Phase 1 Erlotinib and Dovitinib (TKI258) in Advanced Non-small Cell Lung Cancer (NSCLC)

PRIMARY OBJECTIVES:

I. To characterize the safety and tolerability of the combination of erlotinib (erlotinib
hydrochloride) and dovitinib (dovitinib lactate), assessing for toxicity using the Common
Terminology Criteria for Adverse Events (CTCAE) version 4.0.

II. To determine the maximum tolerated dose (MTD) of the combination of erlotinib and
dovitinib.

SECONDARY OBJECTIVES:

I. To evaluate overall response rate (ORR), progression free survival (PFS), and overall
survival (OS) of patients receiving the combination of erlotinib and dovitinib, although
this phase will allow for patients who received any number of prior treatments, including
prior treatment with erlotinib.

II. To evaluate the potential impact of dovitinib on erlotinib pharmacokinetics (PK).

OUTLINE: This is a dose-escalation study.

Patients receive erlotinib hydrochloride orally (PO) once daily (QD). Starting on day 15,
patients also receive dovitinib lactate PO QD on days 1-5 of each week. Treatment continues
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 months.

Inclusion Criteria:

- Histologically-confirmed metastatic non-small cell lung cancer

- One or more primary or metastatic lesions measurable in at least one dimension by
modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria (v1.1) within
4 weeks prior to entry of study

- Patients who have failed any number of prior therapies, including those previously
treated with erlotinib

- Life expectancy > 2 months

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

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500/mm^3)

- Platelets (PLT) >= 100,000/mm^3

- Hemoglobin (Hgb) >= 9 g/dL

- Serum creatinine =< 1.5 x upper limit of normal (ULN)

- Serum bilirubin =< 1.5 x ULN (regardless of whether liver metastases are present at
baseline)

- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) =< 3.0 x
ULN (regardless of whether liver metastases are present at baseline)

- Ability to understand and the willingness to provide verbal and written informed
consent

- Patients - both males and females- with reproductive potential (i.e. menopausal for
less than 1 year and not surgically sterilized) must practice effective contraceptive
measures throughout the study; women of childbearing potential must provide a
negative pregnancy test (serum or urine) within 14 days prior to registration

Exclusion Criteria:

- Patients who have received the last administration of chemotherapy or immunotherapy
=< the timeframe defined below after the end of the cycle of the last treatment,
prior to starting study drug, or who have not recovered from the side effects of such
therapy:

- Patients who have received the last administration of chemotherapy/immunotherapy
in a daily schedule =< 7 days prior to starting study drug

- Patients who have received the last administration of chemotherapy/immunotherapy
in a weekly schedule =< 2 weeks prior to starting study drug

- Patients who have received the last administration of chemotherapy/immunotherapy
in a 2-weekly schedule =< 3 weeks prior to starting study drug

- Patients who have received the last administration of chemotherapy/immunotherapy
in a 3-weekly schedule =< 4 weeks prior to starting study drug

- Patients who have received the last administration of chemotherapy/immunotherapy
in a 4-weekly schedule =< 5 weeks prior to starting study drug

- Patients who have received the last administration of nitrosourea, mitomycin-C
=< 6 weeks prior to starting study drug, or who have not recovered from the side
effects of such therapy

- Patients who have received wide field radiotherapy (including therapeutic
radioisotopes such as strontium 89) =< 4 weeks or limited field radiation for
palliation =< 2 weeks prior to starting study drug or who have not recovered from
side effects of such therapy

- Patients who have undergone major surgery =< 4 weeks prior to starting study drug or
who have not recovered from side effects of such therapy

- If history of other primary cancer, subject will be eligible only if she or he has:

- Curatively resected non-melanomatous skin cancer, basal cell carcinoma, squamous
cell carcinoma

- Curatively treated cervical carcinoma in situ

- Other primary solid tumor curatively treated with no known active disease
present and no treatment administered for the last 3 years

- Subjects known to have chronic or active hepatitis B or C infection with impaired
hepatic function (ineligible if AST and ALT > 2.5 x ULN)

- History of any medical or psychiatric condition or laboratory abnormality that in the
opinion of the investigator may increase the risks associated with study
participation or study drug administration or may interfere with the conduct of the
study or interpretation of study results

- Patients who continue to smoke (given that smoking decreases serum levels of
erlotinib)

- Female subject who is breast-feeding or who has positive serum pregnancy test 72
hours prior to enrollment

- Any of the following concurrent severe and/or uncontrolled medical conditions within
6 months of enrollment which could compromise participation in the study:

- Unstable angina pectoris

- Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm
Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without
anti-hypertensive medication; initiation or adjustment of antihypertensive
medication(s) is allowed prior to study entry

- Left ventricular ejection fraction (LVEF) assessed by 2-D echocardiogram (ECHO)
< 50% or lower limit of normal (whichever is higher) or multiple gated
acquisition scan (MUGA) < 45% or lower limit of normal (whichever is higher)

- Myocardial infarction

- Serious uncontrolled ventricular arrhythmia

- Clinically significant resting bradycardia

- Uncontrolled diabetes

- Transient Ischemic Attach (TIA)

- Cerebrovascular accident (CVA)

- Pulmonary embolism (PE)

- Impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of dovitinib (e.g. ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel
resection)

- Serious active or uncontrolled infection

- Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
lung

- Chronic renal disease

- Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

- Patients who are currently receiving anticoagulation treatment with therapeutic doses
of warfarin or enoxaparin

- Women of child-bearing potential, who are biologically able to conceive, not
employing two forms of highly effective contraception; highly effective contraception
(e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device)
must be used by both sexes during the study and must be continued for 8 weeks after
the end of study treatment; oral, implantable, or injectable contraceptives may be
affected by cytochrome P450 interactions, and are therefore not considered effective
for this study; women of child-bearing potential, defined as sexually mature women
who have not undergone a hysterectomy or who have not been naturally postmenopausal
for at least 12 consecutive months (e.g., who has had menses any time in the
preceding 12 consecutive months), must have a negative serum pregnancy test =< 14
days prior to starting study treatment

- Patients unwilling to or unable to comply with the protocol

- There may be danger of harm to study participants because of human immunodeficiency
virus (HIV) comorbidity or drug interactions