Osimertinib in Treating Patients With Stage IIIB-IV or Recurrent Non-small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations

PRIMARY OBJECTIVES:

I. To evaluate the best objective response rate of AZD9291 (osimertinib) among patients with
EGFR exon 20 insertions.

SECONDARY OBJECTIVES:

I. To determine the safety profile of 160 mg once daily (QD) dose of AZD9291 (osimertinib) in
patients with EGFR Exon 20 insertion mutations.

II. To determine the progression-free survival. III. To determine the overall survival.

TERTIARY OBJECTIVES:

I. To characterize molecular markers of response to treatment in circulating tumor
deoxyribonucleic acid (DNA).

II. To evaluate biomarkers of response to treatment through retrospective analyses of
pre-treatment tumor tissue.

III. To identify resistance mechanisms to AZD9291 (osimertinib) through post-progression
tumor biopsies and circulating tumor (ct)DNA.

OUTLINE:

Patients receive osimertinib orally (PO) once daily (QD) on days 1-21. Courses repeat every
21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28 days and every 3 months
for up to 5 years.

Inclusion Criteria:

- Participants must have a pathologically-confirmed diagnosis of non-small cell lung
cancer (NSCLC)

- Participants must have advanced disease - either stage IV disease, stage IIIB disease
not amenable to definitive multi-modality therapy, or recurrent disease after a prior
diagnosis of stage I-III disease; all staging is via the American Joint Committee on
Cancer (AJCC)/International Association for the Study of Lung Cancer (IASLC) 7th
edition staging criteria

- An EGFR exon 20 insertion mutation must be detected in the tumor tissue; patients may
be enrolled in the study based on an exon 20 insertion EGFR mutation detected by any
Clinical Laboratory Improvement Act (CLIA)-certified tissue assay

- NOTE: Testing results are to be submitted via Medidata Rave and the study chair
or delegate will review the reports

- Patients must have measurable disease; baseline measurements and ALL sites of disease
must be obtained within 4 weeks to registration

- Patients must have previously received at least one line of therapy for their advanced
lung cancer; there are no restrictions on the maximum number of prior therapies
allowed

- Participants may not have received any prior treatment with therapies targeting PDL1,
PD1 or CTLA4

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1

- Hemoglobin >= 9.0 g/L (within 4 weeks before registration)

- Leukocytes >= 3,000/mcL (within 4 weeks before registration)

- Absolute neutrophil count >= 1,500/mcL (within 4 weeks before registration)

- Platelets >= 100,000/mcL (within 4 weeks before registration)

- Total bilirubin < 1.5 x upper limit of normal (ULN) if no liver metastases or =< 3
times ULN in the presence of documented Gilbert's syndrome (unconjugated
hyperbilirubinemia) or liver metastases (within 4 weeks before registration)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal; for patients with known hepatic metastases
AST and/or ALT =< 5 x ULN (within 4 weeks before registration)

- Creatinine =< 1.5 x institutional upper limit of normal (within 4 weeks before
registration)

- Participants may not have clinically active or symptomatic interstitial lung disease
or interstitial pneumonitis (i.e., affecting activities of daily living or requiring
therapeutic intervention), or a history of clinically significant interstitial lung
disease or radiation pneumonitis

- Participants may not have had radiation to the lung fields within four weeks (28 days)
of starting treatment; for patients receiving palliative radiation to thoracic
vertebrae, ribs or other sites where the radiation field includes the lungs, radiation
must be completed at least two weeks before starting treatment; for all palliative
radiation to all other sites, at least 7 days must have elapsed prior to starting to
treatment; at least six months (180 days) must have elapsed from radiation given with
curative intent

- Participants may not have clinically symptomatic brain metastases or leptomeningeal
disease; patients may be on a stable dose of corticosteroids to control brain
metastases if they have been on a stable dose for two weeks (14 days) prior to study
treatment and are clinically asymptomatic

- Patients must have an echocardiogram (ECHO) or a nuclear study (multi-gated
acquisition scan [MUGA] or first pass) within 4 weeks (28 days) prior to registration
to treatment and must not have a left ventricular ejection fraction (LVEF) <
institutional lower limit of normal (LLN); if the LLN is not defined at a site, the
LVEF must be >= 50% for the patient to be eligible

- Participants may not have any of the following cardiac criteria:

- Mean resting corrected QT interval (QTc) >= 470 msec obtained from 3
electrocardiograms (ECGs) using the screening clinic ECG machine-derived QTc
value

- No history of QT prolongation associated with other medications that required
discontinuation of that medication

- Patient must not be receiving any concomitant medications that are known to be
associated with Torsades de Pointes

- 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, 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

- Symptomatic heart failure - New York Heart Association (NYHA) grade II-IV

- Participants may not have a second, clinically active, cancer; patients with second
cancers which have been treated with curative intent and/or are currently inactive are
allowed

- Participants may not be receiving any other investigational agents; patients
previously treated with investigational agents must complete a washout period of at
least two weeks or five half-lives, whichever is longer, before starting treatment

- Participants may not have uncontrolled intercurrent illness including, but not limited
to, ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- No history of hypersensitivity active or inactive excipients of AZD9291 (osimertinib)
or drugs with a similar chemical structure or class to AZD9291 (osimertinib)

- Patients must not currently be receiving (or unable to stop use prior to receiving the
first dose of study treatment) medications or herbal supplements known to be 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 effects on CYP3A4

- If medically feasible, patients taking regular medication, with the exception of
potent inducers of CYP3A4, should be maintained on it throughout the study period;
patients taking concomitant medications whose disposition is dependent upon breast
cancer resistance protein (BCRP) and which have a narrow therapeutic index should be
closely monitored for signs of changed tolerability as a result of increased exposure
of the concomitant medication whilst receiving AZD9291 (osimertinib) NOTE: Use of St
John's wort is a contra-indication for AZD9291 (osimertinib) use

- It is recommended that the starting and maintenance dose of rosuvastatin (due to BCRP
inhibition by AZD9291 [osimertinib]) should be as low as possible and should be guided
by the statin label; monitoring of low-density lipoprotein (LDL) cholesterol levels is
advised; if the subject experiences any potentially relevant adverse events suggestive
of muscle toxicity including unexplained muscle pain, tenderness, or weakness,
particularly if accompanied by malaise or fever, the statin should be stopped,
creatine kinase (CK) levels should be checked, and any appropriate further management
should be taken

- Subjects taking warfarin should be monitored regularly for changes in prothrombin time
or international normalized ratio (INR)

- No 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

- 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 (osimertinib)

- Women must not be pregnant or breast-feeding; all females of childbearing potential
must have a blood test or urine study within 2 weeks prior to registration to rule out
pregnancy; a female of childbearing potential is any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not
been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
at any time in the preceding 24 consecutive months)

- Women of childbearing potential (WOCBP) and sexually active males must use an accepted
and effective method of contraception while receiving protocol treatment or abstain
from sexual intercourse for the duration of their participation in the study; WOCBP
must use birth control for two weeks prior to the start of the treatment and continue
for 6 weeks after the last dose of the study drug; sexually active male patients must
use effective contraception from day 1 of treatment and continue for 4 months after
the last dose of the study drug

- Other anticancer agents and investigational agents should not be given while the
subject is on study treatment

- Supportive care and other medications that are considered necessary for the subject's
wellbeing may be given at the discretion of the investigator

- A guidance regarding potential interactions with concomitant medications is provided