INC280 and Erlotinib Hydrochloride in Treating Patients With Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of INC280 (c-Met inhibitor INCB028060) plus
erlotinib (erlotinib hydrochloride) in patients with met proto-oncogene (MET) expressing
non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To describe the toxicity profile of INC280 plus erlotinib. II. To determine the
preliminary efficacy of INC280 plus erlotinib. III. To characterize the pharmacokinetic
behavior of this combination.

TERTIARY OBJECTIVES:

I. To collect blood and tumor samples for exploratory analysis of the MET and epidermal
growth factor receptor (EGFR) signaling pathways.

OUTLINE: This is a dose-escalation study.

Patients receive c-Met inhibitor INCB028060 orally (PO) twice daily (BID) and erlotinib
hydrochloride PO once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must provide written informed consent prior to any screening procedures

- Willing and able to comply with scheduled visits, treatment plan and laboratory tests

- Patient is able to swallow and retain oral medication

- Histologically or cytologically documented diagnosis of NSCLC

- Must have evidence of MET expression by fluorescence in situ hybridization (FISH), MET
immunohistochemistry (IHC) score of 2-3+, reverse-transcriptase polymerase chain
reaction (RT-PCR) or a mutation

- Tumor tissue for correlative studies is mandatory

- Patients in expansion cohort A will have a biopsy (which is standard of care) at the
time of progression that shows evidence of MET positivity and meets the criteria for
acquired resistance per the Jackman criteria

- Previously received treatment with a single-agent erlotinib

- A tumor that harbors an EGFR mutation known to be associated with drug
sensitivity (i.e. G719X, exon 19 deletion, L858R, L861Q)

- Systemic progression of disease (Response Evaluation Criteria in Solid Tumors
[RECIST] or World Health Organization [WHO]) while on continuous treatment with
gefitinib or erlotinib

- Patients must have measurable disease; disease in previously irradiated sites is
considered measurable if there is clear disease progression following radiation
therapy

- Failed 1-2 prior chemotherapies for advanced disease; prior erlotinib is allowed in
the dose finding phase and expansion cohort A (Patients in expansion cohort B must be
erlotinib naïve and have v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS]
wild type tumor)

- Patients must be willing to be off therapy for a minimum of two weeks (In expansion
cohort A patients on erlotinib do not have to discontinue treatment)

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Life expectancy greater than 3 months

- Hemoglobin > 9 g/dL (International System [SI] units: 90 g/L) without transfusion
support or growth factors within 10 days of starting INC280

- Platelet count >= 75 x 10^9/L

- Absolute neutrophil count (ANC) >= 1.2 x 10^9/L without growth factor support

- Total bilirubin =< 2 x upper limit of normal (ULN)

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or
alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 2.5 x
upper limit of normal (ULN)

- Serum creatinine =< 2 x ULN

- Serum amylase =< ULN

- Serum lipase =< ULN

- Fasting serum triglyceride level =< 500 mg/dL

Exclusion Criteria:

- Patients who have had major surgery within 4 weeks of initiation of study medication,
excluding the placement of vascular access

- Patients with concurrent uncontrolled medical conditions that may interfere with their
participation in the study or potentially affect the interpretation of the study data

- Unstable angina pectoris, symptomatic congestive heart failure, myocardial
infarction =< 6 months prior to first study treatment, serious uncontrolled
cardiac arrhythmia

- Severely impaired lung function

- Active (acute or chronic) or uncontrolled infection

- Nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy

- Liver disease (i.e. cirrhosis, chronic active hepatitis, chronic persistent
hepatitis)

- Symptomatic central nervous system (CNS) metastases that are neurologically unstable
or requiring increasing doses of steroids to control CNS disease

- Note: Patients with controlled CNS metastases are allowed; radiotherapy or
surgery for CNS metastases must have been completed > 2 weeks prior to study
entry; patients must be neurologically stable, having no new neurologic deficits
on clinical examination, and no new findings on CNS imaging; steroid use for
management of CNS metastases must be at a stable dose for two weeks preceding
study entry

- Receiving drugs known to be strong inducers of cytochrome P450 3A4 (CYP3A4) or
inhibiting drugs known to interact with erlotinib including, but not limited to:
enzyme-inducing anticonvulsants, rifampicin, rifabutin, St John wort and ketoconazole

- Treatment with proton pump inhibitors within 3 days prior to study entry

- Currently receiving any prohibited medications including vitamins and herbal
supplements

- Any other condition that would, in the investigator's judgment, contraindicate
participation in the clinical study due to safety concerns or compliance with clinical
study procedures, e.g., infection/inflammation, intestinal obstruction, unable to
swallow medication, social/ psychological issues, etc.

- 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 (> 5 mIU/mL)

- 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 stopping study drug; highly effective
contraception methods include:

- Total abstinence or

- Male or female sterilization or

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

- (a) Use of oral, injected or implanted hormonal methods of contraception

- (b) Placement of an intrauterine device (IUD) or intrauterine system (IUS)

- (c) Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository

- 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 ago;
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

- Sexually active males must use a condom during intercourse while taking the drug and
for 3 months after stopping study drug and 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

- Patients unwilling or unable to comply with the protocol

- Prior treatment with a MET inhibitor or hepatocyte growth factor (HGF) targeting agent

- No history of another active cancer

- Human immunodeficiency virus (HIV) seropositivity