This is a phase II, open-label, single centre study of AZD9291 administered orally in
patients with advanced lung cancer with activating mutations of EGFR gene with or without
T790M which were detected from circulating tumor DNA. EGFR-TKI naïve patients with activating
EGFR mutation will be enrolled in cohort 1. Patients with acquired resistance to prior EGFR
tyrosine kinase inhibitor (TKI) due to T790M mutation is going to be enrolled in cohort 2.
Inclusion Criteria:
< Cohort 1 >
1. Provision of informed consent prior to any study specific procedures
2. Patients (male/female) must be > 18 years of age.
3. Locally advanced or metastatic non-small cell lung cancer, not amenable to curative
surgery or radiotherapy with or without pathologic diagnosis
4. No prior exposure to EGFR TKI (multiple lines of prior cytotoxic chemotherapy are
permitted.)
5. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from
circulating tumor DNA either by PANA mutyper® or Cobas® EGFR mutation test.
6. Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) detected from tumor
tissue or cytology specimen.
7. World Health Organization (WHO) performance status 0-2.
8. Patients must have a life expectancy ≥ 12 weeks.
9. Females should be using 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 by fulfilling one of
the following criteria at screening:
- Post-menopausal defined as aged more than 50 years and amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments
- Women under 50 years old would be consider postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with luteinizing 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
10. Male patients should be willing to use barrier contraception.
11. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
12. At least one lesion, not previously irradiated, that can be accurately measured at
baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short
axis ≥ 15 mm) with computed tomography (CT)
< Cohort 2 >
1. Provision of informed consent prior to any study specific procedures
2. Patients (male/female) must be > 18 years of age.
3. Locally advanced or metastatic non-small cell lung cancer, not amenable to curative
surgery or radiotherapy with or without pathologic diagnosis
4. Progression after prior exposure to gefitinib, erlotinib, afatinib or dacomitinib.
Multiple lines of prior cytotoxic chemotherapy are permitted and there is no specified
order of treatment.
5. Patients must fulfil one of the following:
5.1) Activating EGFR mutation (G719X, exon 19 deletion, L858R, L861Q) from tumor
tissue or cytology or circulating tumor DNA 5.2) Must have experienced clinical
benefit from prior EGFR-TKI, according to the Jackman criteria (Jackman 2010) followed
by systemic objective progression (RECIST) while on continuous treatment with EGFR-TKI
6. T790M mutation detected from circulating tumor DNA either by PANA mutyper® or Cobas®
EGFR mutation test.
7. World Health Organization (WHO) performance status 0-2.
8. Patients must have a life expectancy ≥ 12 weeks.
9. Females should be using 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 by fulfilling one of
the following criteria at screening:
- Post-menopausal defined as aged more than 50 years and amenorrheic for at least
12 months following cessation of all exogenous hormonal treatments
- Women under 50 years old would be consider postmenopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and with LH and 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
10. Male patients should be willing to use barrier contraception.
11. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up.
12. At least one lesion, not previously irradiated, that can be accurately measured at
baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have short
axis ≥ 15 mm) with computed tomography (CT)
Exclusion Criteria:
1. Previous treatment with AZD9291, or other 3rd generation EGFR TKI
2. Treatment with an investigational drug within five half-lives of the compound
3. 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)
(Appendix A). 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.
4. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the
exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
5. 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 trial or which would jeopardise
compliance with the protocol, or active infection including hepatitis B, hepatitis C
and human immunodeficiency virus (HIV). Screening for chronic conditions is not
required.
6. Patients with symptomatic central nervous system (CNS) metastases who are
neurologically unstable
7. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation
pneumonitis requiring steroid treatment, or any evidence of clinically active ILD
8. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
Absolute neutrophil count <1.5 x 109/L Platelet count <100 x 109/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 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:
1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec
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 such as heart failure, hypokalemia, congenital long QT syndrome, family
history of long QT syndrome or unexplained sudden death under 40 years of age in
first degree relatives or any concomitant medication known to prolong the QT
interval
10. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product or previous significant bowel resection that would
preclude adequate absorption of AZD9291
11. History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or
class to AZD9291) or any excipients of these agents
12. Males and females of reproductive potential who are not using an effective method of
birth control and females who are pregnant or breastfeeding or have a positive (urine
or serum) pregnancy test prior to study entry
13. Judgment by the Investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and requirements
14. Previous allogeneic bone marrow transplant.
15. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
genetic sample collection.
