BIBF 1120 Versus Bevacizumab in Metastatic Colorectal Cancer

Colorectal Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00904839
• Other study ID #: 1199.51
• Secondary ID: 2008-005364-14
• Status: Completed
• Phase: Phase 2
• First received: May 18, 2009
• Last updated: February 3, 2015
• Start date: May 2009
• Est. completion date: January 2012

Study information

• Verified date: February 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Belgium: Federal Agency for Medicinal and Health ProductsFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesItaly: Ethics CommitteeSpain: Spanish Agency of MedicinesUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 128
• Est. completion date: January 2012
• Est. primary completion date: January 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Neoplasms

Intervention

Drug:
• BIBF 1120
BIBF 1120 100 and 150 mg capsules
• BIBF 1120
BIBF 1120 100 and 150 mg capsules
• mFolfox
standard i.v chemotherapy
• Bevacizumab
100 mg/Kg solution , IV infusion
• mFolfox 6
IV standard chemotherapy
• bevacizumab
100 mg/4 ml solution

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Maximum Tolerable Dose (MTD)	Determination of Maximum Tolerable Dose based on DLT incidence.	First two treatment cycles, up to 28 days	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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.	No
Secondary	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	No
Secondary	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	No

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