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Signed informed consent (after informing the patient) |
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Age ≥18 years old. Patients above 70 years old will be screened according to the G-8 screening tool. If required (G-8 score ≤14), a consultation with an onco-geriatrician will be held in order to confirm the patient eligibility |
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Histologically confirmed cancer of the uterine cervix: squamous cell carcinoma (SCC), adenocarcinoma, or adenosquamous carcinoma |
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At least one evaluable lesion according to RECIST v1.1 criteria for the assessment of the principal judgment criteria. At baseline, lesion(s) must be ≥10 mm in the longest diameter (except lymp nodes which must have a short axis ≥15 mm) |
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International Federation of Gynecology and Obstetrics (FIGO 2009) classification (confirmed by both clinical staging and/or imaging) |
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(i) stage IB1-IIA tumour with positive pelvic nodal status, as assessed by |
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magnetic resonance imaging (MRI) and/or fluorine-18 fluorodeoxyglucose |
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positron emission tomography (18-FDG PET)/computerised tomography (CT); (ii) |
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stage IIB-IVA tumour, regardless of pelvic lymph node involvement; (iii) stage |
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IVB tumours only if the metastases are limited to the paraaortic lymph nodes |
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No evidence of metastatic disease outside the para-aortic area by primary |
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staging (including clinical examination, pelvic MRI, 18-FDG PET, +/- |
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laparoscopic para-aortic lymph node staging) |
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Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 |
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Adequate haematologic and end-organ function, defined by the following laboratory results obtained within 15 calendar days prior to the first study treatment |
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Absolute neutrophil count (ANC) ≥1,500/mm3 (≥1.5 x 10^9/L) without granulocyte colony-stimulating factor (G-CSF) support |
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Total white blood cells (WBC) >2,000/mm3 (>2.0 x 10^9/L) (including Polymorphonuclear neutrophils > 1,500/mm3 or 1.5 x 10^9/L) |
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Lymphocyte count ≥500/mm3 (≥ 0.5 x 10^9/L) |
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Platelet count ≥ 100,000/mm3 (≥ 100 x 10^9/L) without transfusion |
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Haemoglobin ≥ 9.0 g/dL (90 g/L; patients may be transfused to meet this criterion) |
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International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × upper limit of normal (ULN) for patients not receiving therapeutic anticoagulation |
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Patients receiving therapeutic anticoagulation should be on a stable dose |
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Creatinine <1.5 ULN or calculated creatinine clearance (CrCL) ≥ 45 mL/min (calculated using the Cockcroft-Gault formula) |
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Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase <2.5 x ULN |
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Serum bilirubin <1.5 x ULN |
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Proteinuria < 200 mg/dL (2 g/L). Patients with ureteral stent or with bladder invasion |
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are eligible if the proteinuria is above the former threshold |
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Ability to comply with the study protocol |
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Geographical, social and psychological ability to undergo the followup required by the study |
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Women who are not postmenopausal (≥ 12 months of non-therapy induced amenorrhoea) and not surgically sterile |
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Must agree to either use an acceptable contraceptive method _or to remain abstinent_ (refrain from heterosexual intercourse) during the treatment period and for at least 5 months after the last dose of atezolizumab in arm B and at least 6 months after the last cisplatin/carboplatin dose in arm A |
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Acceptable contraceptive methods include single or combined contraceptive methods that result in a failure rate of < 1% per year, such as: tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide |
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Abstinence is acceptable only if it is in line with the preferred and usual |
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lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation |
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symptothermal, or postovulation methods) and withdrawal are not acceptable |
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methods of contraception |
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Must have a negative serum pregnancy test result within 7 days prior to |
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initiation of study drug |
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Patients must be affiliated to a social security system or beneficiary of the same, as |
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per local regulatory requirements |
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Histological types of cervical cancer other than those listed in the inclusion
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criteria (based on FIGO 2009 classification), including
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Stage IB1 and IIA cervical cancer with no regional lymph node metastases (N0)
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Stage IVB cervical cancer with presence of distant metastases other than
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para-aortic lymph node metastases
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Prior surgery for cervical cancer unless cone resection and paraaortic
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lymphadenectomy
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Prior pelvic radiotherapy, other radiotherapy, chemotherapy or immunotherapy
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Any malignancy other than the disease under study in the past 5 years excepting skin
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cancers such as BCC or SCC
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Pregnant or lactating women, or intending to become pregnant during the study
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For patient ≥ 70 years old with a G-8 score ≤ 14, unconfirmation of patient
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eligibility done by the onco-geriatrician at screening
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History of clinically relevant cardiovascular disease, congestive heart failure (New
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York Heart Association [NYHA] Class II or greater), or a known left ventricular
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ejection fraction (LVEF) <50%, symptomatic coronary artery disease, poorly controlled
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cardiac arrhythmia, or myocardial infarction
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Active inflammatory bowel disease, lack of physical integrity of the upper
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gastrointestinal tract, malabsorption syndrome
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Serious infection requiring oral or IV antibiotics within 4 weeks prior to
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randomisation, including but not limited to hospitalization for complications of
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infection, bacteraemia, or severe pneumonia
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Treatment with another investigational therapy within 30 days prior to initiation of
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the study drug
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Major surgical procedure within 4 weeks prior to randomisation or anticipation of the
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need for a major surgical procedure during the study other than for diagnosis. The
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following are not considered a major surgical procedure and are therefore permitted
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(i) placement of central venous access catheter(s) (e.g., port or similar); (ii)
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surgical lymph node staging with no perioperative complications; (iii) placement of
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ureteral catheters
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History of severe allergic anaphylactic reactions to chimeric, human or humanized
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antibodies, or fusion proteins
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Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component
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of the atezolizumab formulation
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Any contraindication to the use of Cisplatin and/or carboplatin
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History of autoimmune disease, including but not limited to myasthenia gravis
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myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis
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inflammatory bowel disease, vascular thrombosis associated with antiphospholipid
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syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome
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multiple sclerosis, meningoencephalitis, or glomerulonephritis (see Appendix 6 for a
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more comprehensive list of autoimmune diseases) with the following exceptions
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patients with a history of autoimmune-related hypothyroidism on a stable dose of
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thyroid replacement hormone, patients with controlled Type 1 diabetes mellitus on a
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stable insulin regimen, and patients with mild autoimmune skin disorders (such as
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eczema or atopic dermatitis involving <10% of the skin) may be eligible for this
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study
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History of idiopathic pulmonary fibrosis (IPF, including pneumonitis), drug-induced
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pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic
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organizing pneumonia), or active pneumonitis
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Pre-existing hearing impairment
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Peripheral neuropathy ≥grade 2
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Positive test for human immunodeficiency virus (HIV)
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Active hepatitis B (positive hepatitis B surface antigen [HBsAg] test at screening) or
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hepatitis C (positive hepatitis C virus antibody [HCVAb] test at screening). Note
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Patients with past hepatitis B virus (HBV) infection or resolved HBV infection
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(defined as having a negative HBsAg test and a positive hepatitis B core antibody
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[HBcAb] test) are eligible
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Known active tuberculosis
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Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation or
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anticipation that such a live, attenuated vaccine will be required during the study
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Note: Patients must agree not to receive live, attenuated influenza vaccine (e.g
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FluMist®) within 28 days prior to randomisation, during treatment or within 5 months
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following the last dose of atezolizumab
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Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or
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immune checkpoint targeting agents
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