The amendment concerned mainly: -Modifications in inclusion/exclusion criteria: restriction for normal serum potassium level at entry and normal creatinine clearance (> 60 ml/min). -Addition of clinical management rules in case of QTcF prolongation > 500 msec and LVEF decrease. -Addition of ECG and LVEF evaluation time points at C1D1 (pre-dose and tmax) and Day 28 respectively.

The amendment aimed to, principally: -Implement an Independent Data Monitoring Committee, to provide the Steering Committee with independent recommendations regarding the continuation, modification or interruption of the trial based on benefice/risk ratio analysis. -Modify inclusion criteria: only one archived tumour sample mandatory at screening and ability to give consent. -Modify exclusion criteria: history of thromboembolic events and hereditary risk factors added. -Remove the serum blood sample for soluble growth factor analysis at the end of treatment visit. -Add a 10mL plasma blood sample at C1D1. -Collect archived primary tumour tissue, if available, to perform comparative assays with metastatic tissue samples. -Add optional new biopsies collection at baseline for cohort 1 and 2. -Add optional new biopsy collection between C1D14-C1D28, and at EOT for cohort 3. -Add Hungary to the study countries. -Clarify sample nature (free circulating DNA, circulating growth factors). -Prohibit radiotherapy during the study. -Postpone the study initiation date to November 2013.

The main purpose of this mendment was to increase the level of safety management, following the temporary interruption of the study due to the incidence of hypertensive events observed. Main changes were: -Addition of a C1D4 visit to monitor early toxicities especially early increase in blood pressure. -Modification and strengthening of the management of hypertension, QTc prolongation, LVEF decreases and liver toxicities. A paragraph was added for nausea and vomiting management. The toxicity managements included also the possibility to reduce the daily dose to 10 mg, 7.5 mg and 5 mg. -Patients were to measure blood pressure daily at home on the 1st cycle and at least twice a week afterwards and at screening. -Update of the background information section: platelet count decrease and anorexia have been added as expected adverse events. -Inclusion criteria update (any prior first-line of anticancer therapy in the metastatic setting, AST/ALT ≤ 3 ULN irrespective of the presence of liver metastases). -Exclusion criteria update (history of clinically significant or uncontrolled cardiac disease, hypertension criterion, history of thrombotic disorders criterion, history of renal diseases, involvement in another clinical trial except for observational trials, uncontrolled diabetes mellitus). -Prohibition of any oral anticoagulant as concomitant treatment and prohibition of aspirin if taken concomitantly with oral anti-platelet agents. -Mention that patients with evidence of liver disease or injury should avoid drugs known to be hepatotoxic, ie paracetamol/acetaminophen. -Possibility to use tumours imagery anterior to ICF for baseline assessment if performed within the 28 day screening period prior to the 1st drug intake. -Implementation of time windows for scheduled visits and LVEF examination. -Possibility to send 20 slides of the screening tumour samples to ICR instead of the whole tumour block.

It concerned mainly the update of prohibited, contraindicated and not recommended medications in association with lucitanib: -Exclusion criteria update and clarification: patients receiving administration of strong inhibitors of CYP2C8 and/or CYP3A4 or strong inducers of CYP3A4 added, mutation of Factor V of Leiden as an example of thromboembolism hereditary risk factors removed, serum potassium below LLN at screening. -Clarifications about coagulation test, time window to perform laboratory tests, ER/PR and HER2 testing, troponin test to be evaluated, liver toxicity management, decrease LVEF management and hypothyroidism management. -Implementation of recommendations in case of missed or incomplete intake of drug dose. -Update on permitted medication: LHRH analogue provided that the treatment was initiated prior to the initiation of study drug with documented disease progression. -Update on prohibited drugs: strong inhibitors of CYP3A4 or CYP2C8, strong dual inhibitors of CYP3A4 and CYP2C8 and strong inducers of CYP3A4 to be prohibited. Moderate inhibitors of CYP3A4 or CYP2C8 and moderate dual inhibitor of CYP3A4 and CYP2C8 not recommended. Herbal supplement strongly not recommended. Verapamil and diltiazem deleted from prohibited drugs.

The amendment concerned mainly the reduction of the starting dose of lucitanib from 15 mg to 10 mg daily. Patients who were already on the 15 mg daily dose were permitted to continue at their current dose based on the investigator's decision (if well controlled hypertension and others toxicities at 15mg and patients benefited from this dose). Otherwise, lucitanib dose was to be reduced to 10 mg at the start of following cycle. Other changes included: -Introduction of the new formulation of lucitanib (tablets). -Clarification and updates on management of hypertension, minor clarification of general and renal toxicities management. -Possibility to send 20 representative and serial slides for the optional biopsies instead of tumour block in case of strict internal policy of the site. -Addition of 10 ml of blood collected at each time point (C1D1, C1D14, EOT) for circulating tumour DNA analysis. -Removal of optional on-treatment biopsy. -Clarification of adverse events definition .

Following the report of a case of Posterior Reversible Encephalopathy Syndrome (PRES), this amendment was designed to add precautionary measures in case a patient experienced symptoms suggestive of PRES. It included: -An update of the background information section: information about a case of PRES with lucitanib observed within the context of FINESSE. -The addition of a paragraph for the management of symptoms suggestive of PRES and confirmed PRES. -Clarification of the exclusion criteria relative to treatment withdrawal window in case a patient received another IMP before the first dose of lucitanib.