST response | 90 days after the end of chemoradiation | 
| Response duration | Time from maximum response to disease progression | Through study completion, an average of 3 year | 
| To evaluate health related quality of life (HRQoL): defined as the change from baseline of disease-related symptoms and quality of life of patients undergoing treatment Nivolumab-ipilimumab and Chemoradiation for Cervical Cancer | Evaluate health related quality of life using the instrument EORTC QLQ-C30 v3 based on European Organization for Research and Treatment of Cancer (EORTC). The EORTC QLQ-C30 v3 questionnaire, consisting of 30 questions covering 15 domains, divided into three distinct scales: state scale global health and quality of life (it has only one domain, global health measure); functional scale (physical function, role performance, emotional function, cognitive function and social function domains); and symptom scale (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea and financial difficulties). The scores on each scale range from 0 - 100. The global and functional health scales indicate better quality of life as their score approaches 100. For the symptoms scale, the analysis is inverse, with better performance for quality of life when the scores approach the score minimum (zero). | Baseline (time from screening - before starting treatment) and at the end of treatment (56 days after the last dose of radiotherapy). | 
| Evaluate health related quality of life using supplemental cervical cancer module (EORTC CX24) to evaluate patients submitted to treatment with Nivolumab-ipilimumab and Chemoradiation for Cervical Cancer. | The EORTC - CX24 questionnaire contains 24 questions, divided into three multiple-item scales and six single-item scales, of which 11 refer to symptoms (questions 31-37, 39 and 41-43), three about body image. (questions 45-47), four questions on sexual/vaginal function (questions 50-53), one on lymphedema (question 38), one for evaluation of peripheral neuropathy (question 40), one for evaluation of menopausal symptoms (question 44) ), one on sexual concerns (question 48), one on sexual activity (question 49) and one on sexual pleasure (question 54). The answers are transformed into a score from 0 - 100 and calculated separately for each scale. | Baseline (time from screening - before starting treatment) and at the end of treatment (56 days after the last dose of radiotherapy). | 
| Treatment-related toxicity | Treatment-related toxicity according to CTCAE version 4.0 (Common Toxicity Criteria for Adverse Events ) | Through study completion, an average of 3 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Uterine Cervical Neoplasms, Nivolumab, Ipilimumab, Chemoradiation, Anti-PD1, Anti-PDL1, Anti-CTLA4, Immunotherapy