BIBF 1120 Versus Bevacizumab in Metastatic Colorectal Cancer

PFS-9 is defined as the time from first treatment with the trial drug until either the onset of progressive disease or death. A patient is defined as progression-free for 9 months if their PFS was at least 270 days. Progression is assessed according to following mentioned RECIST criteria (version 1.0). 1. 20% increase in the sum of the longest diameter of target lesions. 2. The appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

Time frame: First treatment administration to nine months

Population: Treated Set (TS) - The treated set includes all patients who were dispensed and were documented to have taken at least one dose of the trial drug.

Area under the plasma concentration time-curve over 12 hours for Nintedanib in the dosing interval at steady state and normalized by the dosing unit administered (AUCtau,ss,norm) (Phase I)

Time frame: -0:05h before drug administration and 1h, 2h, 2.5h, 3h, 4h, 6h, 8h and 10h after drug administration.

Population: Treated Set (TS).

Objective response rate is defined as a best response of either complete (CR) or partial response (PR) according to RECIST version 1.0. To be assigned a status of PR or CR, changes in tumour measurements had to be confirmed by repetition of the CT or MRI scan no less than 4 weeks after the criteria for response were first met. This confirmation was necessary to avoid overestimating the response rate observed. The 95% confidence interval represent the Clopper-Pearson exact confidence interval

Time frame: First treatment administration until end of treatment, up to 892 days

Population: Treated Set (TS).

Exploratory biomarker and pharmacogenetic analysis for Vascular endothelial growth factor (VEGF). Note: This endpoint was not statistically analysed in this study.

Time frame: Day 1, Day 29, Day 57, Day 85 and Day 127

Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

Time frame: From the first dose of study medication up to 28 days after the day of the last intake of study medication, up to 920 days

Population: Treated Set (TS)

Maximum plasma concentration for Nintedanib at steady state and normalized by the dosing unit administered (Cmax,ss,norm) (Phase I)

Time frame: -0:05h before drug administration and 1h, 2h, 2.5h, 3h, 4h, 6h, 8h, and 10h after drug administration.

Population: Treated Set (TS).

Determination of Maximum Tolerable Dose based on DLT incidence.

Time frame: First two treatment cycles, up to 28 days

Population: MTD Set

Number of participants for Quality of life evaluation by a standardised questionnaires of European Organisation for Research and Treatment of Cancer (EORTC): EORTC-QLQ-CR38 for the first use of stoma bag.

Time frame: from baseline until end of treatment, up to 892 days

Population: Treated Set (TS).

Overall survival is defined as the time from first treatment until death. Greenwood variance was used for the calculation of 95% confidence interval.

Time frame: First treatment administration until end of treatment, up to 892 days

Population: Treated Set (TS).

Percentage of patients with DLTs,AE were observed in Gastrointestinal,Hepatobiliary & skin and subcutaneous tissue disorder.Drug related DLT was defined:1)Gastrointestinal toxicity(vomiting, nausea and diarrhoea)or hypertension of CTCAEgrade(G)3 despite optimal supportive care/intervention.2)Non-haematological toxicity of G≥3 except AE:alopecia,nail modifications,& isolated elevation of gamma glutamyl transpeptidase.3)G4 neutropenia for\>7days(not associated with fever≥38.5°C).4)Neutropenia of G≥3 of any duration associated with fever≥38.5ºC.5)Platelets \<25,000/μLorG3 thrombocytopenia associated with bleeding requiring transfusion.6)Inability to resume nintedanib dosing within14days of stopping due to treatment related toxicity.7)ALT and/or AST elevation of G≥3orG≥2 in conjunction with bilirubin G\>1. 8)Inability to recover from increase ALT/AST in conjunction with increase of bilirubin toALT/AST toG≤1 &bilirubin to normal or baseline within14days after nintedanib treatment interruption

Time frame: First two treatment cycles, up to 28 days

Population: MTD set: The first 12-18 patients randomised to the nintedanib treatment group, treated with nintedanib according to the dose escalation part of the study. The outputs (updated with cleaned and more complete data) that were used to decide on the MTD of nintedanib while the study was ongoing.

PFS is defined as the time from first treatment with the trial drug until either the onset of progressive disease or death throughout the whole study. Progression is assessed according to RECIST criteria (version 1.0). In this endpoint, the Greenwood's variance estimate was used to calculate the Kaplan-Meier progression free survival median and its corresponding 95% confidence interval

Time frame: First treatment administration until end of treatment, up to 892 days

Population: Treated Set (TS).

Quality of life evaluation by a standardised questionnaires of European Organisation for Research and Treatment of Cancer (EORTC): EORTC-QLQ-C30 for the change from baseline at 9 months for Global health status scores. Raw scores are transformed to scales of 0-100. A higher score is associated with a better quality of life for Global health status scores

Time frame: Baseline and 9 months.

Population: Treated Set (TS). Number of analysed patients are the total number of patients who were analysed for the change from baseline at 9 months for Global health status scores

Quality of life evaluation by a standardised questionnaires of European Organisation for Research and Treatment of Cancer (EORTC): EORTC-QLQ-CR38 for the change from baseline at 9 months for functional scales, Symptom scales Chemotherapy side effects . The EORTC-QLQ-CR38 was composed of functioning scales (body image, future perspective, sexual enjoyment, sexual functioning) and symptom scales (chemotherapy side effects, defecation problems, symptoms of the gastrointestinal tract, micturition problems,female sexual problems, male sexual problems, stoma related problems, and weight loss). Raw scores are transformed to scales of 0-100. A higher score is associated with a better quality of life for functional scales and a worse quality of life for symptom scales.

Time frame: Baseline and 9 months.

Population: Treated Set (TS)

Surgical excision of the lesions is allowed if the previous assessment of tumoral response occurred after at least 6 cycles of treatment. Resection Rate includes resection rates R0, R1 and R2 before progressive disease. Peto's variance estimate was used.

Time frame: First treatment administration until end of treatment, up to 892 days

Population: Treated Set (TS)

For each patient, the minimum percentage increase from baseline measurement (≤ 28 days before the beginning of the treatment) of the sum Longest diameter (LD) of target lesions was calculated based on the measurements of tumor size. The minimum percentage increase has been divided to four groups: 1. \<= - 30% 2. \> - 30% and \< 0% 3. \>= 0% and \< 20% 4. \>=20%

Time frame: Baseline and day 85

Population: Treated Set (TS)

Objective response is defined as a best response of either complete (CR) or partial response (PR) according to RECIST version 1.0. To be assigned a status of PR or CR, changes in tumour measurements had to be confirmed by repetition of the CT or MRI scan no less than 4 weeks after the criteria for response were first met. This confirmation was necessary to avoid overestimating the response rate observed. The 95% Confidence interval represent the Clopper- Pearson exact confidence interval.

Time frame: First treatment administration until end of treatment, up to 892 days

Population: Treated Set (TS).