A phase 2 study of tarloxotinib in patients with NSCLC harboring EGFR exon 20 insertion or HER2-activating mutations (RAIN)

• Histologically and/or cytologically confirmed primary diagnosis of NSCLC, stage IV, stage IIIB or IIIC not amenable to definitive curative intent therapy, or recurrent disease after prior diagnosis of stage I-III disease
• Progression of disease on or after a platinum-based chemotherapy regimen
• EGFR exon 20 insertion mutation (Cohort A) or HER2 activating mutation (Cohort B)
• Measurable disease according to RECIST v.1.1
• ECOG performance status of 0 or 1
• Serum creatinine ≤ 1.5 x ULN (or calculated creatinine clearance ≥ 60 mL/min using Cockcroft Gault equation)
• Total bilirubin: ≤ 1.5 x ULN or ≤ 3 x ULN in the presence of liver metastases
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN, or ≤ 5 x ULN, in the presence of liver metastases
• Absolute neutrophil count (ANC) ≥ 1,500 cells/μL
• Hemoglobin ≥ 9 g/dL or 5.6 mmol/L
• Platelet count ≥ 100,000/μL
• No evidence of second or third degree atrioventricular block
• No clinically significant arrhythmia (i.e.; pauses of > 4 seconds, VT of any duration, SVT > 4 beats/minute)
• QRS interval ≤ 110 ms
• QTcF interval of < 450 ms
• PR interval ≤ 200 ms
• Adequate pretreatment tumor sample (125 µm of FFPE block or at least 8 prepared slides)

Excluding patients who meet the following criteria:

• Histologically and/or cytologically confirmed primary diagnosis of NSCLC, stage IV, stage IIIB or IIIC not amenable to definitive curative intent therapy, or recurrent disease after prior diagnosis of stage I-III disease
• Another known activating oncogene driver mutation
• Previously received anti EGFR or anti HER2 tyrosine kinase inhibitors
• Previously received anti EGFR or anti HER2 monoclonal antibodies or EGFR or HER2 antibody drug conjugates
• Investigational therapy administered within the 28 days or five half lives
• Chemotherapy or radiation within 14 days prior to Cycle 1 Day 1
• Immunotherapy within 21 days
• Clinically active or symptomatic interstitial lung disease (ILD) or interstitial pneumonitis, or a history of clinically significant ILD or radiation pneumonitis
• Untreated and/or symptomatic CNS malignancies (primary or metastatic);
• Receiving medication that prolongs QT interval, with a risk of causing Torsade de Pointes (TdP)
• Personal or familial history of Long QT Syndrome
• NYHA class III or IV or LVEF < 55 percent
• Myocardial infarction, severe or unstable angina within 6 months
• History of TdP, ventricular arrhythmia
• Significant thrombotic or embolic events within 3 months
• Uncontrolled or severe cardiovascular disease
• Concurrent malignancy expected to require treatment within 2 years or interfere with study outcomes
• History of severe allergic reactions or hypersensitivity to compounds of similar chemical or biologic composition as tarloxotinib
• Known HIV infection or active Hepatitis B or C