BIBF 1120 Versus Bevacizumab in Metastatic Colorectal Cancer

Boehringer Ingelheim128 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

128

Conditions

Colorectal Neoplasms

Interventions

BIBF 1120DRUG

BIBF 1120 100 and 150 mg capsules

BIBF 1120DRUG

BIBF 1120 100 and 150 mg capsules

mFolfoxDRUG

standard i.v chemotherapy

Bevacizumab

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion criteria: 1. Age \>= 18 years 2. Histologically proven colorectal adenocarcinoma 3. No previous oxaliplatin based chemotherapy is allowed unless disease free survival after the end of chemotherapy \> = 12 months 4. No previous therapy with VEGFR or EGFR inhibitors 5. No prior systemic therapy for metastatic CRC 6. No previous adjuvant therapy with fluoropyrimidines is allowed unless disease free survival after the end of chemotherapy \> 6 months 7. ECOG performance status \< = 2 8. Adequate hepatic, renal and bone marrow functions: 9. No uncontrolled hypertension 10. Signed and dated written informed consent prior to admission to the study Exclusion criteria: 1. Treatment with any investigational drug within 28 days of trial onset. 2. History of other malignancies in the last 5 years, in particular those that could affect compliance with the protocol or interpretation of results. 3. 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, 4. Major injuries and/or surgery or bone fracture within 4 weeks of trial inclusion, or planned surgical procedures during the trial period. 5. Significant cardiovascular diseases 6. History of severe haemorrhagic or thromboembolic event in the past 12 months. Known inherited predisposition to bleeding or to thrombosis. 7. Patient with brain metastases that are symptomatic and/or require therapy. 8. Pregnancy or breast-feeding.

Locations (47)

Outcomes

Primary Outcomes

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). 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

Secondary Outcomes

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.

Time frame: 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

Time frame: 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

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

Data from ClinicalTrials.gov

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100 mg/Kg solution , IV infusion

mFolfox 6DRUG

IV standard chemotherapy

bevacizumabDRUG

100 mg/4 ml solution

1199.51.32002 Boehringer Ingelheim Investigational Site

Bonheiden, Belgium

1199.51.32005 Boehringer Ingelheim Investigational Site

Brussels, Belgium

1199.51.32006 Boehringer Ingelheim Investigational Site

Brussels, Belgium

1199.51.32001 Boehringer Ingelheim Investigational Site

Leuven, Belgium

1199.51.3306A Boehringer Ingelheim Investigational Site

Nice, France

1199.51.3306B Boehringer Ingelheim Investigational Site

Nice, France

1199.51.3306C Boehringer Ingelheim Investigational Site

Nice, France

1199.51.3306D Boehringer Ingelheim Investigational Site

Nice, France

1199.51.3301A Boehringer Ingelheim Investigational Site

Paris, France

1199.51.3301B Boehringer Ingelheim Investigational Site

Paris, France

...and 37 more locations

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.

Time frame: 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.

Time frame: 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: 1. \<= - 30% 2. \> - 30% and \< 0% 3. \>= 0% and \< 20% 4. \>=20%

Time frame: 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).

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

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

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

Maximum Tolerable Dose (MTD)

Determination of Maximum Tolerable Dose based on DLT incidence.

Time frame: 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)

Time frame: -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)

Time frame: -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

Time frame: 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.

Time frame: 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.

Time frame: 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.

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