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

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ClinicalTrials.gov Identifier: NCT02182102
Recruitment Status : Completed
First Posted : July 8, 2014
Last Update Posted : July 18, 2014
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief 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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: BIBF 1120 Drug: Pemetrexed Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : September 2005
Actual Primary Completion Date : May 2010

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: BIBF 1120 + Pemetrexed Drug: BIBF 1120
Drug: Pemetrexed



Primary Outcome Measures :
  1. MTD (maximum tolerated dose) of BIBF 1120 in combination with pemetrexed (500 mg/m2). [ Time Frame: up to 126 days ]
  2. 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. [ Time Frame: up to 126 days ]

Secondary Outcome Measures :
  1. AUC0-24 (Area under the plasma concentration-time curve over the dosing interval τ (24 h) following the first dose of uniform intervals τ) [ Time Frame: before and up to 6 hours after adminstration in cycle 2 ]
  2. AUC0-tz (AUC over the time interval from zero to the time of the last quantifiable drug concentration) [ Time Frame: before and up to 6 hours after adminstration in cycle 2 ]
  3. AUC0-∞ (AUC over the time interval from zero extrapolated to infinity) [ Time Frame: before and up to 6 hours after adminstration in cycle 2 ]
  4. %AUCtz-∞ (the percentage of AUC0-∞ that is obtained by extrapolation) [ Time Frame: before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2 ]
  5. Cpre,1 (Pre-dose plasma concentration) [ Time Frame: before first administration of BIBF 1120 on day 2 of cycle 2 ]
  6. C24,1 (Plasma concentration at 24 h following the first dose) [ Time Frame: 24 hours after the first administration of BIBF 1120 in cycle 2 ]
  7. Cmax (Maximum measured plasma concentration following the first dosing intervals τ) [ Time Frame: before and up to 6 hours after adminstration in cycle 2 ]
  8. tmax (Time from dosing to the maximum plasma concentration following the first dosing intervals τ) [ Time Frame: before and up to 6 hours after adminstration in cycle 2 ]
  9. λz (Terminal rate constant in plasma) [ Time Frame: before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2 ]
  10. t1/2 (Terminal half-life) [ Time Frame: before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2 ]
  11. MRTpo (Mean residence time after oral administration) [ Time Frame: before and 1, 2, 3, 4, 6 hours after first adminstration in cycle 2 ]
  12. CL/F of BIBF 1120 (Apparent clearance) [ Time Frame: before and 1, 2, 3, 4, 6 hours after first adminstration of BIBF 1120 in cycle 2 ]
  13. Vz/F of BIBF 1120 (Apparent volume of distribution during the terminal phase) [ Time Frame: before and 1, 2, 3, 4, 6 hours after first adminstration of BIBF 1120 in cycle 2 ]
  14. % AUCtz-∞ for pemetrexed [ Time Frame: before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2 ]
  15. C24,1 C48,1 (Plasma concentration at 24 h and 48 h following the first dose of treatment cycle [ Time Frame: 24 and 28 hours after administration in cycle 2 ]
  16. MRTiv for pemetrexed (Mean residence time after i.v. administration) [ Time Frame: before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2 ]
  17. CL (Clearance) for pemetrexed [ Time Frame: before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2 ]
  18. Vz for pemetrexed (apparent volume of distribution during the terminal phase following an intravascular dose) [ Time Frame: before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2 ]
  19. Vss for pemetrexed (Apparent volume of distribution at steady state) [ Time Frame: before and 0.25, 1, 2, 4, 6 hours after administration in cycle 2 ]
  20. Objective tumor response according to the response evaluation criteria in solid tumors (RECIST) [ Time Frame: up to 56 months ]
  21. Duration of objective tumor response (time from best response to onset of tumor progression) [ Time Frame: up to 56 months ]
  22. Time to tumor progression (time from start of treatment to time of documented tumor progression) [ Time Frame: up to 56 months ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Additional Information:
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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02182102    
Other Study ID Numbers: 1199.18
First Posted: July 8, 2014    Key Record Dates
Last Update Posted: July 18, 2014
Last Verified: July 2014
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Pemetrexed
Nintedanib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors