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

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

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

Inclusion criteria:

1. Male or female patients of age >=20 and <=74 years at informed consent

2. Histologically or cytologically confirmed, Non Small Cell Lung Cancer (NSCLC) of stage IIIB or IV or recurrent NSCLC

3. Relapse or failure of 1 first-line prior chemotherapy

4. Life expectancy of at least 3 months

5. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1

6. 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%

7. Patient has given written informed consent which must be consistent with ICH-GCP and local legislation.

Exclusion criteria:

1. 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)
2. 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) .
3. 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)
4. Previous therapy with other vascular endothelial growth factor receptor (VEGFR) inhibitors or vascular endothelial growth factor (VEGF) ligand inhibitors for treatment of NSCLC
5. Previous therapy with BIBF 1120 and/or pemetrexed for treatment of NSCLC and any contraindications for therapy with pemetrexed
6. Patients who have active brain metastases
7. Leptomeningeal disease
8. 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).
9. Radiographic evidence of cavitary or necrotic tumors
10. Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels
11. History of clinically significant haemoptysis within the past 3 months
12. History of major thrombotic or clinically relevant major bleeding event in the past 6 months
13. Known inherited predisposition to bleeding or thrombosis
14. Significant cardiovascular diseases
15. Significant weight loss (>10%) within the past 6 weeks prior to treatment in the present trial
16. Current peripheral neuropathy CTCAE grade 2 or greater except due to trauma
17. Pre-existing ascites and/or clinically significant pleural effusion
18. Major injuries and/or surgery within the past 4 weeks prior to randomisation with incomplete wound healing
19. Clinically serious infections
20. Decompensated diabetes mellitus
21. Contraindication to high dose steroid therapy
22. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
23. Patients who have active or chronic hepatitis C and/or B infection and diagnosis of human immunodeficiency virus (HIV) infection
24. 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
25. History of serious drug hypersensitivity
26. 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
27. Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy
28. Patients who are sexually active and unwilling to use a medically acceptable method of contraception
29. Pregnancy or breast feeding
30. Active alcohol or drug abuse
31. Patients unable to comply with the protocol
32. Other patients judged ineligible for enrolment in the study by the investigator or subinvestigator.