MEK Inhibitor and Thoracic Radiotherapy Trial

As above

Inclusion criteria

• Histologically or cytologically confirmed NSCLC either inoperable, stage III NSCLC or stage IV NSCLC with dominant chest symptoms.
• Patient age ≥18
• Willingness and able to comply with treatment, tests and attend the required follow-up
• Prior chemotherapy is permitted provided the interval between day 8 of the last cycle of chemotherapy and day 1 of AZD6244 dosing is ≥2 weeks
• No prior radiotherapy or investigational agents
• Life expectancy estimated to be greater than 3 months
• Performance status(ECOG) 0 or 1
• MRC dyspnoea score <3
• Patient considered able to tolerate radical radiotherapy
• FEV1 >40% of predicted and DLCO (transfer factor for carbon monoxide) >40% of predicted
• Disease which can be encompassed within a radical radiotherapy treatment volume(V20 ≤35% and maximum cord dose 48Gy) on the radiotherapy planning scan
• Left ventricular ejection fraction >50% on baseline echocardiogram
• Adequate renal function - defined by GFR >50 ml/min (calculated Cockcroft and Gault) or by isotope GFR.
• Adequate bone marrow reserve: white cell count >3 x 109/l, absolute neutrophil count >1.5 x 109/l, haemoglobin >10.0 g/dl and platelet count >100 x 109/l (Blood transfusion permitted to achieve Hb >10g/dl)
• AST/ALT < 2.5 ULN and bilirubin <1.5 ULN
• Group D (expanded cohort) only: diameter of the primary tumour should be > 2 cm

Exclusion criteria

• Mixed non-small cell and small cell tumours
• Other previous or current malignant disease likely to interfere with protocol treatment or comparisons
• Lack of recovery from prior chemotherapy toxicity to grade ≤2 except alopecia d)Refractory nausea and vomiting, chronic gastrointestinal diseases (eg, inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption of AZD6244
• Presence of clinically significant fluid accumulations in third spaces which cannot be adequately controlled by drainage or other procedures prior to inclusion in the study.
• History / evidence of active bleeding diatheses
• History of unstable diabetes
• History of interstitial pneumonitis
• Arterial hypertension defined as SBP≥ 160 or DBP ≥100 (antihypertensive medication to achieve these parameters are permissible)
• Myocardial infarction, or unstable or uncontrolled angina, congestive heart failure (NYHA > class II) within 1 year of enrollment
• Active infection on day of enrollment
• Uncontrolled hypercalcemia >3.0 or symptomatic
• History of hypersensitivity to active or inactive excipients of AZD6244
• Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) which would prevent administration of study treatment
• Known and symptomatic brain metastases. Brain imaging is not mandatory if patient is asymptomatic.
• Clinical judgement by the investigator that the patient should not participate in the study
• Patients of reproductive potential who are unable to comply with effective contraception if sexually active during the study and for a period of at least 90 days (men) or 6 months after treatment (women)
• Women who are breastfeeding