Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer

This is a Phase 2, therapeutic-exploratory, adaptive design, open-label, multicenter,
multinational study evaluating neratinib monotherapy and neratinib plus temsirolimus
combination therapy in patients with NSCLC and documented somatic HER2 mutations. Patients
randomized at study entry into 1 of 2 treatment arms:

- Arm A: neratinib 240 mg orally once daily

- Arm B: neratinib 240 mg orally once daily plus temsirolimus 8 mg once weekly by
intravenous (IV) infusion

In the case of disease progression, patients initially assigned to neratinib monotherapy arm
given option to add temsirolimus 8 mg IV once weekly.

Patients on combination therapy given option to dose-escalate temsirolimus to 15 mg/week at
the end of first cycle of treatment, if well tolerated and at the physician's discretion. If
neratinib 240 mg/day plus temsirolimus 15 mg/week dose not well tolerated, patient
subsequently dose reduced back to neratinib 240 mg/day plus temsirolimus 8 mg/week.

Dosing continuous on nominal 3-week cycles until evidence of progressive disease,
unacceptable toxicity, or patient withdrawal of consent.

Disease measured radiographically at baseline and every 6 weeks until disease progression or
withdrawal from the study.

Inclusion Criteria

1. Aged ≥18 years at the time of signing the informed consent.

2. Histologically confirmed diagnosis of NSCLC, advanced (stage IIIB) or metastatic
(stage IV).

3. Documented somatic ErbB2 (HER2) activating mutation.

4. Patients with anaplastic lymphoma kinase (ALK) translocations must have received
crizotinib, except for cases of intolerable toxicity to crizotinib.

5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid
Tumors version 1.1 (RECIST v1.1).

6. Eastern Cooperative Oncology Group (ECOG) status <2.

7. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple -gated acquisition
scan (MUGA) or echocardiogram (ECHO).

8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women
of reproductive capacity (those who are biologically capable of having children) and
for women less than 12 months after menopause.

9. Men and women of childbearing potential must agree and commit to the use of a highly
effective method of contraception, as determined to be acceptable by the Investigator,
from the time of informed consent until 3 months after the last dose of the
investigational products.

10. Provide written, informed consent to participate in the study and follow the study
procedures.

Exclusion Criteria

1. Previous treatment with any investigational agent ≤14 days prior to the initiation of
investigational products.

2. Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or
sensitive P-glycoprotein (P-gp) substrates ≤30 days prior to the initiation of
investigational products.

3. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart
failure (New York Heart Association functional classification of ≥2), unstable angina,
myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.

4. Major surgery <30 days of starting treatment.

5. Chronic steroid use (prednisone >12.5 mg/day or dexamethasone >2 mg/day, excluding
inhaled steroids).

6. Currently breast feeding.

7. Symptomatic or unstable brain metastases.

8. QTc interval >0.450 seconds for men and >0.470 seconds for women, or known history of
QTc prolongation or Torsades de Pointes (TdP).

9. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g.,
Crohn's disease, malabsorption, or Grade ≥2 (National Cancer Institute [NCI] Common
Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any
etiology at baseline).

10. Prior exposure to neratinib or mTOR inhibitor.

11. Active infection or unexplained fever >38.5°C (101.3°F).

12. Unable or unwilling to swallow tablets.

13. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric
illness/social situations that would, in the Investigator's judgment, make the patient
inappropriate for this study.

14. Known hypersensitivity to any component of the investigational products.

15. Unstable or uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c] >6.5%).

16. Screening laboratory assessments outside the following limits: ANC <1000/μL (<1.0 x
109/L), Platelet count <75,000/μL (<75 x 109/L), Hemoglobin <8 g/dL, transfusions
allowed, must be at least 7 days prior to baseline, Total bilirubin >1.5 x
institutional upper limit of normal (ULN), AST and/or ALT 5 minutes, Creatinine
clearance <50 mL/min.