| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The project aims for screening for potential biomarkers and biomarker combinations relevant for second line setting in NSCLC during combinational therapy with docetaxel and nintedanib. The predicitve value of such profiles should then be evaluated in larger cohorts. |
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| E.1.1.1 | Medical condition in easily understood language |
| Screening for potential biomarkers and biomarker combinations relevant for second line setting in non-small cell lung cancer (NSCLC) during combinational therapy with docetaxel and nintedanib. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
| The aim of the study is to explore novel biomarkers and to evaluate biomarker combinations measured in different biosamples (plasma, whole blood, DNA, tumor tissue) when combined with clinical parameters. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients of at least 18 years of age
2. Histologically confirmed, adenocarcinoma of the lung, after failure of first line platinum-based chemotherapy. First line chemotherapy for locally advanced, or metastatic (stage IIIB or IV NSCLC according to American Joint Committee on Cancers, Version 7) or recurrent disease may include continuation or switch maintenance therapy administered in the absence of disease progression. One prior adjuvant and/or neoadjuvant chemotherapy is permissible.
3. Time between start of first-line chemotherapy and relapse (defined by RECIST criteria, date of CT) ≥ 9 months (275 days) or ≤ 6 months (183 days). (Commentary: Patients relapsing between 184 – 274 days after start of first-line chemotherapy are not evaluable).
4. At least one target tumor lesion that has not been irradiated within the past three months and that can be accurately measured by computerized tomography (CT) with a longest diameter of ≥ 10 mm or ≥15 mm in the short-axis diameter for a lymph node. If there is only one target lesion, and it is a non-lymph node, it should have a longest diameter of ≥15 mm
5. ECOG performance status score (0 or 1)
6. Signed and dated written informed consent in accordance with ICH-GCP guidelines and the local legislation
7. Before study entry a re-biopsy of the tumor is mandatory for inclusion. A CT-guided biopsy or bronchoscopy with 5-6 core biopsies is required to enable the acquisition of adequate tissue. Routine IHC analysis for tumor diagnostics should be performed. EGFR mutational status and EML4/ALK status have to be assessed on the biopsies.
8. Patients will be asked if they voluntarily agree to obtain tumor tissue post mortem.
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| E.4 | Principal exclusion criteria |
1) More than one prior line of chemotherapy (i.e. 2nd or 3rd line chemotherapy) for advanced and/or metastatic (stage III B or IV NSCLC) or recurrent disease. Patients known to be positive for activating Epidermal Growth Factor Receptor (EGFR) mutation. Patients known to be positive for ALK translocation. Non-permissible treatments: Previous therapy with other VEGF or VEGFR inhibitors or docetaxel for the treatment of NSCLC at any time.
2) Prior monotherapy with an EGFR inhibitor except as maintenance therapy
3) Non-permissible treatments within 4 weeks prior to start of study therapy:
a) Other investigational drugs
b) Chemo-, hormone-, radiotherapy (except for radiotherapy to extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors
c) Radiotherapy (except extremities and brain) within the past three months prior to baseline imaging
d) Persistence of clinically relevant therapy related toxicities from previous chemotherapy and/or radiotherapy (AE from previous treatment ≥ Grade 2)
e) In case of prior maintenance treatment the last administration should have been performed at least 3 weeks or longer prior to start of study therapy
f) Patients receiving erythropoiesis stimulating agents (ESA)
4) Laboratory values outside the following ranges:
a) Serum creatinine > 1.5 times the upper limit of normal (ULN)
b) Proteinuria CTCAE grade 2 or greater
c) Total bilirubin above the upper limit of normal
d) ALT or AST > 1.5 x upper limit of normal
e) Prothrombin time and/or partial thromboplastin time greater than 50 % deviation from normal limits
f) International normalised ratio ( INR) > 3
g) Absolute neutrophil count (ANC) < 1500/mm3
h) Platelets < 100000/ mm3
i) Haemoglobin < 9.0 g/dL
5) Any of the following conditions:
a) Pre-existing ascites and/or clinically significant pleural effusion
b) Significant weight loss (> 10 %) within the past 6 weeks prior to treatment in the present trial
c) Current peripheral neuropathy, CTCAE grade 2, except due to trauma
d) Major injuries and/or surgery within the past ten days prior to randomisation with incomplete wound healing
e) Decompensated diabetes mellitus or other contraindication to high dose corticosteroid therapy
f) Active or chronic hepatitis C and/or B infection
g) Serious illness or concomitant non-oncological disease such as neurologic-, psychiatric active alcohol or drug abuse, infectious disease or active ulcers (gastro-intestinal malabsorption or other conditions, skin), history of hollow-organ perforations or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study
h) Other malignancy within the past three years other than basal cell skin cancer, or carcinoma in situ of the cervix
i) Leptomeningeal disease or active brain metastases. If brain metastases have been treated, they must be stable for >4 weeks. Dexamethasone therapy will be allowed if administered as stable dose for at least two weeks before randomisation
j) Radiographic evidence of cavitary tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels
k) History of clinically significant haemoptysis within the past 3 months (more than one teaspoon of fresh blood per day)
l) Bleeding or thrombotic disorders requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low molecular weight heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device is allowed) or anti-platelet therapy (except for chronic low-dose therapy with acetylsalicylic acid ≤ 325mg per day)
m) History of major thrombotic event or known inherited predisposition to thrombosis, or clinically relevant major bleeding event in the past 6 months
n) Significant cardiovascular diseases (i.e. hypertension not controlled by medical therapy, unstable angina, history of myocardial infarction within the past 6 months, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion
6) Patients of childbearing potential who are sexually active and unwilling to use a highly effective method of contraception during the trial and for at least 3 months after the end of the treatment with nintedanib and for at least 6 months after the end of the therapy with docetaxel.
7) Pregnancy or breast feeding
8) Any contraindications for therapy with docetaxel or history of severe hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80 (Tween 80). Hypersensitivity to nintedanib and/or the excipients of the trial drugs. Hypersensitivity to contrast media
9) Patients unable to comply with the study protocol and follow-up schedule, for any reason
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study will be an exploratory primary endpoint which combines progression free survival (PFS) in conjunction with the planned biomarker analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Tumor progression has to be performed at six weeks intervals starting six weeks (+/- 2 days) after very first administration of doxetacel. |
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| E.5.2 | Secondary end point(s) |
o Eploratory primary endpoint Progression free survival (PFS) in conjunction with biomarker analysis.
o Progression free survival (PFS): This is defined as the interval of time between start of the actual therapy and the first documentation of progression or death.
o Time to progression during AAT (aTTP): This modified endpoint is defined as the interval of time between the time of marker analysis and the first documentation of progression or death.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression free survival (PFS) is evaluated in intervals of six weeks together with biomarker analysis.
Final analyses will be performed at the end of the study. |
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| 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 | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Prognosis
The project aims for screening for potential biomarkers and biomarker combinations relevant for second line setting in NSCLC during combinational therapy with docetaxel and nintedanib. The predicitve value of such profiles should then be evaluated in larger cohorts. In the future such profiles could possibly help clinicians to identify those patients who might probably benefit and to use these agents more effectively. |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
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