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

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

Multicenter, open-label, randomized, seeking signal (non-comparative), Phase II aiming to assess the clinical activity of the combination relatlimab + nivolumab in locally advanced cervical cancer eligible to standard CCRT

Primary Objective

* To evaluate the clinical activity of relatlimab and nivolumab induction treatment before standard CCRT in locally advanced cervical cancer

Secondary Objectives

• To further document the clinical activity of relatlimab and nivolumab
• To document the safety of the proposed combination in the target population

Exploratory Objectives

• To identify candidate biomarkers that may correlate with likelihood of clinical benefit/response using serial blood and tumor sample collection.
• To explore the factors (including biomarkers) that may influence response (where response is defined broadly to comprise efficacy, tolerability or safety) or to explore mechanisms of resistance to study treatment.

Inclusion Criteria:

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

• Patients must have histologically confirmed diagnosis of cervical squamous or adenosquamous carcinoma stage IIB to IVA according to FIGO 2018 (Appendix 1) and no evidence of metastatic disease (M0). Note: Nodal staging may be either surgical or by imaging (MRI/PET-CT) with pathological lymph node size defined by a short-axis diameter of ≥10mm (axial plane) or FDG uptake greater than that of the surrounding tissue and corresponding to the LN structure on CT when CT was performed for PETCT analysis.

• Patients must be naïve from prior anti-cancer treatment (all type) and eligible to standard 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 a diameter ≥10 mm, visible by medical imaging and accessible to percutaneous sampling (needle biopsies 16 gauge or larger) that permit core needle biopsy (ideally 4 cores) 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 before C1D1:

  • 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's syndrome
  • 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 current antihypertensive treatment.
  • No congestive heart failure New York Heart Association class 3 or 4, unstable angina 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 first dose.
  • No prior history of myocarditis.

• Women of childbearing potential

  • must have a negative serum pregnancy test within 7 days prior C1D1 and use adequate contraceptive methods (for example, intrauterine device [IUD], birth control pills unless clinically contraindicated, or barrier device - see Appendix 4) beginning 2 weeks before the first dose of study drugs and for up to 6 months after the final dose of study drugs (i.e., 30 days [duration of ovulatory cycle] plus the time required for relatlimab and nivolumab to undergo approximately 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 amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries, fallopian tubes, and/or uterus).

• Ability to understand and sign informed consent and willingness to comply with the study 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 cervical intraepithelial 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 B surface antigen [HBsAg] test at screening) unless their HBV is stably controlled on nucleoside analogs (eg entecavir or tenofovir) which will be continued for the duration of the study. Note: Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to C1D1.
  • Active hepatitis C. Patients positive for hepatitis C virus (HCV) antibody are eligible 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 not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 5 for a more comprehensive list of pre-existing autoimmune diseases and immune deficiencies) with the following exceptions:

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

  • patients with controlled Type 1 diabetes mellitus,

  • patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 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 potency topical steroids.
    • no acute exacerbations of underlying condition within the previous 12 months 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 during the study of the following medications:

  1. For "Systemic immunosuppressive medication (e.g.corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents)", 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 at physiological doses, which are not to exceed 10mg/day of prednisone, or an equivalent corticosteroid.

  2. For "Systemic immunostimulatory (e.g., interferons and IL-2), a minimal wash out 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 of the investigator, may have increased the risk associated with trial participation or trial treatment administration, impaired the ability of the patients to receive protocol therapy, or interfered with the interpretation of trial results.
• Patients have received a live/attenuated vaccine within 30 days of C1D1 (inactivated vaccines were permitted).
• Pregnant or lactating women.
• Patients deprived of liberty, under guardianship, or under curatorship.