A MULTICENTER, SEEKING SIGNAL, RANDOMISED, OPEN-LABEL PHASE II OF RELATLIMAB AND NIVOLUMAB VS NIVOLUMAB ALONE IN LOCALLY ADVANCED CERVICAL CANCERS

Inclusion Criteria:

• Female patients aged ≥18 years at time of inform consent signature.

• Patients must have histologically confirmed diagnosis of cervical squamous oradenosquamous carcinoma stage IIB to IVA according to FIGO 2018 (Appendix 1) and noevidence of metastatic disease (M0). Note: Nodal staging may be either surgical orby imaging (MRI/PET-CT) with pathological lymph node size defined by a short-axisdiameter of ≥10mm (axial plane) or FDG uptake greater than that of the surroundingtissue and corresponding to the LN structure on CT when CT was performed for PETCTanalysis.

• Patients must be naïve from prior anti-cancer treatment (all type) and eligible tostandard CCRT as per standard practice and investigator' judgement.

• Known HPV status as per local assessment.

• Patient accepting to undergo a new cervix biopsy and with at least one lesion with adiameter ≥10 mm, visible by medical imaging and accessible to percutaneous sampling (needle biopsies 16 gauge or larger) that permit core needle biopsy (ideally 4cores) without unacceptable risk of a major procedural complication.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix 2).

• Adequate organ and marrow function with following lab values within 7 days beforeC1D1:

• Absolute neutrophil count (ANC) ≥1500/μL

• White blood cell (WBC) >3000/μL

• Platelets ≥100 000/μL

• Hemoglobin (Hb) ≥9 g/dL

• Total bilirubin ≤1.5× upper limit of normal (ULN) unless due to Gilbert'ssyndrome

• ASAT /ALAT ≤3 ULN

• Creatinine ≤1.5 within normal limit, or

• Creatinine clearance ≥ 40 mL/min according to CKD-EPI formula (Appendix 3)

• Troponin T or I < 2 x ULN

• Adequate cardiovascular function documented by:

• QTc interval <450 msec.

• Left ventricular Ejection fraction > 50% based on screening echocardiogram (ECHO) or multigated acquisition scan (MUGA).

• Controlled blood pressure (BP, <150/90mmHg), with or without currentantihypertensive treatment.

• No congestive heart failure New York Heart Association class 3 or 4, unstableangina pectoris, serious cardiac arrhythmias (eg, ventricular flutter,ventricular fibrillation, Torsades de pointes).

• No stroke (including transient ischemic attack [TIA]), myocardial infarction,or other clinically significant ischemic event within 12 months before firstdose.

• No prior history of myocarditis.

• Women of childbearing potential

• must have a negative serum pregnancy test within 7 days prior C1D1 and useadequate contraceptive methods (for example, intrauterine device [IUD], birthcontrol pills unless clinically contraindicated, or barrier device - seeAppendix 4) beginning 2 weeks before the first dose of study drugs and for upto 6 months after the final dose of study drugs (i.e., 30 days [duration ofovulatory cycle] plus the time required for relatlimab and nivolumab to undergoapproximately five halflives).

• A woman is considered to be of childbearing potential if she is postmenarcheal,has not reached a postmenopausal state (≥ 12 continuous months of amenorrheawith no identified cause other than menopause), and has not undergone surgicalsterilization (removal of ovaries, fallopian tubes, and/or uterus).

• Ability to understand and sign informed consent and willingness to comply with thestudy procedures before study entry.

• Covered by a medical insurance.

Exclusion Criteria:

• Evidence or treatment for another malignancy within 3 years prior to study entry.Curatively treated non-melanoma skin cancer, in situ carcinoma, or cervicalintraepithelial neoplasia is allowed.

• History of severe allergic or other hypersensitivity reactions to:

• chimeric or humanized antibodies or fusion proteins,

• biopharmaceuticals produced in Chinese hamster ovary cells, or

• any component of the study treatments formulation.

• Patients with:

• Active hepatitis B (chronic or acute; defined as having a positive hepatitis Bsurface antigen [HBsAg] test at screening) unless their HBV is stablycontrolled on nucleoside analogs (eg entecavir or tenofovir) which will becontinued for the duration of the study. Note: Patients with past hepatitis Bvirus (HBV) infection or resolved HBV infection (defined as the presence ofhepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBVDNA test must be performed in these patients prior to C1D1.

• Active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody areeligible only if PCR is negative for HCV RNA, or

• HIV infection. Patients with prior organ or bone marrow transplant.

• Patients with active, suspected or history of autoimmune disease including but notlimited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosisassociated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren'ssyndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, orglomerulonephritis (see Appendix 5 for a more comprehensive list of pre-existingautoimmune diseases and immune deficiencies) with the following exceptions:

• patients with a history of autoimmune-related hypothyroidism who are on thyroidreplacement hormone,

• patients with controlled Type 1 diabetes mellitus,

• patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis wouldbe excluded) are permitted provided that they meet the following conditions:

• rash must cover less than 10% of body surface area (BSA).

• disease is well controlled at baseline and only requiring low potencytopical steroids.

• no acute exacerbations of underlying condition within the previous 12months requiring PUVA [psoralen plus ultraviolet A radiation],methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,high potency or oral steroids.

• Patients not respecting the minimal washout period or anticipation of need duringthe study of the following medications:

1. For "Systemic immunosuppressive medication (e.g.corticosteroids,cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alphaagents)", a minimal wash out period before C1D1 ≥ 2 weeks is requested.But use during the study is not allowed with the exceptions of intranasal,inhaled, or topical corticosteroids or systemic corticosteroids atphysiological doses, which are not to exceed 10mg/day of prednisone, or anequivalent corticosteroid.

2. For "Systemic immunostimulatory (e.g., interferons and IL-2), a minimal washout period ≥ 4 weeks or 5 * t(1/2) of medication whichever is longer.

But use during the study is not allowed.

• Patients with any serious or uncontrolled medical disorder that, in the opinion ofthe investigator, may have increased the risk associated with trial participation ortrial treatment administration, impaired the ability of the patients to receiveprotocol therapy, or interfered with the interpretation of trial results.

• Patients have received a live/attenuated vaccine within 30 days of C1D1 (inactivatedvaccines were permitted).

• Pregnant or lactating women.

• Patients deprived of liberty, under guardianship, or under curatorship.