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Coordinating investigator: Prof Dr. Ignace Vergote Rationale and objectives • Rationale – Dominant role of angiogenesis related to HPV inhibition of p53 and stabilization of HIF-1 alfa → increase of VEGF. – Previous studies confirmed activity of anti-angiogenesis agents in advanced and recurrent cervical cancer. • Objectives – Primary: • Progression free survival (RECIST 1.1) – Secondary: • Toxicity and safety • Response rate and overall survival • Patient reported health status (QOL-CX24 and QOQ-C30) Patients (# 120) with histologically or cytologically confirmed squamous, adenosquamous or adenocarcinoma of the cervix Advanced stage (FIGO stage IVB) OR Recurrent/persistent disease 1:1 Randomization IXRS Nintedanib 200 mg p.o. BID Placebo p.o. BID PLUS PLUS Paclitaxel 175 mg/m2 + carboplatin AUC5 Paclitaxel 175 mg/m2 + carboplatin AUC5 Every 21 days for 6 cycles Every 21 days for 6 cycles Nintedanib monotherapy up to 120 weeks Placebo monotherapy up to 120 weeks End of Treatment Randomization * * * * * * * No Nintedanib on day 1 of each cycle! 6 Combi-Cycles Screening -28 to –D1 Required CT /MRI scans (baseline, week 9, 18, 25, 49,61,121) Maintenance therapy Treatment duration: up to 120 weeks 3 Weekly Pacl/Carbo + Nintedanib/Placebo Maintenance therapy with Nintedanib/Placebo FU 3 y BGOG-cx1: Locations European Network of Gynaecological Oncological Trial Groups (ENGOT) Sites participating in: - Belgium (BGOG) - Spain (GEICO) - Germany (NOGGO) - Italy (MITO / ManGO) - UK (NCRI) Target: 120 patients, 30 sites Study Timelines Milestone Estimated timing First patient in March 2014 Last patient in Dec 2017 Last patient out Dec 2019 Primary analysis 1,5 y after LPI (July 2019) Secondary analysis 5 y after LPI (Dec 2022) Accrual overview Group Randomized On treatment End of treatment (chemo+nint) End of trial (FU compl) BGOG 22 7 9 6 GEICO 15 11 3 1 NOGGO 0 0 0 0 MANGO 0 0 0 0 MITO 0 0 0 0 37/120 18/37 12/37 7/37 Status MITO • AIFA did not authorize the study • An amended protocol is being submitted New exclusion criteria: • Active or chronic hepatitis C and/or B infection or known HIV infection (based on medical file, only for Italy a mandatory screening test for HIV should be performed for all patients who did not have this test within the last 3 months before the study treatment start). • Extra slides with inclusion and exclusion criteria follow if needed Inclusion criteria • Women age > 18. • Histologically or cytologically confirmed advanced (FIGO stage IVB), or recurrent/persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix • ECOG score 0 or 1 • At least one measurable lesion according to RECIST 1.1 criteria. • Life expectancy of at least 3 months • Informed consent Inclusion criteria continued • No prior chemotherapy for recurrent cervical cancer, except: – Prior concomitant cisplatinum chemotherapy during radiotherapy is allowed (except if recurrence is within 6 months after the end of the platinum containing chemotherapy). – Cases primarily treated with neoadjuvant chemotherapy before radical local surgery are eligible at the time of first recurrence. (except if…) – Cases primarily treated with neoadjuvant chemotherapy before radical local surgery followed by adjuvant radiochemotherapy are eligible at the time of first recurrence (except if …) – Cases primarily treated with neoadjuvant chemotherapy before radical local surgery followed by adjuvant radiotherapy are eligible at the time of first recurrence (except if …) Exclusion criteria • Prior chemotherapy for advanced (FIGO stage IVB) or recurrent disease (except if…) • Prior treatment with nintedanib or any other VEGFR inhibitor. • Known hypersensitivity to the trial drugs or to their excipients (including peanut or soya). • Brain or leptomeningeal metastases. • Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels. • Tumor infiltrating the mucosa of the bowel or bladder, or known fistulas between the tumor and the gastrointestinal or urinary tract. • Radiographic evidence of cavitary or necrotic tumours • Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial. Exclusion criteria continued • Therapeutic anticoagulation with drugs requiring INR monitoring (except low dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous device) or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid <325 mg per day). • Major injuries within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period. • History of clinically significant haemorrhagic or thromboembolic event, cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage in the past 6 months • Known inherited predisposition to bleeding or thrombosis. • Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months, congestive heart failure, serious cardiac arrhythmia, pericardial effusion) Exclusion criteria continued • Abnormal renal, liver or bone marrow function defined as: – Proteinuria CTCAE grade 2 or greater – Creatinine > 1,5 ULN or GFR < 45 ml/min – Hepatic function: • total bilirubin outside of normal limits; • ALT or AST > 1.5 ULN in pts without liver metastasis. • For Pts with liver metastases: total bilirubin outside of normal limits, ALT or AST > 2.5 ULN – Absolute neutrophil count ( ANC) < 1500/µl, platelets < 100000/µl, – Haemoglobin < 9.0 g/dl • Coagulation parameters: – International normalised ratio (INR) > 2, prothrombin time (PT) and partial thromboplastin time (PTT) > 50% of deviation of institutional ULN Exclusion criteria continued • Other malignancies within the past 3 years or other malignancy with recurrence in the past 3 years or with high risk of recurrence in the first year. In exception nonmelanomatous skin cancer (if adequately treated) , any premalignant (e.g. in situ) carcinoma, or basocellular carcinoma. • Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy • Active or chronic hepatitis C and/or B infection or known HIV infection (based on medical file, only for Italy a mandatory screening test for HIV should be performed for all patients who did not have this test within the last 3 months before the study treatment start). • Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug. • Serious illness or concomitant non-oncological disease (neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality Exclusion criteria continued • Patients of child-bearing potential* who are sexually active and unwilling to use a medically acceptable method of contraception (during the trial and for at least three months after end of active therapy). • Pregnancy or breast feeding, female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment, if applicable. • Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule • Active alcohol or drug abuse. *all patients unless those who are surgically sterilised by hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least one year, or above the age of 60. Randomization • After assessment in-and exclusion criteria • Patient will be stratified at the end of screening (3 strata): – Advanced disease Stage IVB – Recurrent disease with prior neoadjuvant chemo or chemoradiotherapy (p12 protocol) – Recurrent disease without prior neoadjuvant chemo or chemoradiotherapy (p12 protocol) In IXRS, the stratification is performed by answering 2 questions: 1) Disease status of the patient (Stage IVB / recurrent) 2) Prior neoadjuvant chemo or chemoradiotherapy (Y / N)