Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months

Phase 1

Completed

• Conditions: Locally Advanced Cervical Cancer; Cervical Cancer
• Interventions: Drug: Nivolumab Injection; Drug: Cisplatin; Radiation: radiotherapy

• Registration Number: NCT03298893
• Lead Sponsor: Institut Curie

Brief Summary

To date, the majority of clinical trials on checkpoint inhibitors have tested these agents as monotherapy, and the next logical step is to evaluate rational therapeutic associations. The aim of the NiCOL study is to assess the safety of nivolumab in association with chemoradiation therapy and to gain initial insight into its efficacy in association with the current standard of care, including chemoradiation.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-09-27
• Study First Submitted QC: 2017-09-27
• Study First Posted: 2017-10-02
• Study Start: 2017-11-27
• Primary Completion: 2020-10-30
• Study Completion: 2022-03-07
• Status Verified: 2022-04
• Last Update Submitted: 2024-02-01
• Last Update Posted: 2024-02-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 21

Inclusion Criteria

1. Adult patients at least 18 years of age;

2. Ability to understand and the willingness to sign a written informed consent document.;

3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1;

4. Histologically confirmed locally advanced cervical cancer, i.e. FIGO stages IB2 to IVA, squamous-cell carcinoma or adenocarcinoma, with indication for radiotherapy and cisplatin-based chemotherapy with a curative intent as confirmed by a multidisciplinary board including a radiation oncologist. PD-L1 expression on tumor will not be required for inclusion; (staging may include [18F]-fluorodeoxyglucose (FDG) PET-CT and/or para-aortic dissection in accordance with usual practice in each investigational center and at the Investigator's discretion);

5. Disease amenable to biopsy since three tumor samples are mandatory prior to treatment;

6. Laboratory values at Screening must meet the following criteria :

   neutrophils ≥ 1.0 x 109/L, lymphocytes ≥ 0.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 8.0 g/dL, creatinine ≤ 2 times the upper limit of normal (ULN), aspartate aminotransferase (AST) ≤ 3 ULN, alanine aminotransferase (ALT) ≤ 3 x ULN, total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if genetically documented Gilbert's syndrome).

7. For women with child-bearing potential, negative blood or urinary pregnancy test within 24 hours of initiation of nivolumab, as well as appropriate method of contraception throughout the study ;

8. Affiliated to the French Social Security System.

Exclusion Criteria

1. Metastases (except pelvic and/or para-aortic nodal metastases) ;

2. Peritoneal carcinosis;

3. Sensory or motor neuropathy ≥ grade 2;

4. Active or recent history of known autoimmune disease or recent history of a syndrome that required systemic corticosteroids or immunosuppressive drugs, except for :

   • hydrocortisone, which is permitted at physiological doses;
   • syndromes that would not be expected to recur in the absence of an external trigger, e.g. glomerulonephritis;
   • vitiligo or autoimmune thyroiditis;

5. Type-1 or type-2 diabetes;

6. History of or current immunodeficiency disease, including known history of infection with human immunodeficiency virus;

7. Prior systemic treatment or radiotherapy for cervical cancer;

8. Prior allogeneic stem cell transplantation;

9. Prior immunotherapy, including tumor vaccine, cytokine, anti-CTLA4, anti-PD-1, anti-PD-L1 or similar agents;

10. Any non-oncologic vaccine for prevention of infectious disease within 28 days prior to inclusion, including but not limited to measles, mumps, rubella, chicken pox, yellow fever, seasonal influenza, H1N1, rabies, BCG, and typhoid vaccine;

11. Positive serology for hepatitis B surface antigen;

12. Positive for hepatitis-C ribonucleic acid on polymerase chain reaction;

13. Active infection requiring therapy;

14. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on chest CT-scan at Screening;

15. History of malignancy (excepting non-melanoma skin cancer) unless complete remission was achieved at least 3 years prior to inclusion and no additional therapy is required or planned during the study;

16. Underlying medical condition that, in the Investigator's opinion, could render the administration of the study treatment hazardous; additional severe and/or uncontrolled concurrent disease;

17. Concomitant use of other investigational drugs;

18. Pregnancy or breastfeeding.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Nivolumab + radiochemotherapy	Nivolumab Injection	5 weeks of radiochemotherapy + nivolumab followed by 5 months of nivolumab alone
Nivolumab + radiochemotherapy	radiotherapy	5 weeks of radiochemotherapy + nivolumab followed by 5 months of nivolumab alone
Nivolumab + radiochemotherapy	Cisplatin	5 weeks of radiochemotherapy + nivolumab followed by 5 months of nivolumab alone

Primary Outcome Measures

Name	Time	Method
rate of occurrence of dose-limiting toxicity (DLT)	within 11 weeks after the initiation of treatment.	DLT is defined as any of the following treatment-related adverse events or laboratory abnormalities, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0: * non-hematological toxicity ≥ grade 3; * immune-related adverse event ≥ grade 3; * symptomatic immune-related adverse event ≥ grade 2 resistant to optimal supportive care for \> 7 days; * dosing delay in RT ≥ 1 week due to toxicity related to nivolumab, chemotherapy or RT; * colitis or diarrhea ≥ grade 3.

Secondary Outcome Measures

Name	Time	Method
Incidence of Serious Adverse Events (SAEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy	from the first intake of the IMP until 100 days after the last intake of the IMP
Disease Free Survival (DFS)	2 years	DFS is defined as the length of time from the start of complete response to the time of relapse from complete response. DFS applies only to patients in complete response.
tumor microenvironment description	2 years	phenotypic analysis of the different components of the tumor microenvironment using various technologies
Objective Response Rate (ORR)	after the end of RT and before brachytherapy and again up to 2 months after brachytherapy	ORR is defined as the proportion of all subjects whose best response is either a complete response or a partial response.
Progression Free Survival (PFS)	2 years	PFS is defined as the length of time from the start of treatment to disease progression or death, regardless of the cause of death
Incidence of Adverse Events (AEs) to assess the overall safety profile of the association of nivolumab and pelvic radio-chemotherapy	from the first intake of the IMP until 100 days after the last intake of the IMP
ctDNA heterogeneity	baseline, at Weeks 3, 6 and 12 and every 12 weeks up to Week 104	Retrospective exome and targeted sequencing analyses will be performed on all patients treated and for whom tissue samples are available at the different timepoints
validation of molecular alterations detected by molecular analyses	2 years	Retrospective exome, RNA and targeted sequencing analyses will be performed on all patients treated and for whom tumor samples are available.
tumor PD-L1 immunohistochemistry	2 years

Trial Locations

Locations (3)

Institut Curie; 🇫🇷 Paris, France

Institut Curie Hopital René Huguenin; 🇫🇷 Saint Cloud, France

Hopital Européen Georges Pompidou; 🇫🇷 Paris, France