Study to Determine the Effect of Food on the Blood Levels of AZD9291 Following Oral Dosing of a Tablet Formulation in Patients With Non-Small Cell Lung Cancer

An Open-label, Randomised, Phase I, Study to Determine the Effect of Food on the Pharmacokinetics of Single Oral Doses of AZD9291 in Patients With EGFRm Positive NSCLC Whose Disease Has Progressed on an EGFR TKI

This is a 2-part study in patients with epidermal growth factor receptor mutation positive (EGFRm+) non-small cell lung cancer (NSCLC) whose disease has progressed on treatment with an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI): Part A will determine the effect of food on the pharmacokinetics (PK) of AZD9291; Part B will allow patients further access to AZD9291 and will provide for additional safety data collection.

Part A is a randomised, open-label, 2 treatment period crossover study in which patients will each receive a single oral dose of AZD9291 (1 x 80 mg tablet) at breakfast time (approximately 0800) in each of 2 treatment periods (once immediately following a high fat meal [fed], and once in the fasted state [fasted]), with a washout period of 9 days between doses.

Approximately 38 patients are planned to be enrolled and dosed; at least 30 evaluable patients will be required to complete Part A (ie, the last PK sample in Treatment Period 2 [TP 2] has been collected). Additional patients may be enrolled to allow for at least 30 evaluable patients

For inclusion in the study patients should fulfil the following criteria:

1. Male or female, aged at least 18 years.
2. Able to eat a high-fat meal within a 30-minute period, as provided by the study site.
3. Histologically or, where appropriate, cytologically confirmed NSCLC.
4. Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI. In addition, other lines of therapy may have been given. All patients must have documented radiological progression on the last treatment administered prior to enrolling in the study.
5. Confirmation that the tumour harbours an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
6. ECOG performance status 0-1 with no deterioration over the previous 2 weeks.
7. Patients must have a life expectancy of ≥12 weeks, as estimated at the time of screening.
8. Females should be using adequate contraceptive measures 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 by fulfilling one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments; Women under 50 years old would be considered post-menopausal if they have been amenorrhoeic 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; Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, but not tubal ligation.
9. Male patients should be willing to use barrier contraception, ie, condoms, until 6 months after last study drug is taken.

Patients should not enter the study if any of the following exclusion criteria are fulfilled:

1. Participation in another clinical study with an IP during the last 14 days (or a longer period depending on the defined characteristics of the agents used).
2. Treatment with any of the following: Treatment with an EGFR TKI w/in 8 days or approximately 5x half-life, whichever is the longer, of the first dose of study treatment; Any cytotoxic chemotherapy, investigational agents or other anticancer drugs w/in 14 days of the first dose of study treatment; Major surgery (excluding placement of vascular access) within 4 weeks of the first dose; 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 or with a wide field of radiation which must be completed within 4 weeks of the first dose of study treatment; Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inhibitors of CYP2C8 and of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on CYP3A4, CYP2C8, and/ or CYP1A2.
3. Any intake of grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, or other products containing grapefruit or Seville oranges within 7 days of the first administration of the IP until the end of Part A.
4. Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study treatment with the exception of alopecia and Grade 2, prior platinum therapy related neuropathy.
5. Patients unable to fast for up to 14 hours.
6. Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 4 weeks prior to start of study treatment.
7. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required.
8. Patients with type I diabetes.
9. Patients unable to swallow orally administered medication or patients with gastrointestinal disorders or significant gastrointestinal resection likely to interfere with the absorption of AZD9291.
10. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
11. Women who are breastfeeding.
12. Patients with a known hypersensitivity to AZD9291
13. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values: Absolute neutrophil count (ANC) <1.5 x 109/L; Platelet count <100 x 109/L; Haemoglobin <90 g/L; ALT >2.5 x the institutional ULN if no demonstrable liver metastases or >5 x institutional ULN in the presence of liver metastases; AST >2.5 x institutional ULN if no demonstrable liver metastases or >5 x institutional ULN in the presence of liver metastases; Total bilirubin >1.5 x institutional ULN if no liver metastases or >3 x institutional ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases; Creatinine >1.5 x institutional ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft-Gault formula); confirmation of creatinine clearance is only required when creatinine is >1.5 x institutional ULN.
14. Any of the following cardiac criteria: Mean resting corrected QT interval corrected for heart rate using Fridericia's correction factor (QTcF) >470 msec obtained from 3 ECGs; Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec; Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval.
15. For optional genetic research: Previous allogenic bone marrow transplant or non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.