Non–Small Cell Lung Cancer

Primary Objectives: Phase 1 (Safety Run-In Phase): To evaluate the safety and tolerability of INCB039110 in combination with erlotinib and select a dose for further evaluation. Phase 2 (Randomized Phase): To evaluate and compare the overall survival (OS) and progression-free survival (PFS) of subjects with Stage IIIB/IV or recurrent non–small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR)-activating mutations when treated with INCB039110 in combination with erlotinib versus erlotinib alone. Secondary Objectives (Phase 2): To evaluate and compare the efficacy of the 2 treatment groups with respect to overall tumor response and duration of response. To evaluate and compare the safety and tolerability of INCB039110 in combination with erlotinib versus erlotinib alone. Exploratory Objectives (Phase 2): To evaluate and compare the 2 treatment groups with respect to changes in quality of life (QOL) as measured by the Functional Assessment of Cancer Therapy–Lung (FACT-L) questionnaire To evaluate and compare the 2 treatment groups with respect to changes in tissue and plasma biomarkers. To evaluate molecular signatures that may be associated with response or resistance to treatment. To evaluate the pharmacokinetics (PK) of INCB039110 in combination with erlotinib. To evaluate and compare the 2 treatment groups with respect to changes in body weight relative to baseline.

INCB039110

INCB039110 Adipate

tablet

100

Primary Endpoints：
Phase 1: Determination of the dose of INCB039110 that is safe and tolerable in combination with erlotinib.
Phase 2 (dual primary endpoints):
Overall survival as determined from the date of randomization until death due to any cause.

Progression-free survival as determined from the randomization date until the earliest date of disease progression, as measured by investigator assessment of objective radiographic disease assessments per RECIST v1.1, or death due to any cause if earlier.

Secondary Endpoints for Phase 2:
Objective response rate and duration of response determined by radiographic disease assessments per RECIST v1.1.

Safety and tolerability of the treatment regimens assessed by monitoring the frequency, duration, and severity of AEs; performing physical examinations; and evaluating change in vital signs and laboratory results.

Exploratory Endpoint(s) for Phase 2:
Change in health-related quality of life assessed using the FACT-L questionnaire from baseline to each visit where the variable is measured.

x Changes in cytokine and other marker levels from baseline to each visit where the variable is
measured. Plasma and tissue markers may include, but are not limited to, carcinoembryonic
antigen, interleukin (IL)-6, IL- 1 receptor antagonist, tumor necrosis factor (TNF) α、TNF receptor II, and CRP.

Investigate molecular signatures that may be associated with response or resistance to treatment.

Pharmacokinetics of INCB039110 analyzed and compared in the absence or presence of
concomitant erlotinib. Pharmacokinetics of erlotinib will be compared between the INCB039110 and placebo groups of the study.

Change and percent change in body weight from baseline to each visit where the variable is
measured.

Key Inclusion Criteria:
Subjects who meet all of the following criteria may be included in the study:

Men or women aged 18 years or older.

Histologically or cytologically confirmed diagnosis of nonsquamous NSCLC that is Stage IIIB,
Stage IV, or recurrent (including prior Stage II).

Subjects who have recurrent NSCLC after prior surgery or radiation therapy, or who have prior adjuvant, neoadjuvant, or chemoradiation therapy are allowed to enter. At least 4 weeks must have elapsed between prior radiation therapy and randomization, and all radiation therapy– related toxicities must have resolved or stabilized at a new baseline that is < Grade 2. Palliative radiation must have been completed 2 weeks prior to randomization.

Subjects must not have received prior chemotherapy, immunotherapy, or EGFR target therapy for advanced or metastatic disease.

Documented evidence of an activating mutation in EGFR in tumor samples (exon 19 deletions or point mutation L858R in exon 21 or point mutations at codon 719). The EGFR mutation testing must be performed using a test system approved by appropriate regulatory authorities. The laboratory report must document the specific mutations detected. In the case where no tissue sample can be obtained, use of an approved test to measure circulating tumor DNA will be allowed (such as the Qiagen therascreen EGFR RGQ Plasma PCR kit); the laboratory report must document the specific mutations detected.

Radiographically measurable or evaluable disease.

Measurable lesions may be in the field of prior radiation; however, there must be at least a
4-week period between the last radiation treatment and demonstration of interval progression of the lesion compared with the baseline scan documenting disease status for the lesion to be considered measurable.

Life expectancy of at least 12 weeks.

ECOG performance status of 0 to 2.

Negative pregnancy test at screening if female of childbearing potential (defined as not having undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy and not postmenopausal, defined as•• ≧ 12 months of amenorrhea). All female subjects of childbearing potential must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through follow-up. Permitted methods that are at least 99% effective in preventing pregnancy (Appendix B) should be communicated to the subjects and their understanding confirmed.

Male subjects must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through follow-up. Permitted methods that are at least 99% effective in preventing pregnancy (Appendix B) should be communicated to the subjects and their understanding confirmed.

Ability to swallow and retain orally administered medications.

Ability to comprehend and willingness to sign an informed consent form.

Key Exclusion Criteria:
Subjects who meet any of the following will not be included in the study:

Known presence of the T790M mutation in EGFR in tumor samples.

Candidates for curative radiation therapy or surgery.

Significant gastrointestinal disorders with diarrhea as a major symptom (eg, Crohn's disease,malabsorption, or ongoing > Grade 2 diarrhea per CTCAE v4.03 at screening or baseline visits).

Distinct or suspected, or history of, pulmonary fibrosis or interstitial lung disease.

Active central nervous system (CNS) metastases that require treatment or history of uncontrolled seizures. Subjects with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 4 weeks before randomization, defined as:

No evidence of new or enlarging CNS metastasis or new neurological symptoms attributable to CNS metastases.
Asymptomatic and receiving either no or stable doses of anticonvulsants and/or corticosteroids for the 4 weeks prior to randomization.

Current or previous other malignancy within 2 years of randomization, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive indolent or Stage I malignancy without sponsor approval.

Inadequate renal, hepatic, or bone marrow function demonstrated by Protocol-specified laboratory parameters at the screening visit.
ANC < 1.5 × 109/L.
Platelet count < 100 × 109/L.
Hemoglobin < 90 g/L (transfusion support to maintain this hemoglobin level is acceptable).
Alanine aminotransferase/aspartate aminotransferase > 2.5 × the upper limit of normal (ULN), or > 5 × ULN in the presence of liver metastases.
Total bilirubin > 1.5 × ULN with direct bilirubin also > 1.5 × ULN.
Creatinine clearance < 50 mL/min measured or calculated by Cockroft-Gault equation or
glomerular filtration rate (GFR) < 50 mL/min/1.73 m2 as calculated using the Modification of
Diet in Renal Disease formula.

Clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, and arrhythmia-requiring therapy.

Significant concurrent, uncontrolled medical condition, including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurological, cerebral, or psychiatric disease.

Concurrent therapy with a potent cytochrome P450 (CYP) 3A4 inducer or inhibitor (Appendix E). Subjects may enter screening when therapy with the potent inhibitor or inducer is completed and may begin study treatment after 1 week or 5 half-lives, whichever is longer. Subjects with a need for chronic treatment with a potent CYP3A4 inducer or inhibitor may be enrolled with sponsor approval with suitable adjustments in erlotinib dose administration.

Chronic or current active infectious disease requiring systemic antibiotics, antifungals, or antivirals.

Known human immunodeficiency virus infection, or hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or at risk for HBV reactivation. Hepatitis B virus DNA and testing for HCV RNA must be undetectable. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or hepatitis B core antibody positive.

Pregnant or breastfeeding women.

Unwillingness to be transfused with blood components (eg, packed red blood cells, platelets).

Active alcohol or drug addiction that would interfere with the subject's ability to comply with the study requirements.

Known hypersensitivity to any of the active substances or any of their excipients, including
INCB039110 and erlotinib.

Prior use of any JAK inhibitor.

Any condition that, in the investigator's opinion, would jeopardize the subject's safety or
compliance with the Protocol.