| Eligibility |
1. Provision of informed consent prior to any study specific procedures
2. Male or female, aged at least 18 years.
3. Group A: treatment-naïve advanced NSCLC with an sensitizing EGFR mutation.
- Patients who received adjuvant/neo-adjuvant chemotherapy/chest
irradiation/palliative irradiation (other than brain) allowed.
- Exon 19 deletion, L858R, T790M and uncommon sensitizing EGFR mutations in
treatment-naïve patients are allowed.
Or
Group B: patients advanced NSCLC previously treated with 1st/2nd-generation EGFR TKIs
(either gefitinib. erlotinib or afatinib) in whom T790M was diagnosed in the tumor
specimen or ctDNA after testing it following the most recent disease progression.
- No restriction regarding the number of prior EGFR TKIs or cytotoxic chemotherapy
lines of treatment is applied.
- Group C: patients advanced NSCLC previously treated with 1st/2nd generation EGFR
TKIs (either gefitinib. erlotinib or afatinib) who progressed unrelated to T790M
(T790M-). No restriction regarding the number of prior EGFR TKIs or cytotoxic
chemotherapy lines of treatment is applied.
4. Asymptomatic untreated brain metastases (previously SRS more than 6 month).
5. Measurable intracranial disease by mRECIST criteria (less or equal to 5 mm).
6. Normal hematologic, renal and liver function:
Absolute neutrophil count above 1500/mm3, platelets above 100,000/mm3, hemoglobin
above 9 g/dL; createnine concentration is less or equal to 1.5 mg/dL, or createnine
clearance less then 60 ml/min. Total bilirubin less or equal to 1.5 mg/dL, ALT+ AST
levels 5 times above the upper normal limit.
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. 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.
11. All patients with reproductive potential must agree to use barrier contraception
methods while receiving the study treatment.
12. Patients has the ability to read and write and use the electronic devices.
13. At least one lesion (measurable and/or non-measurable) that can be accurately assessed
by CT/MRI at baseline and follow up visits.
3.2 Exclusion criteria
1. Involvement in the planning and/or conduct of the study (applies to both sponsor staff
and/or staff at the study site).
2. Previous treatment with AZD9291.
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. EGFR TKI - resistant EGFR mutations (e.g., insertion in exon 20).
6. T790M is allowed.
7. Patients previously treated with WBRT.
8. Pregnant or lactating women.
9. Inability to sign the informed consent form.
10. Any concurrent and/or other active malignancy that has required systemic treatment
within 2 years of first dose of study drug.
11. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled
hypertension and active bleeding diatheses; or active infection including hepatitis B,
hepatitis C and human immunodeficiency virus (HIV), uncontrolled diabetes.
12. Inability to swallow the formulated product, malabsorption syndrome, refractory nausea
and vomiting that would preclude adequate absorption of AZD9291.
13. Any of the following cardiac criteria:
1. Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 consequent
ECGs, using the screening clinic ECG machine-derived QTc value;
2. Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG;
3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events, including unexplained sudden death under 40 years of age in a
first-degree relative, or any concomitant medication known to prolong the QTc
interval.
14. Any evidence/past medical history of cardiomyopathy.
15. Any evidence/past medical history of interstitial lung disease (ILD) or radiation
pneumonitis which required steroid treatment.
16. History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or
class to AZD9291) or any excipients of these agents
17. 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
18. 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.
|
