Selumetinib and Paclitaxel as Second-Line Treatment in Treating Patients With Stage IIIB-IV Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of three pre-planned arms of continuous,
intermittent, and pulsatile selumetinib with paclitaxel as second-line treatment in patients
with stage IIIB or IV NSCLC.

SECONDARY OBJECTIVES:

I. To determine the preliminary clinical response of continuous, intermittent, and pulsatile
selumetinib with paclitaxel as second-line treatment in patients with stage IIIB or IV NSCLC.

TERTIARY OBJECTIVES:

I. To characterize the pharmacokinetics (PK) of selumetinib in this patient population.

II. To determine progression-free survival (PFS) and overall survival (OS) in patients
treated with selumetinib/paclitaxel.

III. To assess correlations between cell-free deoxyribonucleic acid (DNA) (cfDNA) molecular
features from blood and molecular features and pathways from the biopsy samples, and use this
as a surrogate measure of tumor response and duration of response as evaluated in the primary
and secondary objectives.

OUTLINE: This is a dose-finding study of selumetinib. The goal is to find out what dose and
dosing schedule is the most effective in this population. Patients are randomized to 1 of 3
treatment arms.

ARM I: Patients receive selumetinib orally (PO) twice daily (BID) on days 1-21 and paclitaxel
intravenously (IV) over 30 minutes on days 1 and 8.

ARM II: Patients receive selumetinib PO BID on days 1-5, 8-12, and 15-19 and paclitaxel as in
Arm I.

ARM III: Patients receive selumetinib PO BID on days 1-3, 8-10, and 15-17 and paclitaxel as
in Arm I.

In all three arms, treatment repeats every 21 days for 6 courses in the absence of disease
progression or unacceptable toxicity. Patients experiencing clinical benefit from study
treatment may continue treatment based on the principal investigator (PI) approval on a
patient-by-patient basis.

After completion of study treatment, patients are followed up at 30 days, every 8 weeks for
12 months, and then every 3 months thereafter.

Inclusion Criteria:

- Histologically and/or cytologically confirmed, non-small cell lung cancer (NSCLC) of
adenocarcinoma histology at the time of initial diagnosis.

1. Mixed tumors will be categorized by the predominant cell type; (Note: If small
cell elements are present the patient is ineligible)

2. Known mutational status of KRAS and BRAF oncogenes.

3. For patients in whom mutational testing result is unknown or unavailable from a
prior test, KRAS and BRAF testing will be performed (at a CLIA-certified
laboratory) using an archived or fresh biopsy as per Standard of Care, prior to
enrollment.

- Stage IIIB-IV, locally advanced or metastatic disease according to the 7 th edition of
the AJCC lung cancer TNM classification system

- Measurable disease as defined by RECIST v1.1 criteria. Baseline measurements and
evaluation of ALL sites of disease must be obtained within 4 weeks prior to
Enrollment.

- Failure of at least one line of systemic anti-cancer therapy for advanced NSCLC
defined as either of the following:

1. Radiological documentation of disease progression (or failure to achieve a
response) or

2. Discontinuation due to toxicity

- ECOG Performance Status of 0 or 1

- Estimated life expectancy, in the judgment of the investigator, which will permit
receipt of treatment of 12 weeks or more

- Adequate bone marrow function as defined below:

- Absolute neutrophil count >= 1.5x109 /L (1500 per mm3)

- Platelets >= 100x109 /L (100,000 per mm3)

- Hemoglobin > 9.0 g/dL

- Adequate liver function as defined below:

- Serum Bilirubin < 1.5 x upper limit of normal (ULN) for institution [Exception:
Patients who have elevated serum bilirubin due to underlying Gilbert's Syndrome
or familial benign unconjugated hyperbilirubinemia are allowed.]

- AST (SGOT) < 2.5 x upper limit of normal (ULN) for institution (or < 5.0 x ULN in
presence of liver metastases)

- ALT (SGPT) < 2.5 x upper limit of normal (ULN) for institution (or < 5.0 x ULN in
presence of liver metastases)

- Adequate renal function as defined by one of the following:

- Serum Creatinine <= 1.5 mg/dl OR

- Serum Creatinine clearance > 50ml/min (calculated by Cockcroft-Gault formula)

- 18 years and older

- Females of child bearing potential that are sexually active must agree to either
practice 2 medically accepted highly effective methods of contraception at the same
time or abstain from heterosexual intercourse from the time of signing the informed
consent through 30 days after the last dose of study drug.

- Negative test for pregnancy is required for females of child-bearing potential; A
female of child bearing 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 or 730 days).

- Conception while on treatment must be avoided

- Males of child bearing potential must agree to practice effective barrier
contraception during the entire study treatment period and through 6 months) after the
last dose of study drug, (includes males surgically sterilized (i.e. status post
vasectomy).

- Ability to understand and the willingness to sign a written Informed Consent and HIPAA
document/s

Exclusion Criteria:

- Known actionable mutations (e.g., EGFR, ALK, ROS1), against which there is available
treatment. Patients who progressed on such treatment, i.e., have developed acquired
resistance and are no longer reasonably expected to derive therapeutic benefit are
eligible for the trial.

- Any prior treatment with either a MEK, RAS, or RAF inhibitor for advanced or
metastatic NSCLC.

- A history of hypersensitivity to selumetinib, or any excipient agents (e.g. Captisol
or TPGS- a water soluble form of Vitamin E)

- Any unresolved toxicity > CTCAE grade 2 despite optimal care/support, from previous
anti-cancer therapy, except for alopecia, within 7 days prior to Cycle 1, day 1

- Cardiac conditions as follows:

- Uncontrolled hypertension (BP >= 150/95 mmHg, despite medical therapy)

- Left ventricular ejection fraction (LVEF) < 55%, measured by echocardiography

- Atrial fibrillation with a ventricular rate > 100 bpm on ECG at rest

- Symptomatic heart failure (NYHA grade II-IV)

- Prior or current cardiomyopathy

- Severe valvular heart disease

- Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical
therapy)

- Acute coronary syndrome within 6 months prior to starting treatment

- Ophthalmological conditions as follows:

- Intra-ocular pressure > 21 mmHg, or uncontrolled glaucoma (irrespective of
intra-ocular pressure)

- Current or past history of central serous retinopathy or retinal vein occlusion

- Prior treatment with chemotherapy or immunotherapy within 14 days prior to enrollment.
Subjects receiving palliative radiation to CNS disease within 7 days may be eligible
with PI approval. If the most recent treatment line is an EGFR-TKI, the washout period
is a minimum of 3 days before the start of paclitaxel/selumetinib (i.e. treatment with
the EGFR-TKI may continue until 3 days before start of study treatment). For other
targeted therapy agents, the washout period will be 5 half-lives, prior to start of
treatment on study.

- Caution should be exercised when administering paclitaxel (Taxol) concomitantly with
medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals,
erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir
and nelfinavir) OR induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz and
nevirapine) either CYP2C8 or CYP3A4. Based on the in vitro data and SimCYP
simulations, selumetinib is considered unlikely to perpetrate clinically significant
drug-drug interaction via inhibition or induction of CYP enzymes

- Major surgical procedure within 21 days prior to enrollment

- Brain metastases or spinal cord compression unless asymptomatic, treated and stable
off steroids and anti-convulsants for at least 30 days

- Received an investigational drug within 30 days of starting treatment, or have not
recovered from side effects of an investigational drug

- Female patients who are pregnant or breast-feeding (confirmation that the patient is
not pregnant must be by a negative pregnancy test result obtained during screening;
pregnancy testing is required of women of childbearing potential but not required for
post-menopausal or surgically, sterilized women)

- Any evidence of severe or uncontrolled systemic disease, including, but not limited
to, ongoing or active infection, active bleeding diatheses or renal transplant,
including any patient known to have hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV)

- Serious medical or psychiatric illness/condition likely in the judgment of the
Investigator to interfere with compliance with protocol treatment/research