Nivolumab-ipilimumab and Chemoradiation for Cervical Cancer

Phase 2

Recruiting

• Conditions: Uterine Cervical Neoplasms
• Interventions: Drug: Nivolumab 40 mg in 4 ml Injection; Drug: Ipilimumab 200 MG in 40 ML Injection; Radiation: Chemoradiation

• Registration Number: NCT05492123
• Lead Sponsor: Hospital Israelita Albert Einstein

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2022-07-22
• Study First Submitted QC: 2022-08-05
• Study First Posted: 2022-08-08
• Study Start: 2022-08-30
• Status Verified: 2023-01
• Last Update Submitted: 2024-01-03
• Last Update Posted: 2024-01-05
• Primary Completion: 2026-12-31
• Study Completion: 2028-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: Female
• Target Recruitment: 112

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:

1. WBC count (WBC) < 2000/μL ;

2. Neutrophil count < 1500/μL;

3. Platelet count < 100 x 103/μL;

4. Hemoglobin level < 9.0 g/dL;

5. 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);

6. Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT): > 3.0 x ULN;

7. Total bilirubin > 1.5 x ULN (except participants with Gilbert Syndrome who must have a total bilirubin level of < 3.0 x ULN);

8. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Immunotherapy	Ipilimumab 200 MG in 40 ML Injection	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.
Immunotherapy	Chemoradiation	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.
Standard Chemoradiation	Chemoradiation	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
Immunotherapy	Nivolumab 40 mg in 4 ml Injection	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.

Primary Outcome Measures

Name	Time	Method
3-year progression-free survival	3 years	No evidence of disease recurrence/regrowth after 3 years of follow-up

Secondary Outcome Measures

Name	Time	Method
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.	Baseline (time from screening - before starting treatment) and at the end of treatment (56 days after the last dose of radiotherapy).	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.
Objective response rate	90 days after the end of chemoradiation	RECIST response
Response duration	Through study completion, an average of 3 year	Time from maximum response to disease progression
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	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 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).
Treatment-related toxicity	Through study completion, an average of 3 year	Treatment-related toxicity according to CTCAE version 4.0 (Common Toxicity Criteria for Adverse Events )
3-year overall survival	3 years	Rate of survival 3 years after the end of chemoradiation

Trial Locations

Locations (14)

Hospital das Clinicas da UFMG; 🇧🇷 Belo Horizonte, Minas Gerais, Brazil

Multi Oncoclinicas Recife; 🇧🇷 Recife, Pernambuco, Brazil

CRIO -Centro Regional Integrado de Oncologia; 🇧🇷 Fortaleza, Ceará, Brazil

AC Camargo Cancer Center; 🇧🇷 São Paulo, Brazil

Hospital Municipal Vila Santa Catarina; 🇧🇷 São Paulo, Brazil

Hospital São Lucas - PUCRS; 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil

Universidade Federal de Roraima; 🇧🇷 Boa Vista, Roraima, Brazil

INCA - Instituto Nacional do Cancer; 🇧🇷 Rio De Janeiro, Brazil

Hospital Israelita Albert Einstein; 🇧🇷 São Paulo, Brazil

Hospital Erasto Gaertner; 🇧🇷 Curitiba, Paraná, Brazil

Clinica AMO; 🇧🇷 Salvador, Bahia, Brazil

CEPON - Florianópolis; 🇧🇷 Florianópolis, Santa Catarina, Brazil

Hospital de Amor; 🇧🇷 Barretos, São Paulo, Brazil

Hospital De Base de São José do Rio Preto - CIP São José; 🇧🇷 São José Do Rio Preto, São Paulo, Brazil