Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors, AZD3759 or AZD9291, in Patients Who Have Advanced Non-Small Cell Lung Cancer

This is the first time in patient study to assess the safety, tolerability and preliminary efficacy of AZD3759 in patients with advanced Non Small Cell Lung Cancer (NSCLC) In this study, patients with Leptomeningeal Metastasis and Brain Metastasis may also be enrolled to assess the anti-tumour efficacy, safety, pharmacokinetics and potential biological activity of AZD9291

A Phase I, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-Tumour Activity of AZD3759 or AZD9291 in Patients with EGFR Mutation Positive Advanced Stage Non Small Cell Lung Cancer (NSCLC) who failed standard treatment and developed brain or leptomeningeal diseases

Eligibility Criteria:
Inclusion Criteria:

1. Obtained written informed consent
2. Male or female aged at least 18 years. Aged at least 20 if Japanese.
3. Histologically or cytologically confirmed diagnosis of NSCLC with single activating EGFR mutations (L858R or Exon19Del).
4. Eastern Cooperative Oncology Group performance status of 0 to1. For LM patients, 0 to 2 is acceptable.
5. In Part A, prior treatment with at least one line of a single agent EGFR TKI and at least 1 line of chemotherapy.
6. In Part B-BM expansion, patients must have not received any EGFR TKI and have asymptomatic brain metastasis, either found during screening process which does not require local treatment in the opinion of the investigator or local treatment has been given (surgery or radiation), patient must be stable without corticosteroid and/or anti-convulsants treatment for at least 2 weeks before study enrollment. For Part B-LM expansion, patients who received previous EGFR TKI treatment must have stable extracranial disease;EGFR TKI treatment naïve patients can also be enrolled into AZD9291 cohorts, or AZD3759 cohorts if efficacy signal seen in Part A and agreed by Safety Review Committee.
7. For patients with neither LM nor measurable BM: At least one measurable extracranial lesion. For patients with measurable BM but without LM: at least one measurable intracranial lesion
8. For patients with LM: Confirmed diagnosis of LM by positive CSF cytology.
9. Male patients should be willing to use barrier contraception, i.e., condoms, until 3 months after last study drug is taken.
10. Females should agree to use adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential
11. In Part B-AZD9291 LM expansion (sub-cohort of T790M+ LM patients), patients must have central confirmation of T790M+ mutation status from a sample taken after documented progression on the last treatment administered prior to enrolling in the study. Patients must have received prior therapy with an EGFR TKI and may also have received additional lines of treatment. Stable extracranial disease is not required.

Exclusion Criteria:

1. For patients with LM and/or BM, CNS complications that require urgent neurosurgical intervention
2. For patient with LM, inability to undergo collection of CSF
3. Treatment with an EGFR TKI (e.g., erlotinib or gefitinib) within 8 days or approximately 5 x half-life, whichever is the longer, of the first dose of study treatment.
4. Any cytotoxic chemotherapy,or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen within 14 days of the first dose of study treatment
5. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment with the exception of patients receiving radiation to more than 30% of the bone marrow which must be completed within 4 weeks of the first dose of study treatment.
6. Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of AZD3759/AZD9291) medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 3A4/5 and potential inhibitors of cytochrome P450 2C8 (for patients to be enrolled into AZD9291 cohorts only).
7. Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
8. Known intracranial haemorrhage which is unrelated to tumour
9. Refractory nausea and vomiting if not controlled by supportive therapy, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD3759/AZD9291
10. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses
11. Inadequate bone marrow reserve or organ function
12. Clinically significant ECG abnormalities or any factors that increase the risk of corrected QT interval prolongation or risk of arrhythmic events
13. Prior history of whole brain radiotherapy (only applicable for AZD3759 BM expansion)