Dose Escalation of BIBF 1120 Combined With Pemetrexed in Advanced Non Small Cell Lung Cancer

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

A Phase I Open Label Study of Continuous Oral Treatment With BIBF 1120 Together With Pemetrexed in Previously Treated Patients With Non-small Cell Lung Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02182102
• Other study ID #: 1199.18
• Status: Completed
• Phase: Phase 1
• First received: July 2, 2014
• Last updated: July 17, 2014
• Start date: September 2005

Study information

• Verified date: July 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Ministry of Health & Long Term Care, Ontario
• Study type: Interventional

Clinical Trial Summary

The primary objective was to determine the safety, tolerability and maximum tolerate dose (MTD) of BIBF 1120 in combination with pemetrexed. Secondary objectives were to characterize the pharmacokinetic profiles of BIBF 1120 and pemetrexed and to obtain preliminary anti-tumour efficacy information.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 26
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Pathologic confirmation of metastatic, unresectable, or locally advanced NSCLC (non-small cell lung cancer)

• Disease progression during or following one prior platinum-based (including prior neoadjuvant or adjuvant therapy) chemotherapy regimen for advanced disease

• Bi-dimensionally measurable disease by one or more techniques (CT (computed tomography), MRI (magnetic resonance imaging), X-ray)

• Age 18 years or older

• Life expectancy of at least three (3) months

• Eastern Cooperative Oncology Group (ECOG) performance score 0-2

• Written informed consent that is consistent with ICH-GCP (International Conference on Harmonization - Good Clinical Practice) guidelines

Exclusion Criteria:

• Participation in another clinical study within the past 28 days prior to the start of therapy or concomitantly with this study

• Treatment for NSCLC (except radiotherapy for palliative reasons) within the past 28 days prior to Treatment Day 1 of this trial. All toxicities of the previous therapy must have resolved to baseline prior to Treatment Day 1

• Patient has received more than one prior chemotherapy regimen for advanced disease

• Radiotherapy to an area of measurable disease (unless disease progression had been documented following completion of therapy)

• Patients who are unwilling or unable to take folic acid and vitamin B12 supplementation

• Radiotherapy within 4 weeks prior to Treatment Day 1

• Prior treatment with agents that target the vascular endothelial growth factor (VEGF) pathways, including monoclonal antibody therapy (such as bevacizumab) or tyrosine kinase inhibitors

• Active brain metastases (stable for <28 days, symptomatic, or requiring concurrent steroids or antiepileptic therapy). Patients who have received prior whole brain irradiation and whose brain metastases are stable according to the criteria above will not be excluded

• Centrally located tumors with radiologic evidence (CT or MRI) of local invasion of major blood vessels, with exception of those tumors which have received prior irradiation and are stable

• Cavitary or necrotic tumors

• Sanguinous pleural effusion due to disease or pericardial effusion suspicious for disease

• Other active malignancy diagnosed within the past 3 years (other than non-melanomatous skin cancer)

• Gastrointestinal abnormalities that would interfere with intake or absorption (with exception of patients with gastric esophageal reflux disease controlled with proton pump inhibitors) of the study drug, such as a requirement for intravenous alimentation, prior surgical procedures affecting absorption, treatment for peptic ulcer disease within the last 6 months, active gastrointestinal bleeding unrelated to cancer (as evidenced by either hematemesis, hematochezia, or melena in the past 3 months and without endoscopic documented resolution), or malabsorption syndromes

• Significant cardiovascular disease (i.e., uncontrolled hypertension, myocardial infarction within 6 months, unstable angina, serious cardiac arrhythmia, >2 New York Heart Association (NYHA) Grade 2 congestive heart failure)

• History of hemorrhagic or thrombotic event (including transient ischemic attacks) in the past 12 months or clinically significant hemoptysis in the past 3 months

• Patients receiving any anti-coagulant therapy (including coumadin, heparin, low molecular weight heparin, and aspirin

• Patient has received prior therapy with pemetrexed

• Absolute neutrophil count (ANC) =1,500/µl, platelet count =100,000/µl, or hemoglobin <9 gm/dL

• Total bilirubin >1.5 mg/dL (26 µmole/L, SI-Unit equivalent), alanine amino transferase (ALT) and/or aspartate amino transferase (AST) =1.5 X upper limit of normal (ULN)

• Inadequate renal function determined by a serum creatinine level >1.5 X ULN

• Patient is unable or unwilling to interrupt aspirin or other NSAIDS for a 5-day period (8 days period for long lasting agents like piroxicam)

• Persistent hematuria or proteinuria (more than trace)

• Women and men who are sexually active and unwilling to use a medically acceptable method of contraception

• Pregnancy or breast feeding

• Known or suspected active alcohol or drug abuse

• Patients unable to comply with the protocol

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung

Intervention

Drug:
• BIBF 1120

• Pemetrexed

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MTD (maximum tolerated dose) of BIBF 1120 in combination with pemetrexed (500 mg/m2).		up to 126 days	No
Primary	Incidence and intensity of Adverse Events according to the Common Terminology Criteria for Adverse Events (Version 3.0) associated with increasing doses of BIBF 1120.		up to 126 days	No
Secondary	AUC0-24 (Area under the plasma concentration-time curve over the dosing interval t (24 h) following the first dose of uniform intervals t)		before and up to 6 hours after adminstration in cycle 2	No
Secondary	AUC0-tz (AUC over the time interval from zero to the time of the last quantifiable drug concentration)		before and up to 6 hours after adminstration in cycle 2	No
Secondary	AUC0-8 (AUC over the time interval from zero extrapolated to infinity)		before and up to 6 hours after adminstration in cycle 2	No
Secondary	%AUCtz-8 (the percentage of AUC0-8 that is obtained by extrapolation)		before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2	No
Secondary	Cpre,1 (Pre-dose plasma concentration)		before first administration of BIBF 1120 on day 2 of cycle 2	No
Secondary	C24,1 (Plasma concentration at 24 h following the first dose)		24 hours after the first administration of BIBF 1120 in cycle 2	No
Secondary	Cmax (Maximum measured plasma concentration following the first dosing intervals t)		before and up to 6 hours after adminstration in cycle 2	No
Secondary	tmax (Time from dosing to the maximum plasma concentration following the first dosing intervals t)		before and up to 6 hours after adminstration in cycle 2	No
Secondary	?z (Terminal rate constant in plasma)		before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2	No
Secondary	t1/2 (Terminal half-life)		before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2	No
Secondary	MRTpo (Mean residence time after oral administration)		before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2	No
Secondary	CL/F of BIBF 1120 (Apparent clearance)		before and 1, 2, 3, 4, 6 hours after first adminstration of BIBF 1120 in cycle 2	No
Secondary	Vz/F of BIBF 1120 (Apparent volume of distribution during the terminal phase)		before and 1, 2, 3, 4, 6 hours after first adminstration of BIBF 1120 in cycle 2	No
Secondary	% AUCtz-8 for pemetrexed		before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2	No
Secondary	C24,1 C48,1 (Plasma concentration at 24 h and 48 h following the first dose of treatment cycle		24 and 28 hours after administration in cycle 2	No
Secondary	MRTiv for pemetrexed (Mean residence time after i.v. administration)		before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2	No
Secondary	CL (Clearance) for pemetrexed		before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2	No
Secondary	Vz for pemetrexed (apparent volume of distribution during the terminal phase following an intravascular dose)		before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2	No
Secondary	Vss for pemetrexed (Apparent volume of distribution at steady state)		before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2	No
Secondary	Objective tumor response according to the response evaluation criteria in solid tumors (RECIST)		up to 56 months	No
Secondary	Duration of objective tumor response (time from best response to onset of tumor progression)		up to 56 months	No
Secondary	Time to tumor progression (time from start of treatment to time of documented tumor progression)		up to 56 months	No

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