| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Non Small Cell Lung Cancer (recurrent or stage IIIB/IV) with squamous cell histology. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced cancer of the lung of a certain type of histology |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001184 |
| E.1.2 | Term | Adenocarcinoma of lung stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001183 |
| E.1.2 | Term | Adenocarcinoma of lung stage IIIB |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001177 |
| E.1.2 | Term | Adenocarcinoma of lung recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Run-in Phase I: To confirm that up to a 200mg b.i.d dose of BIBF 1120, added to gemcitabine and cisplatin, is safe and tolerable added to a standard dose of cisplatin/gemcitabine in patients with stage IIIB/IV or recurrent non small cell lung cancer (NSCLC) with squamous cell histology. Pharmacokinetics of BIBF 1120 and clinically relevant metabolites, gemcitabine and cisplatin.
Phase II: To investigate the efficacy and safety of BIBF 1120 compared to placebo in first line NSCLC patients with squamous cell histology, and at least stable disease after two cycles of cisplatin/gemcitabine chemotherapy.
|
|
| E.2.2 | Secondary objectives of the trial |
Run-in Phase I: The evaluation of objective response and best overall response by means of descriptive statistics. Descriptive statistics of plasma concentrations per analyte and time point and of standard pharmacokinetic parameters will also be calculated.
Phase II : The analysis of objective response, disease control and overall survival. Duration of objective response and duration of disease control will also be evaluated for patients achieving objective response and disease control respectively.
In addition to that Health-Related Quality of Life (HRQOL) questionnaires – namely the QLQ-C30, QLQ-LC13 and EQ-5D questionnaire – will be analysed.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Run-in Phase I
1.Histologically or cytologically confirmed diagnosis of stage IIIB/IV or recurrent NSCLC with squamous cell histology.
2.Measurable disease according to RECIST 1.1.
3.Patient Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
4.Male or female patients age ≥ 18 years.
5.Life expectancy of at least three (3) months.
6.Written informed consent in accordance with ICH-GCP guidelines.
Phase II
In addition to the above inclusion criteria:
7.Radiologically-confirmed at least stable disease after 2 prior cycles of cisplatin / gemcitabine chemotherapy.
|
|
| E.4 | Principal exclusion criteria |
1.Prior therapy for advanced or metastatic or recurrent NSCLC. One prior adjuvant, neoadjuvant or adjuvant + neoadjuvant treatment is allowed if at least 12 months have elapsed between the end of the treatment and randomization
2.Prior treatment with other VEGFR inhibitors (other than bevacizumab)
3.Known pre-existing interstitial lung disease e.g. caused by asbestosis
4.Significant weight loss (>10%) within 6 weeks prior to starting treatment in the 1199.82 study.
5.Any contraindications for treatment with gemcitabine and/or cisplatin.
6.Ototoxicity and symptomatic neuropathy > Grade 1 according to the NCI CTCAE
7.Use of any investigational drug within 4 weeks of entering the 1199.82 study.
8.History of clinically significant haemoptysis within the past 3 months (more than one tea spoon of fresh blood per day).
9.Therapeutic anticoagulation (except for prophylactic low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or anti-platelet therapy (except for chronic low-dose therapy with acetylsalicylic acid ≤ 325mg per day).
10.History of major thrombotic or clinically relevant bleeding event in the past 6
months.
11.Known inherited predisposition to bleeding or thrombosis.
12.Significant cardiovascular diseases (i.e. hypertension not controlled by medication,
unstable angina, history of myocardial infarction) within the past 6 months,
congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion).
13.Surgery within 4 weeks (except tumour biopsy) prior randomisation and incomplete wound healing.
14.Active brain metastases (eg stable for <4 weeks, no adequate previous treatment
with radiotherapy, symptomatic, requiring treatment with anti-convulsants;
dexamethasone therapy will be allowed if administered as a stable dose for at least
one month before inclusion into the study.)
15.Leptomeningeal disease.
16.Radiographic evidence of cavitary or necrotic tumours.
17.Centrally located tumours with radiographic evidence (on CT or MRI) of local
invasion of major blood vessels.
18.Radiotherapy (except extremities) within 3 months prior to baseline imaging and radiotherapy for brain metastasis < 4 weeks prior baseline imaging.
19.Any other current malignancy or malignancy diagnosed within the past five (5) years (other than non-melanomatous skin cancer and in situ cervical cancer).
20.Gastrointestinal disorders or abnormalities that would interfere with the absorption of the study drug.
21.Any other concomitant serious illness or organ system dysfunction which in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug.
22.Presence of clinically significant third-space fluid collections (for example ascites or pleural effusions) that cannot be controlled by drainage or other procedures prior tostudy entry.
23.Prothrombin time and / or partial thromboplastin time greater than 50% deviation from normal limits
24.Absolute neutrophil count (ANC) < 1500 / mm3.
25.Platelet count < 100,000 / mm3.
26.Haemoglobin < 9.0 g/dl
27.Impaired renal function demonstrated by the following (assessed within 14 days of randomisation): GFR < 50ml/min as measured by creatinine clearance through EDTA or 24 hour urine collection. Alternatively, the Cockcroft and Gault formula (Appendix 10.2) may be used to estimate GFR, but if GFR < 50 ml/min, then creatinine clearance through EDTA or 24 hour urine collection should be measured.
28.Total bilirubin above the upper limit of normal.
29.ALT and/or AST>2.5 x upper limit of normal in the presence of liver metastases or
ALT/AST> 1.5 x upper limit of normal in patients without liver metastases.
30.Proteinuria CTCAE grade 2 or greater.
31.Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives,some intrauterine devices or vasectomized partner for participating females, condoms (or participating males) during the study and for at least 6 months after the end of active treatment
32.Pregnancy or breast-feeding.
33.Patients unable to comply with the protocol.
34.History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to inclusion.
35.Active or chronic hepatitis B and or hepatitis C infection or known HIV carrier.
36.Known or suspected active drug or alcohol abuse.
37.Requirement for treatment with any of the prohibited concomitant medications listed
in section 4.2.2.
38.Hypersensitivity to contrast media or to BIBF 1120 and / or the excipients of the study drugs.
39.Concomitant yellow fever vaccination or administration of live attenuated vaccines
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Run-in Phase I: To confirm that up to a 200mg b.i.d dose of BIBF 1120, added to gemcitabine and cisplatin, is safe and tolerable added to a standard dose of cisplatin/gemcitabine in patients with stage IIIB/IV or recurrent non small cell lung cancer (NSCLC) with squamous cell histology.
Phase II: To explore the Progression Free Survival of patients treated with BIBF 1120 added to cisplatin/gemcitabine vs. placebo added to gemcitabine and cisplatin. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Phase I & Phase II: Patients can have a minimum of 4 and maximum of 6 21-day cycles of BIBF 1120 added to gemcitabine and cisplatin for as long as patients either tolerate the therapy without clinical disease progression, do not meet one of the treatment withdrawal criteria or patient/ investigator request discontinuation of study treatment. After combination therapy gemcitabine and cisplatin daily doses of BIBF 1120 as monotherapy can be given until progression of disease or occurrence of Adverse Events which would not allow further treatment of the patients. |
|
| E.5.2 | Secondary end point(s) |
Phase I: The secondary objectives for the run-in Phase I part are the evaluation of objective response and best overall response by means of descriptive statistics. Descriptive statistics of plasma concentrations per analyte and time point and of standard pharmacokinetic parameters will also be calculated.
Phase II: The secondary objectives of the Phase II part include the analysis of objective response, disease control and overall survival. Duration of objective response and duration of disease control will also be evaluated for patients achieving objective response and disease control respectively.In addition to that Health-Related Quality of Life (HRQOL) questionnaires – namely the QLQ-C30, QLQ-LC13 and EQ-5D questionnaire – will be analysed.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Phase I & Phase II: Patients can have a minimum of 4 and maximum of 6 21-day cycles of BIBF 1120 added to gemcitabine and cisplatin for as long as patients either tolerate the therapy without clinical disease progression, do not meet one of the treatment withdrawal criteria or patient/ investigator request discontinuation of study treatmen. After combination thereapy gemcitabine and cisplatin daily doses of BIBF 1120 as monotherapy can be given until progression of disease or occurrence of Adverse Events which would not allow further treatment of the patients. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase I Open label, Phase II double-blind placebo controlled. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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