Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

This is a phase I/II study of ceritinib and trametinib in Stage IIIB or IV ALK rearranged
NSCLC.

The phase I portion is a standard 3+3 dose escalation study starting at dose level 1 and will
be open to any patient with ALK-rearranged, or ROS-1 rearranged NSCLC.

The phase II portion will consist of 3 single arm cohorts in ALK-rearranged NSCLC:

- Cohort A (ALKi Naïve): 20 evaluable patients

- Cohort B (Post-crizotinib PD): 21 evaluable patients

- Cohort C (PD second line ALK TKI (e.g., alectinib, ceritinib, PF-06463922 or - AP21163):
10 evaluable patients.

The aim will be to enroll up to 69 patients. Patients may continue treatment for up to 24
months from the time of study entry, and will receive 12 months of follow-up following
completion of the drugs.

Inclusion Criteria:

1. Age 18 years old or older.

2. Able to swallow and retain orally administered medication and does not have any
clinically significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels.

3. Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to randomization and agree to use effective contraception, throughout the
treatment period, and for 4 months after the last dose of study treatment.

4. Patients must have histologically or cytological confirmed stage IIIB or IV non-small
cell lung cancer.

5. Documented ALK-rearrangement (or ROS1 rearrangement for phase I only) break-apart
fluorescence in situ hybridization (FISH) (in at least 15% of tumor cells), or next
generation sequencing assay performed on tumor sample or cell-free DNA in Clinical
Laboratory Improvement Amendments (CLIA)-approved laboratory.

6. Measurable disease defined by RECIST 1.1 criteria

7. Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2.

8. Life expectancy of at least 3 months.

9. Resolution of all acute toxic effects of prior chemotherapy, immunotherapy,
radiotherapy or surgical procedures to ≤ grade 2 (CTCAE v 4.0). Exception to this
criterion: patients with any grade of alopecia are allowed to enter the treatment.

10. The following laboratory criteria have been met:

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Hemoglobin (Hgb) ≥ 9 g/dL

- Platelets ≥ 75 x 109/L

- Prothrombin time (PT) / international normalized ratio (INR) and Partial
thromboplastin time (PTT) ≤1.5 x upper limit of normal (ULN)

- Serum creatinine ≤ 1.5 mg/dL and /or calculated creatinine clearance (using
Cockcroft-Gault formula) ≥ 30 mL/min

- Albumin 2.5 g/dL

- Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert's syndrome who may
be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN

- Aspartate transaminase (AST) ≤ 2.5 x ULN; alanine transaminase (ALT) ≤ 2.5 x ULN,
except for patients with liver metastasis, who are only included if AST and ALT <
5 x ULN

- Alkaline phosphatase (ALP) ≤ 5.0 x ULN

- Fasting plasma glucose ≤ 175 mg/dL (≤ 9.8 mmol/L)

- Serum amylase ≤ 2 x ULN

- Serum lipase ≤ ULN

11. Patient must have the following laboratory values or have the following laboratory
values corrected with supplements to be within normal limits before the first dose of
ceritinib + trametinib:

• Potassium

- Magnesium

- Phosphorus

- Total calcium (corrected for serum albumin)

12. Left Ventricular Ejection fraction (LVEF) ≥ lower limit of normal (LLN) by
echocardiogram (ECHO) or multigated acquisition scan (MUGA)

13. Patient has the ability to understand and provide signed informed consent.

14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other study procedure.

15. Specific inclusion criteria for the phase II dose expansion cohorts:

Documented ALK-rearranged stage IIIB or IV NSCLC and:

- Cohort A: No prior ALK inhibitor therapy (prior chemotherapy or immunotherapy is
allowed).

- Cohort B: Prior treatment with crizotinib and documented disease progression by RECIST
1.1 criteria.

- Cohort C: Prior treatment with 2nd generation ALKi (e.g. ceritinib, alectinib,
loratinib, or brigatinib) and documented disease progression by RECIST 1.1 criteria.

Exclusion Criteria:

1. Patients with known hypersensitivity to any of the excipients of ceritinib
(microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and
magnesium stearate).

2. Patient has history of interstitial lung disease or interstitial pneumonitis,
including clinically significant radiation pneumonitis (i.e., affecting activities of
daily living or requiring therapeutic intervention).

3. Patient who has received thoracic radiotherapy to lung fields ≤4 weeks prior to
starting the study treatment or patients who have not recovered from
radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy
to thoracic vertebrae and ribs) radiotherapy ≤ 2 weeks prior to starting the study
treatment or has not recovered from radiotherapy-related toxicities. Palliative
radiotherapy for bone lesions ≤ 2 weeks prior to starting study treatment is allowed.

4. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy,
vaccine therapy, or investigational treatment) within the last 3 weeks, or
chemotherapy without delayed toxicity within the last 2 weeks preceding the first dose
of the combination. Prior systemic treatment in the adjuvant setting is allowed.

5. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac
event (within 6 months), such as:

• unstable angina within 6 months prior to screening;

• myocardial infarction within 6 months prior to screening;

• history of documented congestive heart failure (New York Heart Association
functional classification III-IV);

• Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without antihypertensive
medication

• initiation or adjustment of antihypertensive medication(s) is allowed prior to
screening;

• ventricular arrhythmias

• supraventricular and nodal arrhythmias not controlled with medication;

• other cardiac arrhythmia not controlled with medication;

• corrected QT (QTcF) > 470 ms using Fridericia's correction on the screening
electrocardiogram (ECG)

6. Patient has impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of orally administered medication (e.g., ulcerative
diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).

7. Receiving medications that meet one of the following criteria and that cannot be
discontinued at least 1 week prior to the start of treatment with ceritinib and for
the duration of participation:

- Medication with a known risk of prolonging the QT interval or inducing Torsades
de Pointes (please refer to
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm)

- Strong inhibitors or strong inducers of CYP3A4/5 (please refer to
http://medicine.iupui.edu/flockhart/table.htm or
http://www.druginteractioninfo.org)

- Medications with a low therapeutic index that are primarily metabolized by
CYP3A4/5, and/or CYP2C9 (please refer to
http://medicine.iupui.edu/flockhart/table.htm or
http://www.druginteractioninfo.org)

- Therapeutic doses of warfarin sodium (Coumadin) or any other coumadin-derived
anti-coagulant. Anticoagulants not derived from warfarin are allowed (eg,
dabigatran, rivaroxaban, apixaban).

- Unstable or increasing doses of corticosteroids; If patients are on
corticosteroids for endocrine deficiencies or tumor-associated symptoms, dose
must have been stabilized (or decreasing) for at least 5 days before first dose
of study treatment.

- Enzyme-inducing anticonvulsive agents

- Herbal supplements

10. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a positive
human Chorionic Gonadotropin (hCG) laboratory test.

11. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception during
dosing and for 3 months after the last dose of study treatment. Highly effective
contraception methods include:

- Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.

- Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow up hormone level assessment.

- Male sterilization (at least 6 months prior to screening) with the appropriate
post-vasectomy documentation of the absence of sperm in the ejaculate. For female
subjects on the study the vasectomized male partner should be the sole partner for
that subject.

- Combination of any two of the following (a+b or a+c or b+c):

1. Use of oral, injected or implanted hormonal methods of contraception or other
forms of hormonal contraception that have comparable efficacy (failure rate <
1%), for example hormone vaginal ring or transdermal hormone contraception.

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).

3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

In case of use of oral contraception, women should have been stable on the same
pill for a minimum of 3 months before taking study treatment.

Women are considered post-menopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile. (e.g., age appropriate, history of vasomotor symptoms) or have
had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
ligation at least six weeks prior to screening. In the case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment is she considered not of child bearing
potential.

12. Sexually active males unless they use a condom during intercourse while
taking drug and for 3 months after the last dose of study treatment. Male
patients for 3 months should not father a child in this period. A condom is
required to be used also by vasectomized men in order to prevent delivery of the
drug via seminal fluid.

13. Patient has a history of pancreatitis or history of increased amylase or
lipase that was due to pancreatic disease.

14. Patient has other severe, acute, or chronic medical conditions including
uncontrolled diabetes mellitus or psychiatric conditions or laboratory
abnormalities that, in the opinion of the investigator, may increase the risk
associated with study participation or may interfere with the interpretation of
study results.

16. Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or
intra-pelvic) within 4 weeks prior to starting study treatment or has not
recovered from side effects of such procedure. Video-assisted thoracic surgery
(VATS) and mediastinoscopy will not be counted as major surgery and patients can
receive study treatment ≥ 1 week after these procedures.

17. History of another malignancy. Exception: Subjects who have been disease-free
for 3 years, or subjects with a history of completely resected non-melanoma skin
cancer and/or subjects with indolent (early stage breast cancer or prostate
cancer) second malignancies are eligible after discussion with the study
principle investigator (PI).

18. History of retinal vein occlusion (RVO)

19. Symptomatic brain metastases or leptomeningeal (LM) disease requiring
corticosteroids for symptom management. Asymptomatic brain metastases or LM will
be allowed on study.

20. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or
Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared
HBV and HCV infection will be permitted).