Icotinib Hydrochloride in Treating Patients With Advanced Cancers

PRIMARY OBJECTIVES:

I. To determine the pharmacokinetic (PK) profiles of icotinib (icotinib hydrochloride) in
patients with advanced cancers.

II. To determine the safety, tolerability and maximum tolerated dose (MTD) of icotinib in
patients with advanced cancers.

SECONDARY OBJECTIVES:

I. To preliminarily assess the anti-tumor activity of icotinib in patients with advanced
cancers.

II. To characterize the effect, if any, of icotinib on corrected QT interval using Bazett's
formula (QTcB).

TERTIARY OBJECTIVES:

I. To evaluate single nucleotide polymorphisms in genes encoding for icotinib's target
(epidermal growth factor receptor [EGFR]), putative transport protein (ATP-binding cassette,
sub-family G [WHITE], member 1 [ABCG1]) and major metabolizing enzyme (cytochrome P450 3A4
[CYP3A4]) as well as other genes that may be found to be important in icotinib activity, and
correlate these single nucleotide polymorphisms (SNPs) with clinical activity and toxicity.

OUTLINE: This is a dose-escalation study.

Patients receive icotinib hydrochloride orally (PO) twice daily (BID) on days 1-28. Courses
repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

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

- Histologically or cytologically confirmed locally advanced, inoperable or metastatic
solid tumor

- Platelet count >= 100 x 10^9/L

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Hemoglobin (Hgb) >= 9 gm/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Alanine transaminase (ALT) and aspartate transaminase (AST) =< 3 x ULN (=< 5 x ULN if
liver metastasis is present)

- Creatinine clearance >= 40 mL/min; use the Cockroft and Gault formula

- QTcB is < 480 msec

- International normalized ratio (INR) =< 1.5

- Activated partial thromboplastin time (APTT) =< 1.5 x ULN if not on anticoagulants;
patients who are receiving therapeutic anticoagulation with heparin are allowed to
participate provided that no prior evidence of underlying abnormality exists in these
parameters; patients on warfarin should have stable doses with INR between 2-3 in the
2 months prior to study registration

- Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria present

- Demonstrate the ability to swallow and retain oral medication

- Women of childbearing potential must have a negative pregnancy test performed within
7 days prior to the start of study drug

- Male and female subjects of child-bearing potential must agree to use double-barrier
contraceptive measures, oral contraception, or avoidance of intercourse during the
study and for 90 days after last investigational drug dose received

- Subject or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure

- Written informed consent granted prior to initiation of any study-specific screening
procedures, given with the understanding that the patient has the right to withdraw
from the study at any time, without prejudice

Exclusion Criteria:

- Previous anti-cancer chemotherapy, immunotherapy or investigational agents =< 4 weeks
prior to the first day of study defined treatment; palliative radiation =< 2 weeks;
patients who receive gamma knife radiosurgery for brain metastases are eligible if
procedure was performed >= 7 days before treatment is started; ongoing hormonal
therapies (luteinizing hormone-releasing hormone [LHRH] antagonists, megestrol,
octreotide, calcitonin, etc.) are allowed

- History of cardiac disease: congestive heart failure defined as class II to class IV
per New York Heart Association (NYHA) classification; active coronary artery disease
(CAD); previously diagnosed bradycardia or other cardiac arrhythmia defined as >=
grade 2 according to National Cancer Institute (NCI)-Common Terminology Criteria for
Adverse Events (CTCAE) (version 4.0), or uncontrolled hypertension; myocardial
infarction occurred within 6 months prior to study entry (myocardial infarction
occurred > 6 months prior to study entry is permitted)

- Active clinically serious infections defined as >= grade 2 according to NCI CTCAE
version 4.0

- Substance abuse, medical, psychological or social conditions that may, in the opinion
of the investigator, interfere with the patient's participation in the study or
evaluation of the study results

- Any condition that is unstable or which could jeopardize the safety of the patient
and his/her protocol compliance

- Known human immunodeficiency virus (HIV) infection

- Pregnancy or breast-feeding

- Significant gastrointestinal disorder, in the opinion of the investigator, could
interfere with the absorption of icotinib (e.g., significant, uncontrolled
inflammatory bowel disease, history of abdominal fistula or gastrointestinal [GI]
perforation within 6 months, extensive small bowel resection and requirement for tube
feeding or parenteral hydration/nutrition)

- Concomitant use of strong inhibitors or inducers of cytochrome P450 2C19 (CYP2C19)
and CYP3A4 should be avoided

- Untreated, symptomatic or unstable brain metastases

- Major surgery < 4 weeks or minor surgery (e.g., talc pleurodesis, excisional biopsy,
etc) < 2 weeks prior to the first day of study defined treatment

- Unwilling or unable to follow protocol requirements

- Any condition which in the investigator's opinion deems the subject an unsuitable
candidate to receive study drug