Olaparib Dose Escalating Trial + Concurrent RT With or Without Cisplatin in Locally Advanced NSCLC

Inclusion Criteria: * ≥18 years of age * Histologically or cytologically confirmed diagnosis of NSCLC * Stage II/III non-operable disease, without malignant pleural effusion * Presence of at least one measurable target lesion * Acceptable pulmonary function as defined by a Fev1 of ≥30% and a DLCO of ≥ 40% of predicted, * NYHA I-II functional status * Expected risk of radiation-induced pulmonary toxicity is modest: MLD ≤ 20 and maximum cord dose 50 Gy * WHO performance 0-1 * Life expectancy of at least 6 months * Adequate hematological, renal and hepatic functions * Hemoglobin ≥ 5.5 mmol/l * Leucocytes \> 3.0 x 109/l * Absolute neutrophil count \> 1.5x109/l * Platelet count \> 100 x 109/l * Total bilirubin \< 1.5 x UNL * ASAT/ALAT \< 2.5 x UNL * Alkaline phosphatase \< 5 x UNL * Creatinine \< 130 mmol/l or creatinine clearance \> 50 ml/min; measured or calculated * Urine dipstick for proteinuria \< 2+. If urine dipstick is ≥ 2, 24 hour urine must demonstrate \< 500 mg of protein in 24 hours * No pre-existing sensory neurotoxicity grade ≥ 1 (CTCAE) * Patients of reproductive potential must agree to practice two effective medically approved contraceptive method during the trial and 3 months afterwards * Signed written informed consent. Exclusion Criteria: * Concurrent active malignancy other than localized, non-melanoma skin cancer or carcinoma-in-situ of the cervix (unless definitive treatment was completed 5 years or more before study entry and the patient has remained disease free) * Anti-cancer therapy including chemotherapy, radiotherapy, endocrine therapy, immunotherapy or use of other investigational agents within the 3 weeks prior to start of therapy (or a longer period depending on the defined characteristics of the agents used e.g. 6 weeks for mitomycin or nitrosourea). Patients may continue the use of LHRH agonists for cancer; bisphosphonates for bone disease and corticosteroids. * Patients, selected for sequential chemoradiotherapy, are excluded if no disease control (all responses except progression) is obtained after induction chemotherapy. * Prior: * Ipsilateral radiotherapy to the chest; * Chemotherapy for other indications than NSCLC within the last 5 years * History of interstitial pneumonitis (to include diffuse alveolar damage, non-malignant causes of pneumonitis, ARDS, alveolitis, cryptogenic organising pneumonia, obliterative bronchiolitis, non-malignant causes of pulmonary fibrosis, eligibility based on the judgement of the primary investigator), active infection on day of enrolment * Significant cardiovascular disease as defined by: * History of congestive heart failure requiring therapy; * History of unstable angina pectoris or myocardial infarction up to 6 months prior to trial entry; * Presence of severe valvular heart disease; * Presence of a ventricular arrhythmia requiring treatment; * Uncontrolled hypertension * Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial. * Participation in other trial with investigational drug or treatment modality * Co-existing serious active infection requiring parenteral antibiotics * Patients with hepatic disease e.g. patients with known serologically positive Hepatitis B or Hepatitis C as they may be more at risk of toxicity from Olaparib * Immunocompromised patients e.g. human immunodeficiency virus (HIV) * Myelodysplastic syndrome/acute myeloid leukaemia or features suggestive of MDS/AML on peripheral blood smear. * Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study * Gastrointestinal disorders that may interfere with absorption of the study drug or patients who are not able to take oral medication * Concomitant medications: * Any previous treatment with a PARP inhibitor, including Olaparib * Patients receiving the following classes of inhibitors of CYP3A4 (see Section 7.4 for guidelines and wash out periods) * Azole antifungals * Macrolide antibiotics * Protease inhibitors * Persistent grade 2 or greater toxicities, from any cause * Pregnant or breast-feeding women