BIBF 1120 Versus Bevacizumab in Metastatic Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate PFS rate at 9 months of BIBF 1120 in combination with mFolfox6 compared with mFolfox6 combined to bevacizumab in first line patients with metastatic colorectal cancer.

Official Title
-----------------
A Phase I-II Study of BIBF 1120 and FOLFOX Compared to Bevacizumab and FOLFOX in First Line Metastatic Colorectal Cancer Patients

Conditions
-----------------
Colorectal Neoplasms

Intervention / Treatment
-----------------
* Drug: BIBF 1120
* Drug: BIBF 1120
* Drug: mFolfox
* Drug: Bevacizumab
* Drug: mFolfox 6
* Drug: bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Age >= 18 years Histologically proven colorectal adenocarcinoma No previous oxaliplatin based chemotherapy is allowed unless disease free survival after the end of chemotherapy > = 12 months No previous therapy with VEGFR or EGFR inhibitors No prior systemic therapy for metastatic CRC No previous adjuvant therapy with fluoropyrimidines is allowed unless disease free survival after the end of chemotherapy > 6 months ECOG performance status < = 2 Adequate hepatic, renal and bone marrow functions: No uncontrolled hypertension Signed and dated written informed consent prior to admission to the study Exclusion criteria: Treatment with any investigational drug within 28 days of trial onset. History of other malignancies in the last 5 years, in particular those that could affect compliance with the protocol or interpretation of results. Serious concomitant disease, especially those affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug, Major injuries and/or surgery or bone fracture within 4 weeks of trial inclusion, or planned surgical procedures during the trial period. Significant cardiovascular diseases History of severe haemorrhagic or thromboembolic event in the past 12 months. Known inherited predisposition to bleeding or to thrombosis. Patient with brain metastases that are symptomatic and/or require therapy. Pregnancy or breast-feeding.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBF 1120 + mFolfox6<br>BIBF1120 medium dose twice daily | Drug: BIBF 1120<br>* BIBF 1120 100 and 150 mg capsules<br>Drug: mFolfox 6<br>* IV standard chemotherapy<br>Drug: bevacizumab<br>* 100 mg/4 ml solution<br>|
| Active Comparator: Bevacizumab + mFolfox6<br>Bevacizumab 5mg/kg once daily every other week | Drug: BIBF 1120<br>* BIBF 1120 100 and 150 mg capsules<br>Drug: mFolfox<br>* standard i.v chemotherapy<br>Drug: Bevacizumab<br>* 100 mg/Kg solution , IV infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival Rate at 9 Months (PFS-9) | 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). 20% increase in the sum of the longest diameter of target lesions. The appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | First treatment administration to nine months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival is defined as the time from first treatment until death. Greenwood variance was used for the calculation of 95% confidence interval. | First treatment administration until end of treatment, up to 892 days | 
| Progression-free Survival (PFS) | 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 | First treatment administration until end of treatment, up to 892 days | 
| Confirmed Objective Response Rate | 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 | First treatment administration until end of treatment, up to 892 days | 
| Unconfirmed Objective Response Rate | 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. | First treatment administration until end of treatment, up to 892 days | 
| Resection Rate | 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. | First treatment administration until end of treatment, up to 892 days | 
| Tumor Shrinkage | 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: <= - 30% > - 30% and < 0% >= 0% and < 20% >=20% | Baseline and day 85 | 
| Incidence and Intensity of Adverse Events With Grading According CTCAE | Incidence and intensity of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0). | 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 | 
| Percentage of Patients With Dose Limit Toxicity (DLTs) Incidence During the First Two Treatment Cycles (Phase I). | 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 | First two treatment cycles, up to 28 days | 
| Maximum Tolerable Dose (MTD) | Determination of Maximum Tolerable Dose based on DLT incidence. | First two treatment cycles, up to 28 days | 
| 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) | 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) | -0:05h before drug administration and 1h, 2h, 2.5h, 3h, 4h, 6h, 8h and 10h after drug administration. | 
| Maximum Plasma Concentration for Nintedanib at Steady State and Normalized by the Dosing Unit Administered (Cmax,ss,Norm) (Phase I) | Maximum plasma concentration for Nintedanib at steady state and normalized by the dosing unit administered (Cmax,ss,norm) (Phase I) | -0:05h before drug administration and 1h, 2h, 2.5h, 3h, 4h, 6h, 8h, and 10h after drug administration. | 
| Quality of Life Evaluation by a Standardised Questionnaires of EORTC: EORTC-QLQ-C30 for the Change From Baseline at 9 Months of Global Health Status Scores. | 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 | Baseline and 9 months. | 
| Quality of Life Evaluation by a Standardised Questionnaires of EORTC: EORTC-QLQ-CR38 for the Change From Baseline at 9 Months. | 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. | Baseline and 9 months. | 
| Number of Participants for Quality of Life Evaluation by a Standardised Questionnaires of EORTC: EORTC-QLQ-CR38 for the First Use of Stoma Bag. | 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. | from baseline until end of treatment, up to 892 days | 
| Exploratory Biomarker and Pharmacogenetic Analysis for VEGF | Exploratory biomarker and pharmacogenetic analysis for Vascular endothelial growth factor (VEGF). Note: This endpoint was not statistically analysed in this study. | Day 1, Day 29, Day 57, Day 85 and Day 127 |