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

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.


Eligibility Criteria:
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.