Nintedanib (Vargatef®) Plus Docetaxel in Second Line of Treatment in Patients With Lung Cancer (REFRACT)

Inclusion Criteria:

• Histologically confirmed non-squamous NSCLC,
• Metastatic NSCLC of stage IV (according to American Joint Committee on Cancers) or recurrent NSCLC)
• Patients without activating epidermal growth factor receptor (EGFR) mutation
• Patients without anaplastic lymphoma kinase (ALK) rearrangement
• Patients must have measurable lesion by RECIST 1.1
• Refractory disease defined by documented progression during the first-line chemotherapy based on a platinum doublet and third-generation drug (four or less cycles) according to RECIST V.1.1
• Age ≥18 years and < 75 years
• Performance status (PS) 0-1
• Life expectancy of more than 12 weeks.
• No history of other malignancy within the last 5 years, except for adequately treated carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin.
• Adequate organ function, evidenced by the following laboratory results within 3 weeks prior to randomization: Normal hepatic function: bilirubin < 1.5 x N, ALT (alanine transaminase) and AST (aspartate aminotransferase ) < 2.5 x N or <5 x N in case of liver metastasis
• Normal renal function (calculated creatinine clearance ≥ 45 mL/min).
• Normal Calcemia
• Normal haematological function (polynuclear neutrophils > 1.5 G/l, platelets > 100 G/l).
• Anticoagulation with a vitamin K antagonist and low-molecular-weight heparin (LMWH) is authorized.
• Antiplatelet treatment (aspirin authorized if < 325 mg/d)
• Treatment with dipyridamole, ticlopidine, clopidogrel is not authorized
• Women of child bearing potential must use double effective contraception.
• Men might be surgically sterile or accept to use an effective contraceptive procedure during and until 6 months after the treatment.
• Written informed consent to participate in the study.

Exclusion Criteria:

• Known hypersensitivity to the trial drugs (nintedanib (vargatef®), docetaxel), peanut, soya, to their excipients
• Controlled disease after first line treatment
• Contra indication to the use of the backbone treatment
• Patients who were withdrawn from first line treatment due to toxicity without documented disease progression or who received placebo (in the context of a clinical trial) as prior treatment are not eligible.
• Previous treatment with docetaxel
• Small-cell lung cancer, bronchioloalveolar cancer, neuroendocrine cancer.
• Previous therapy with vascular endothelial growth factor (VEGF) inhibitors except bevacizumab
• Centrally located tumour with radiographic evidence of local invasion of local blood vessels
• Radiographic evidence of cavitary or necrotic tumours at screening
• Chemo-, hormone-, radio-(except for brain and extremities) or immunotherapy or therapy with monoclonal antibodies or small tyrosine kinase inhibitors within the past 4 weeks prior to treatment with the trial drug.
• Toxicity non resolute due to prior treatment > grade I (except alopecia).
• Radiotherapy (except extremities) within the past 3 months prior to baseline imaging
• Persistence of clinically relevant therapy related toxicity from previous radiotherapy
• Active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before inclusion).
• Uncontrolled arterial hypertension.
• Concurrent radiotherapy, except for palliative bone irradiation.
• Other concurrent severe illnesses (congestive heart failure, unstable angina, significant arrhythmia or myocardial infarction less than 12 months before study entry).
• Stroke less than 6 months before study entry.
• Psychiatric or neurological disorders preventing the patient from understanding the nature of the trial
• Grade >=1 peripheral neuropathy
• Uncontrolled infection.
• Caval syndrome
• Other organic disorders preventing inclusion in the trial
• Malabsorption syndrome
• Pregnancy and breast-feeding
• Surgery less than two months before study entry.
• Follow-up not feasible.
• Incarcerated and institutionalized