Open Label, Prospective Study to Investigate Efficacy and Safety of AZD9291 in BM From NSCLC Patients With EGFR T790M

Exclusion Criteria

• •4. For patients with measurable BM but without LM: At least one measurable intracranial lesion that, if previously irradiated, has progressed or not responded to radiation therapy, that can be accurately measured at baseline as ≥ 10 mm in the longest diameter by magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements. Measurable extracranial disease is not required.
• •5. Prior therapy with an EGFR-TKI. Patients may have also received additional lines of treatment.
• •6. World Health Organization (WHO) performance status 0-2 with no deterioration over the previous 2 weeks and a minimum life expectancy of 3 months.
• •7. Adequate bone marrow reserve and organ function as demonstrated by complete blood count, biochemistry in blood and urine at baseline.
• •8. ECG recording at baseline showing absence of any cardiac abnormality as per exclusion criterion #10.
• •9. Female patients of childbearing potential must be using adequate contraceptive measures (see Restrictions, Section 3.5), must not be breast feeding, and must have a negative pregnancy test prior to start of dosing. Otherwise, they must have evidence of nonchild bearing potential as defined below:
• •1. Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all exogenous hormonal treatments
• •2. Women less than 50 years would be consider post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution
• •3. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
• •10. Male patients must be willing to use barrier contraception, i.e., condoms.
• •1. Previous (within 6 months) or current treatment with AZD9291
• •2. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of AZD9291) any treatment known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 (Appendix B)
• •3. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, active infection\* including hepatitis B, hepatitis C and human immunodeficiency virus, or significantly impaired bone marrow reserve or organ function, including hepatic and renal impairment, which in the investigator's opinion would significantly alter the risk/benefit balance.
• •\* active infection will include any patients receiving intravenous treatment for any infection and patients with hepatitis B or C surface antigen (+) - Patients receiving oral antiviral suppressive therapy for hepatitis B or C will be permitted to enrol in the study.
• •4. Patient with symptomatic central nervous system (CNS) metastases who is neurologically unstable or has required increasing doses of steroids to manage CNS symptoms within the 2 weeks prior to start AZD9291 administration.
• •5. Prior whole brain radiation therapy.
• •6. Known intracranial hemorrhage which is unrelated to tumor.
• •7. For patients with LM and/or BM, CNS complications that require urgent neurosurgical intervention (e.g. resection or shunt placement).
• •8. For patients with LM, inability to undergo collection of CSF.
• •9. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD
• •10. Any of the following cardiac criteria:
• •1. Mean resting corrected QT interval (QTcF) \> 470 ms using Fredericia's formula :
• •2. Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
• •3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
• •11. Any unresolved toxicity from prior therapy CTCAE \> grade 3 at the time of starting treatment
• •12. History of hypersensitivity to excipients of AZD9291 or to drugs with a similar chemical structure or class to AZD9291
• •13. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
• •* Absolute neutrophil count \< 1.5 x 10\^9/L
• •* Platelet count \< 100 x 10\^9/L
• •* Haemoglobin \< 90 g/L
• •* Alanine aminotransferase \> 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or \> 5 times ULN in the presence of liver metastases
• •* Aspartate aminotransferase \> 2.5 times ULN if no demonstrable liver metastases or \> 5 times ULN in the presence of liver metastases
• •* Total bilirubin \> 1.5 times ULN. Total bilirubin \>3 times the ULN in patients with documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or in the presence of liver metastases
• •* Creatinine \>1.5 times ULN concurrent with creatinine clearance \< 50 mL/min (measured or calculated by Cockcroft and Gault equation). Confirmation of creatinine clearance is only required when creatinine is \>1.5 times ULN.
• •* If bone metastases are present and liver function is otherwise considered adequate by the investigator then elevated ALP will not exclude the patient.