BIBF 1120 in Combination With Pemetrexed in Advanced Non Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The objectives of this trial are to estimate the following in Japanese patients with advanced NSCLC of stage IIIB/IV or with recurrence after failure of first-line chemotherapy. Phase I part The objective of the phase I part is to define the Maximum Tolerated Dose (MTD) of BIBF 1120 at a dose level up to twice daily 200 mg with standard dose of pemetrexed (500 mg/m^2) and to determine the Recommended Dose (RD) for the phase II part. Phase II, to investigate the efficacy and safety of BIBF 1120 in combination with pemetrexed (500 mg/m^2) as compared to pemetrexed (500 mg/m^2) + placebo

Official Title
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A Phase I/II Study of Continuous, Concomitant Oral Treatment With BIBF 1120 and Pemetrexed - a Phase I, Open-label, Dose-escalation Study & a Phase II, 2 Arm, Randomized, Double-blind, Placebo-controlled Study in Japanese Patients With Stage IIIB/IV or Recurrent Non-small-cell Lung Cancer After Failure of Chemotherapy

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BIBF 1120 M + Pemetrexed
* Drug: BIBF 1120 H + Pemetrexed
* Drug: BIBF 1120 RD + Pemetrexed
* Drug: BIBF 1120 L + Pemetrexed
* Drug: BIBF 1120 Placebo + Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patients of age >=20 and <=74 years at informed consent Histologically or cytologically confirmed, Non Small Cell Lung Cancer (NSCLC) of stage IIIB or IV or recurrent NSCLC Relapse or failure of 1 first-line prior chemotherapy Life expectancy of at least 3 months Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 Patients who have sufficient baseline organ function over 4 weeks and whose laboratory data meet the following criteria at the enrolment Haemoglobin >=9.0 g/dL Absolute neutrophil count (ANC) >=1500/mm^3 Platelet count >=100 000/mm^3 Total bilirubin under the upper limit of normal AST/SGOT and/or ALT/GPT <=1.5 x upper limit of normal (if related to liver metastases <=2.5 x upper limit of normal also) Proteinuria Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or less Calculated creatinine clearance by Cockcroft Gault >=45 mL/min Prothrombin time-international normalized ratio (PT-INR) and/or partial thromboplastin time (PTT) greater than 50% deviation from normal limits arterial oxgen pressure (PaO2) >=60 torr or oxygen saturation by pulse-oximeter SpO2 >=92% Patient has given written informed consent which must be consistent with ICH-GCP and local legislation. Exclusion criteria: Patients who have received treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial or who have not recovered from side effects of such therapy (except for alopecia) Patients who have received chemo-, hormone-, immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug or who have not recovered from side effects of such therapy (except for alopecia) . Patients who have received radiotherapy within the following period Phase I part: the past 4 weeks prior to treatment with the trial drug (in case of palliative radiotherapy such as for extremities, within the past 2 weeks prior to treatment with the trial drug) Previous therapy with other vascular endothelial growth factor receptor (VEGFR) inhibitors or vascular endothelial growth factor (VEGF) ligand inhibitors for treatment of NSCLC Previous therapy with BIBF 1120 and/or pemetrexed for treatment of NSCLC and any contraindications for therapy with pemetrexed Patients who have active brain metastases Leptomeningeal disease Patients with distinct or suspected pulmonary fibrosis or interstitial lung disease by the CT findings, or patients with a previous history of pulmonary fibrosis or interstitial lung disease (except irradiation-pneumonitis appearing radiation field with past radiotherapy). Radiographic evidence of cavitary or necrotic tumors Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels History of clinically significant haemoptysis within the past 3 months History of major thrombotic or clinically relevant major bleeding event in the past 6 months Known inherited predisposition to bleeding or thrombosis Significant cardiovascular diseases Significant weight loss (>10%) within the past 6 weeks prior to treatment in the present trial Current peripheral neuropathy CTCAE grade 2 or greater except due to trauma Pre-existing ascites and/or clinically significant pleural effusion Major injuries and/or surgery within the past 4 weeks prior to randomisation with incomplete wound healing Clinically serious infections Decompensated diabetes mellitus Contraindication to high dose steroid therapy Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug Patients who have active or chronic hepatitis C and/or B infection and diagnosis of human immunodeficiency virus (HIV) infection Other malignancy other than basal cell skin cancer, carcinoma in situ or intra-mucosal cancer that were judged to be cured by adequate treatment and disease-free interval is more than 5 years History of serious drug hypersensitivity Serious illness or concomitant non-oncological disease such as neurologic-, psychiatric-, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy Patients who are sexually active and unwilling to use a medically acceptable method of contraception Pregnancy or breast feeding Active alcohol or drug abuse Patients unable to comply with the protocol Other patients judged ineligible for enrolment in the study by the investigator or subinvestigator.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBF 1120 BID + Pemetrexed<br>Phase I part: Find MTD by using low, medium or high BIBF 1120 twice daily and 500mg/m^2 pemetrexed once every 3 weeks | Drug: BIBF 1120 M + Pemetrexed<br>* BIBF 1120 medium dose bid+ Pemetrexed 500 mg/m^2<br>Drug: BIBF 1120 H + Pemetrexed<br>* BIBF 1120 high dose bid+ Pemetrexed 500 mg/m^2<br>Drug: BIBF 1120 L + Pemetrexed<br>* BIBF 1120 low dose bid+ Pemetrexed 500 mg/m^2<br>|
| Experimental: BIBF 1120 BID (RD) + Pemetrexed<br>PHase II part: Study arm | Drug: BIBF 1120 RD + Pemetrexed<br>* confirmed dose of BIBF 1120 bid + Pemetrexed 500 mg/m^2<br>|
| Experimental: BIBF 1120 BID(Placebo) + Pemetrexed<br>Phase II part: Comparator arm | Drug: BIBF 1120 Placebo + Pemetrexed<br>* placebo BIBF 1120 bid + Pemetrexed 500 mg/m^2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities | Number of participants with dose limiting toxicity (DLT) in combination therapy of BIBF 1120 and pemetrexed during the first course | During the first course, 21 days | 
| Adverse Events According to Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 for All Courses | Number of patients with adverse events according to worst Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 for all courses. CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE) or 5 (death related to AE). | Between first administration of pemetrexed and 28 days after last administration of pemetrexed and/or BIBF 1120, up to 1020 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Number of participants with complete response (CR) or partial response (PR) according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 | Every 6 weeks after start of study treatment until end of treatment, up to 992 days | 
| Disease Control Rate | Number of participants with complete response (CR), partial response (PR) or stable disease (SD) according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 | Every 6 weeks after start of study treatment until end of treatment, up to 992 days | 
| Duration of Disease Control | Duration of disease control was defined as the time period from the first study drug administration to the progressive disease (PD) or death of patients, whichever occurred earlier. | From first study drug administration until PD or death, up to 1003 days | 
| Number of Participants With Clinically Relevant Abnormalities in Laboratory Parameters | Number of participants with clinically relevant abnormalities in laboratory parameters reported as adverse events which occurred in >= 20% of patients | Between first administration of pemetrexed and 28 days after last administration of pemetrexed and/or BIBF 1120, up to 1020 days | 
| AUC0-inf of Nintedanib | Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf) | 5 minutes (min) before nintedanib administration and 1h, 2h, 3h, 4h, 6h, 7h, 10h and 23h 55min after nintedanib administration in cycle 1 | 
| Cmax of Nintedanib | Maximum measured concentration of nintedanib in plasma (Cmax) | 5 minutes (min) before nintedanib administration and 1h, 2h, 3h, 4h, 6h, 7h, 10h and 23h 55min after nintedanib administration in cycle 1 | 
| AUC0-inf of Pemetrexed | Area under the concentration-time curve of pemetrexed in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf) | 5 minutes (min) before pemetrexed administration and 10min, 40min, 1 hour (h), 2h, 4h, 6h, 23h 55min, 47h 55min after pemetrexed administration in cycles 1 and 2 | 
| Cmax of Pemetrexed | Maximum measured concentration of pemetrexed in plasma (Cmax) | 5 minutes (min) before pemetrexed administration and 10min, 40min, 1 hour (h), 2h, 4h, 6h, 23h 55min, 47h 55min after pemetrexed administration in cycles 1 and 2 |