Nivolumab-ipilimumab and Chemoradiation for Cervical Cancer

Uterine Cervical Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05492123
• Other study ID #: BRAVA- Cervical - SGPP 5031-21
• Status: Recruiting
• Phase: Phase 2
• Start date: August 30, 2022
• Est. completion date: March 31, 2028

Study information

• Verified date: January 2023
• Source: Hospital Israelita Albert Einstein
• Contact: Diogo Bugano, MD
• Phone: +55-11-2151-0240
• Email: diogo.gomes[@]einstein.br
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 112
• Est. completion date: March 31, 2028
• Est. primary completion date: December 31, 2026
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 95 Years

Eligibility

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

Related Conditions & MeSH terms

• Uterine Cervical Neoplasms

Intervention

Drug:
• Nivolumab 40 mg in 4 ml Injection
Nivolumab 1mg/kg every 3 weeks for 4 cycles prior to radiation and 240mg every 2 weeks with concurrent radiation
• Ipilimumab 200 MG in 40 ML Injection
Ipilimumab 3mg/kg every 3 weeks for 4 cycles prior to radiation

Radiation:
• Chemoradiation
Radiation to a dose of 45Gy over 25 1.8Gyfractions and brachytherapy with concurrent weekly cisplatin 40mg/m2/w or carboplatin AUC 2/w

Locations

Country	Name	City	State
Brazil	Hospital de Amor	Barretos	São Paulo
Brazil	Hospital das Clinicas da UFMG	Belo Horizonte	Minas Gerais
Brazil	Universidade Federal de Roraima	Boa Vista	Roraima
Brazil	Hospital Erasto Gaertner	Curitiba	Paraná
Brazil	CEPON - Florianópolis	Florianópolis	Santa Catarina
Brazil	CRIO -Centro Regional Integrado de Oncologia	Fortaleza	Ceará
Brazil	Hospital São Lucas - PUCRS	Porto Alegre	Rio Grande Do Sul
Brazil	Multi Oncoclinicas Recife	Recife	Pernambuco
Brazil	INCA - Instituto Nacional do Cancer	Rio De Janeiro
Brazil	Clinica AMO	Salvador	Bahia
Brazil	Hospital De Base de São José do Rio Preto - CIP São José	São José Do Rio Preto	São Paulo
Brazil	AC Camargo Cancer Center	São Paulo
Brazil	Hospital Israelita Albert Einstein	São Paulo
Brazil	Hospital Municipal Vila Santa Catarina	São Paulo

Sponsors (3)

Lead Sponsor	Collaborator
Hospital Israelita Albert Einstein	Brava, Bristol-Myers Squibb

Country where clinical trial is conducted

Brazil, 

References & Publications (3)

Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol. 2008 Dec 10;26(35):5802-12. doi: 10.1200/JCO.2008.16.4368. Epub 2008 Nov 10. — View Citation

Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, Lopez-Picazo JM, Machiels JP, Delord JP, Evans TRJ, Boni V, Calvo E, Topalian SL, Chen T, Soumaoro I, Li B, Gu J, Zwirtes R, Moore KN. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019 Nov 1;37(31):2825-2834. doi: 10.1200/JCO.19.00739. Epub 2019 Sep 5. — View Citation

Santin AD, Deng W, Frumovitz M, Buza N, Bellone S, Huh W, Khleif S, Lankes HA, Ratner ES, O'Cearbhaill RE, Jazaeri AA, Birrer M. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). Gynecol Oncol. 2020 Apr;157(1):161-166. doi: 10.1016/j.ygyno.2019.12.034. Epub 2020 Jan 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	3-year progression-free survival	No evidence of disease recurrence/regrowth after 3 years of follow-up	3 years
Secondary	3-year overall survival	Rate of survival 3 years after the end of chemoradiation	3 years
Secondary	Objective response rate	RECIST response	90 days after the end of chemoradiation
Secondary	Response duration	Time from maximum response to disease progression	Through study completion, an average of 3 year
Secondary	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).
Secondary	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).
Secondary	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