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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase-I Study of Nivolumab in Association With Radiotherapy and Cisplatin in Locally Advanced Cervical Cancers Followed by Adjuvant Nivolumab for up to 6 Months. NiCOL

Conditions
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Cervical Cancer, Locally Advanced Cervical Cancer

Intervention / Treatment
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* Drug: Nivolumab Injection
* Drug: Cisplatin
* Radiation: radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients at least 18 years of age; Ability to understand and the willingness to sign a written informed consent document.; Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1; 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); Disease amenable to biopsy since three tumor samples are mandatory prior to treatment; 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). 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 ; Affiliated to the French Social Security System. Exclusion Criteria: Metastases (except pelvic and/or para-aortic nodal metastases) ; Peritoneal carcinosis; Sensory or motor neuropathy ≥ grade 2; 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; Type-1 or type-2 diabetes; History of or current immunodeficiency disease, including known history of infection with human immunodeficiency virus; Prior systemic treatment or radiotherapy for cervical cancer; Prior allogeneic stem cell transplantation; Prior immunotherapy, including tumor vaccine, cytokine, anti-CTLA4, anti-PD-1, anti-PD-L1 or similar agents; 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; Positive serology for hepatitis B surface antigen; Positive for hepatitis-C ribonucleic acid on polymerase chain reaction; Active infection requiring therapy; History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia or evidence of active pneumonitis on chest CT-scan at Screening; 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; 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; Concomitant use of other investigational drugs; Pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab + radiochemotherapy<br>5 weeks of radiochemotherapy + nivolumab followed by 5 months of nivolumab alone | Drug: Nivolumab Injection<br>* 2 possible doses : flat dose 240 mg q2 weeks or 1mg/kg q2 weeks<br>Drug: Cisplatin<br>* 40 mg/m2, once a week during radiotherapy<br>Radiation: radiotherapy<br>* Intensity-modulated radiation therapy (including volumetric-modulated arc therapy and tomography) will be used. A dose of 45 Gy will be delivered to the pelvis in 25 fractions of 1.8 Gy using a 6-MV photon energy. An additional dose of 54 Gy in 25 fractions of 2.16 Gy may be delivered to invaded lymph nodes using SIB-IMRT. An additional lateral pelvic dose may be delivered if coverage of the target volumes is judged insufficient. The volumes, doses and techniques will be those usually used in each center.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rate of occurrence of dose-limiting toxicity (DLT) | 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. | within 11 weeks after the initiation of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR is defined as the proportion of all subjects whose best response is either a complete response or a partial response. | after the end of RT and before brachytherapy and again up to 2 months after brachytherapy | 
| Progression Free Survival (PFS) | PFS is defined as the length of time from the start of treatment to disease progression or death, regardless of the cause of death | 2 years | 
| Disease Free Survival (DFS) | 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. | 2 years | 
| 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 | 
| 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 | 
| validation of molecular alterations detected by molecular analyses | Retrospective exome, RNA and targeted sequencing analyses will be performed on all patients treated and for whom tumor samples are available. | 2 years | 
| ctDNA heterogeneity | Retrospective exome and targeted sequencing analyses will be performed on all patients treated and for whom tissue samples are available at the different timepoints | baseline, at Weeks 3, 6 and 12 and every 12 weeks up to Week 104 | 
| tumor microenvironment description | phenotypic analysis of the different components of the tumor microenvironment using various technologies | 2 years | 
| tumor PD-L1 immunohistochemistry |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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radiotherapy, cervical cancer, nivolumab, cisplatin