Osimertinib With or Without Bevacizumab in Treating Patients With EGFR Positive Non-small Cell Lung Cancer and Brain Metastases

PRIMARY OBJECTIVES:

I. To determine the progression-free survival with AZD9291 (osimertinib) plus bevacizumab
compared to AZD9291 (osimertinib) alone.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of AZD9291 (osimertinib) and
bevacizumab.

II. To evaluate the time to progression in the central nervous system (CNS) with AZD9291
(osimertinib) plus bevacizumab versus single-agent osimertinib.

III. To determine the overall response rate and the intracranial response rate to the
combination versus single agent.

IV. To assess the overall survival in patients receiving AZD9291 (osimertinib) plus
bevacizumab compared to AZD9291 (osimertinib) alone.

TRANSLATIONAL OBJECTIVES:

I. To investigate mechanisms of sensitivity and resistance to combination AZD9291
(osimertinib) plus bevacizumab versus AZD9291 (osimertinib) by molecularly characterizing
tumor samples including T790M status.

II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as
an indicator of sensitivity and resistance to treatment.

III. To determine whether an angiogenic signature using a multiplex panel array is associated
with benefit from the combination of AZD9291 (osimertinib) plus bevacizumab.

IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to
determine biomarkers predictive of benefit from combination therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive osimertinib orally (PO) once daily (QD) on days 1-21 and bevacizumab
intravenously (IV) over 30-90 minutes on day 1. Courses repeat every 21 days in the absence
of disease progression or unacceptable toxicity.

ARM II: Patients receive osimertinib PO 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 for a minimum of 4 weeks.

Inclusion Criteria:

- Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion,
L858R point mutation, or any other mutation known to be associated with EGFR TKI
sensitivity); presence of an activating EGFR mutation may be documented in tumor
tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act
(CLIA)-certified laboratory; AND

- The presence of an EGFR T790M mutation after progression on a first- or
second-generation EGFR TKI; presence of an EGFR T790M mutation may be documented from
biopsy material from any site of disease (intra- or extra-cranial) or from plasma
testing if performed in a CLIA-certified laboratory; for patients who have disease
progression in the CNS only (with otherwise stable disease systemically), T790M
positivity is not required

- Disease progression on a first- or second-generation EGFR TKI (i.e. erlotinib,
gefitinib, or afatinib); patient may have also received prior chemotherapy or
immunotherapy but this is not required

- Patients must have at least one measurable CNS lesion that is asymptomatic, untreated,
and does not require local therapy at the time of enrollment; measurable CNS disease
is defined as a brain metastasis that can be accurately measured in at least one
dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain magnetic
resonance imaging (MRI); if the lesion is 5-10 mm in size and is the only measurable
disease, MRI imaging must be performed with 1.5 mm slice thickness or less; a history
of previously treated brain metastases is allowed, however any lesion present at the
time of whole brain radiotherapy or included in the stereotactic radiotherapy field
(or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is
new or documented to have progressed unequivocally since treatment

- Patients are not required to have measurable systemic (i.e. non-CNS) disease; if
present, measurable systemic disease must be able to be accurately measured in at
least one dimension (longest diameter to be recorded for non-nodal lesions and short
axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10
mm (>= 1 cm) with spiral computed tomography (CT) scan, MRI, or calipers by clinical
exam

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Life expectancy of greater than 3 months

- The use of anti-convulsants is allowed, as long as the patient is on a stable dose
with no seizure activity for at least 2 weeks prior to initiating trial therapy

- Female subjects should be using highly effective contraceptive measures, and must have
a negative pregnancy test and not be breast-feeding 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 sterilization by hysterectomy, bilateral
oophorectomy or bilateral salpingectomy but not tubal ligation

- Fertile men should be willing to use barrier contraception during and for 4 months
after AZD9291 (osimertinib), and fertile women must agree to use adequate
contraceptive measures during and for 6 weeks after AZD9291 (osimertinib); fertile men
and women must agree to use adequate contraceptive measures during study therapy and
for at least 6 months after the completion of bevacizumab therapy; should a woman
become pregnant or suspect she is pregnant while she or her partner is participating
in this study, the patient should inform the treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Symptomatic brain metastases

- Patients with brain metastases for whom complete surgical resection is clinically
appropriate

- Prior treatment with a third-generation EGFR TKI (i.e. rociletinib)

- Prior treatment with agents targeting the VEGF pathway, including bevacizumab

- The use of corticosteroids to control cerebral edema or treat neurologic symptoms will
not be allowed, and patients who previously required corticosteroids for symptom
control must be off steroids for at least 3 days without recurrence of symptoms prior
to starting trial therapy; corticosteroids for other indications is allowed

- Presence of leptomeningeal disease

- Patients may not be receiving any other investigational agents and may not have
participated in a study of an investigational agent or using an investigational device
within five half-lives of the compound or 3 months, whichever is greater

- Treatment with an EGFR TKI (i.e. erlotinib, gefitinib or afatinib) within 8 days or
approximately 5 x half-life, whichever is longer, of the first dose of study treatment

- 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 platinum-therapy related neuropathy

- Concurrent, active malignancies in addition to that being studied (other than
cutaneous squamous cell carcinoma or basal cell carcinoma)

- Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted
medical devices)

- Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis which required steroid treatment, or any evidence of
clinically active interstitial lung disease

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to AZD9291 (osimertinib) or bevacizumab

- Urine protein should be screened by urine analysis; if protein is 2+ or higher,
24-hour urine protein should be obtained; patients with 24-hour urine protein >= 1000
mg are excluded

- Serious or non-healing wound, ulcer or bone fracture

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 6 months prior to day 1

- Invasive procedures defined as follows:

- Major surgical procedure, open biopsy or significant traumatic injury within 28
days prior to day 1 therapy

- Anticipation of need for major surgical procedures during the course of the study

- Core biopsy within 7 days prior to day 1 (D1) therapy

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to day 1

- Patients with clinically significant cardiovascular disease are excluded

- Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160
mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive
medication)

- History of cerebrovascular accident (CVA) within 6 months (see additional
requirement for adjuvant protocols)

- Myocardial infarction or unstable angina within 6 months (see additional
requirement for adjuvant protocols)

- New York Heart Association grade II or greater congestive heart failure

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

- Clinically significant peripheral vascular disease

- Any of the following cardiac criteria:

- Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) > 470
ms ms obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG
machine derived corrected QT (QTc) value

- 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

- Evidence of bleeding diathesis or coagulopathy (including clinically significant
hemoptysis)

- 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)

- Patients with known hypersensitivity to Chinese hamster ovary cell products or other
recombinant human antibodies

- 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 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

- Any evidence of severe or uncontrolled systemic diseases, including, but not limited
to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or psychiatric illness/social situations which in the
investigator's opinion makes it undesirable for the patient to participate in the
trial or which would jeopardize compliance with the protocol, or active infection
including hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening
for chronic conditions is not required

- History of hypersensitivity active or inactive excipients of AZD9291 (osimertinib) or
drugs with a similar chemical structure or class to AZD9291 (osimertinib)

- Absolute neutrophil count < 1.5 x 10^9/L

- Platelet count < 100 x 10^9/L

- Hemoglobin < 90 g/L

- Alanine aminotransferase > 2.5 times 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 hyperbilirubinemia) or liver
metastases

- Serum 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

- 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