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

• Aged ≥18 years at the time of signing the informed consent.
• Histologically confirmed diagnosis of NSCLC, advanced (stage IIIB) or metastatic (stage IV).
• Documented somatic ErbB2 (HER2) activating mutation.
• Patients with anaplastic lymphoma kinase (ALK) translocations must have received crizotinib, except for cases of intolerable toxicity to crizotinib.
• At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
• Eastern Cooperative Oncology Group (ECOG) status <2.
• Left ventricular ejection fraction (LVEF) ≥50% measured by multiple -gated acquisition scan (MUGA) or echocardiogram (ECHO).
• 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.
• 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.
• Provide written, informed consent to participate in the study and follow the study procedures.

Exclusion criteria

• Previous treatment with any investigational agent ≤14 days prior to the initiation of investigational products.
• 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.
• 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.
• Major surgery <30 days of starting treatment.
• Chronic steroid use (prednisone >12.5 mg/day or dexamethasone >2 mg/day, excluding inhaled steroids).
• Currently breast feeding.
• Symptomatic or unstable brain metastases.
• QTc interval >0.450 seconds for men and >0.470 seconds for women, or known history of QTc prolongation or Torsades de Pointes (TdP).
• 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).
• Prior exposure to neratinib or mTOR inhibitor.
• Active infection or unexplained fever >38.5°C (101.3°F).
• Unable or unwilling to swallow tablets.
• 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.
• Known hypersensitivity to any component of the investigational products.
• Unstable or uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c] >6.5%).
• 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.