A Dose Escalation Study of BIBF 1120 Together With Paclitaxel and Carboplatin in Patients With Advanced Stage Non-small-cell Lung Cancer

Study Overview
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Brief Summary
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The primary objectives of this trial were to determine the MTD of BIBF 1120 in combination with carboplatin and paclitaxel, pharmacokinetics and objective response of treatment

Official Title
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A Phase I Open Label Dose Escalation Study of Continuous Oral Treatment With BIBF 1120 Together With Paclitaxel and Carboplatin in Patients With Advanced Stage Non-small-cell Lung Cancer

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BIBF 1120
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients with histologically or cytologically confirmed Stage IIIB (including pleural effusion), IV or recurrent NSCLC Bi-dimensionally measurable disease by one or more techniques (CT, MRI, X-ray) Age 18 years or older Life expectancy of at least three (3) months Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 Written informed consent that is consistent with ICH-GCP guidelines Exclusion Criteria: Prior treatment for NSCLC including chemotherapy, biologic response modifier therapy, or any investigational drug Participation in another clinical study within the past four weeks before start of therapy or concomitantly with this study Active brain metastases (stable for <28 days, symptomatic, or requiring concurrent steroids or antiepileptic therapy) Centrally located tumors with radiologic evidence (CT or MRI) of local invasion of major blood vessels Cavitary or necrotic tumors Sanguinous pleural effusion due to disease or pericardial effusion suspicious for disease Radiotherapy to an area of measurable disease (unless disease progression had been documented following completion of therapy) Radiotherapy within 4 weeks preceding Day 0 Other active malignancy diagnosed within the past 3 years (other than non-melanomatous skin cancer) Gastrointestinal abnormalities that would interfere with intake or absorption 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, ≥NYHA Grade 2 congestive heart failure) History of hemorrhagic or thrombotic event (including transient ischemic attacks) in the past 12 months Clinically significant hemoptysis (1 teaspoon or more) in the past 3 months Concurrent therapeutic anticoagulation (except heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except chronic low-dose daily aspirin <325 mg) Known hypersensitivity to paclitaxel, carboplatin, or any of their excipients including Cremophor® (polyoxyethylated castor oil) Absolute neutrophil count (ANC) ≤1,500/μl, platelet count ≤100,000/μl, or hemoglobin <9 gm/dL Total bilirubin >1.5 mg/dL (26 μmol/L, SI Unit equivalent), alanine amino transferase (ALT) and/or aspartate amino transferase (AST) ≥1.5 X ULN, Serum creatinine >1.5 mg/dL (>132 μmol/L, SI Unit equivalent) 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 breastfeeding Known or suspected active alcohol or drug abuse Patients unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBF 1120 with paclitaxel and carboplatin<br> | Drug: BIBF 1120<br> <br> Drug: Paclitaxel<br> <br> Drug: Carboplatin<br> <br> |
| Experimental: BIBF 1120 monotherapy<br> | Drug: Carboplatin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and intensity of adverse events according to Common Terminology Criteria for Adverse Events (version 3.0) associated with increasing doses of BIBF 1120 |  | up to day 126 | 
| Maximum tolerated dose (MTD) of BIBF 1120 in combination with carboplatin and paclitaxel |  | up to day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-dose plasma concentration (Cpre) |  | up to day 42 | 
| Objective tumor response according to response evaluation criteria in solid tumors (RECIST) |  | up to 12 months | 
| Time from best response to onset of tumor progression |  | Up to 12 months | 
| Time from start of treatment to time of documented tumor progression |  | Up to 12 months | 
| area under the curve (AUC) from 0 to 12 hours (AUC0-12) |  | up to day 42 | 
| AUC from 0 to the last quantifiable drug concentration (AUC0-tz) |  | up to day 42 | 
| Maximum plasma concentration (Cmax) |  | up to day 42 | 
| Time to maximum plasma concentration (tmax) |  | up to day 42 | 
| Rate constant (λz) for BIBF 1120 |  | up to day 42 | 
| AUC from 0 to 24 hours (AUC0-24) for paclitaxel |  | up to day 42 | 
| AUC from 0 extrapolated to 48 hours (AUC0-48) for paclitaxel |  | up to day 42 | 
| AUC from 0 extrapolated to infinity (AUC0-∞) |  | up to day 42 | 
| Percentage of AUC0-∞ that is obtained by extrapolation (% AUCtz-∞) |  | up to day 42 | 
| Terminal half-life (t1/2) |  | up to day 42 | 
| Mean residence time after intravenous administration (MRTiv) for paclitaxel and carboplatin |  | up to day 42 | 
| Total Clearance (CL/F) |  | up to day 42 | 
| Volume of distribution during the terminal phase (Vz) |  | up to day 42 | 
| AUC from 0 to 24 hours (AUC0-24) for carboplatin |  | Day 1 and 22 in the treatment time | 
| Plasma concentration 21 hours after start of infusion (C21) for carboplatin |  | up to day 42 | 
| Plasma concentration 24 hours after start of infusion (C24) for paclitaxel |  | up to day 42 |