BIBF 1120 Versus Bevacizumab in Metastatic Colorectal Cancer

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

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 Overview

• Status: Completed
• Conditions: Colorectal Neoplasms
• Intervention / Treatment: Drug: BIBF 1120; Drug: mFolfox 6; Drug: bevacizumab; Drug: mFolfox; Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Bonheiden, Belgium
    • 1199.51.32002 Boehringer Ingelheim Investigational Site
  • Bruxelles, Belgium
    • 1199.51.32005 Boehringer Ingelheim Investigational Site
  • Bruxelles, Belgium
    • 1199.51.32006 Boehringer Ingelheim Investigational Site
  • Leuven, Belgium
    • 1199.51.32001 Boehringer Ingelheim Investigational Site
• France
  • Nice Cedex 2, France
    • 1199.51.3306A Boehringer Ingelheim Investigational Site
  • Nice Cedex 2, France
    • 1199.51.3306B Boehringer Ingelheim Investigational Site
  • Nice Cedex 2, France
    • 1199.51.3306C Boehringer Ingelheim Investigational Site
  • Nice Cedex 2, France
    • 1199.51.3306D Boehringer Ingelheim Investigational Site
  • Paris, France
    • 1199.51.3301A Boehringer Ingelheim Investigational Site
  • Paris, France
    • 1199.51.3301B Boehringer Ingelheim Investigational Site
  • Paris, France
    • 1199.51.3301C Boehringer Ingelheim Investigational Site
  • Paris, France
    • 1199.51.3301D Boehringer Ingelheim Investigational Site
  • Reims Cedex, France
    • 1199.51.3307A Boehringer Ingelheim Investigational Site
  • Reims Cedex, France
    • 1199.51.3307B Boehringer Ingelheim Investigational Site
  • Reims Cedex, France
    • 1199.51.3307C Boehringer Ingelheim Investigational Site
  • Saint Herblain, France
    • 1199.51.3308B Boehringer Ingelheim Investigational Site
  • Saint Herblain, France
    • 1199.51.3308C Boehringer Ingelheim Investigational Site
  • Saint-Herblain cedex, France
    • 1199.51.3308A Boehringer Ingelheim Investigational Site
  • Saint-Herblain cedex, France
    • 1199.51.3308D Boehringer Ingelheim Investigational Site
  • Saint-Herblain cedex, France
    • 1199.51.3308E Boehringer Ingelheim Investigational Site
  • Toulouse Cedex, France
    • 1199.51.3305C Boehringer Ingelheim Investigational Site
  • Toulouse Cedex, France
    • 1199.51.3305D Boehringer Ingelheim Investigational Site
  • Toulouse Cedex 3, France
    • 1199.51.3305E Boehringer Ingelheim Investigational Site
  • Toulouse cedex 3, France
    • 1199.51.3305A Boehringer Ingelheim Investigational Site
  • Toulouse cedex 3, France
    • 1199.51.3305B Boehringer Ingelheim Investigational Site
  • Villejuif Cedex, France
    • 1199.51.3302A Boehringer Ingelheim Investigational Site
  • Villejuif Cedex, France
    • 1199.51.3302B Boehringer Ingelheim Investigational Site
  • Villejuif Cedex, France
    • 1199.51.3302C Boehringer Ingelheim Investigational Site
  • Villejuif Cedex, France
    • 1199.51.3302D Boehringer Ingelheim Investigational Site
  • Villejuif Cedex, France
    • 1199.51.3302E Boehringer Ingelheim Investigational Site
• Germany
  • Celle, Germany
    • 1199.51.49001 Boehringer Ingelheim Investigational Site
  • Dresden, Germany
    • 1199.51.49002 Boehringer Ingelheim Investigational Site
  • Freiburg/Breisgau, Germany
    • 1199.51.49003 Boehringer Ingelheim Investigational Site
  • Halle/Saale, Germany
    • 1199.51.49004 Boehringer Ingelheim Investigational Site
  • Mainz, Germany
    • 1199.51.49006 Boehringer Ingelheim Investigational Site
  • Schwäbisch Hall, Germany
    • 1199.51.49008 Boehringer Ingelheim Investigational Site
• Italy
  • Ancona, Italy
    • 1199.51.39002 Boehringer Ingelheim Investigational Site
  • Genova, Italy
    • 1199.51.39001 Boehringer Ingelheim Investigational Site
  • Macerata, Italy
    • 1199.51.39004 Boehringer Ingelheim Investigational Site
  • Reggio Emilia, Italy
    • 1199.51.39005 Boehringer Ingelheim Investigational Site
  • Udine, Italy
    • 1199.51.39003 Boehringer Ingelheim Investigational Site
• Spain
  • Alicante, Spain
    • 1199.51.34006 Boehringer Ingelheim Investigational Site
  • Barakaldo, Spain
    • 1199.51.34005 Boehringer Ingelheim Investigational Site
  • Barcelona, Spain
    • 1199.51.34001 Boehringer Ingelheim Investigational Site
  • La Coruña, Spain
    • 1199.51.34007 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1199.51.34003 Boehringer Ingelheim Investigational Site
  • Madrid, Spain
    • 1199.51.34004 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: May 18, 2009
• First Submitted That Met QC Criteria: May 19, 2009
• First Posted (Estimate): May 20, 2009

Study Record Updates

• Last Update Posted (Estimate): February 4, 2015
• Last Update Submitted That Met QC Criteria: February 3, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Bevacizumab; Nintedanib
• Other Study ID Numbers: 1199.51; 2008-005364-14 (EudraCT Number: EudraCT)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No