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

• ≥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