This is a Phase I, open-label, 2-part study in patients with a confirmed diagnosis of
epidermal growth factor receptor (EGFR) mutation positive (EGFRm+) non-small cell lung cancer
(NSCLC), who have progressed following prior therapy with an approved EGFR tyrosine kinase
inhibitor (TKI) agent.
Part A will assess the effect of AZD9291 on the pharmacokinetic (PK) parameters of
rosuvastatin, following multiple oral dosing of AZD9291 in the fasted state.
Part B will allow patients further access to AZD9291 after the PK phase (Part A) and will
provide for additional safety data collection. All patients from Part A who completed
treatment may continue to receive AZD9291 80 mg once daily as a single agent until: disease
progression; they are no longer deriving clinical benefit; or any other reason.
For inclusion in the study patients must fulfil the following criteria:
1. Male or female, aged at least 18 years.
2. Histological or cytological confirmation diagnosis of NSCLC.
3. Radiological documentation of disease progression while on a previous continuous
treatment with an EGFR TKI, eg, gefitinib, erlotinib or afatinib. 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.
4. Confirmation that the tumour harbours an EGFR mutation known to be associated with
EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q).
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 with no
deterioration over the previous 2 weeks (Appendix G).
6. Patients must have a life expectancy of ≥12 weeks as estimated at the time of
7. 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
luteinising hormone (LH) and follicle stimulating hormone (FSH) 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.
8. Patients are willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations.
9. Male patients should be willing to use barrier contraception, ie, condoms.
1. Participation in another clinical study with an IP in last 14 days (or longer
depending on the defined characteristics of the agents used).
2. Any patient of Asian ethnicity or has a parent who is of Asian ethnicity (eg, Chinese,
Filipino, Japanese, Korean and Vietnamese). If only a grandparent is Asian, this is
acceptable. Asian Indians are acceptable.
3. Treatment w/ any of the following: an EGFR TKI (eg, erlotinib, gefitinib or afatinib)
within 8 days or approx. 5 x half-life, whichever is the longer, of the first dose of
study treatment; Any cytotoxic chemotherapy, investigational agents or other
anticancer drugs from a previous treatment regimen or clinical study within 14 days of
the first dose of study treatment; Major surgery (excluding placement of vascular
access) w/in 4 weeks of the 1st dose of study treatment; Radiotherapy with a limited
field of radiation for palliation w/in 1 week of the first dose of study treatment,
with the exception of patients receiving radiation to more than 30% of bone marrow or
with a wide field of radiation which must be completed w/in 4 weeks of the 1st 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 CYP3A4 (at least 1 week prior) and potent inducers of
CYP3A4 (at least 3 week prior). All patients must avoid concomitant use of any
medications, herbal supplements and/or ingestion of foods with known
inducer/inhibitory effects on CYP3A4.
4. Unresolved toxicities from prior therapy > CTCAE Grade 1 at the study start besides
alopecia and Grade 2, prior platinum-therapy related neuropathy.
5. 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 final PK sample collection on Day 35 of Part A.
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 PI'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 hep B, hep C and HIV.
Screening for chronic conditions is not required.
8. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values: ANC<1.5 x 10^9/L; Platelet count <100 x 10^9/L;
Haemoglobin <90 g/L; ALT >2.5 times ULN if no demonstrable liver metastases or >5
times ULN in the presence of liver metastases; AST >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 if no liver metastases or >3 times ULN in the presence of documented
Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or 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.
9. 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
10. Patients unable to swallow orally administered medication or patients with
gastrointestinal disorders or significant gastrointestinal resection likely to
interfere with the absorption of AZD9291.
11. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required
steroid treatment, or any evidence of clinically active ILD.
12. Women who are breastfeeding.
13. Patients with a known hypersensitivity to AZD9291 or rosuvastatin or any of the
excipients of the products.
14. Concomitant medication contraindicated for use with rosuvastatin due to drug
interaction and/or associated with increased risk of rhabdomyolysis (including, but
not limited to): fibrates (eg, gemfibrozil, fenofibrate), niacin, cyclosporine,
lopinavir/ritonavir or atazanavir/ritonavir and colchinine.
15. Past medical history of drug-related rhabdomyolysis and/or myalgia.
16. Use of 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase inhibitors, such as lovastatin
and simvastatin (Part A only).