A Phase 1/2 Trial of Trametinib and Erlotinib in Patients With EGFR-Mutant Lung Adenocarcinomas and Acquired Resistance to Erlotinib

A Phase 1/2 Trial of Trametinib and Erlotinib in Patients With EGFR-Mutant Lung Adenocarcinomas and Acquired Resistance to Erlotinib

The purpose of this study is to determine the safety, tolerability and overall response rate of trametinib when given in combination with erlotinib in patients with Stage IV or recurrent lung adenocarcinoma that cannot be treated with curative intent.

Inclusion Criteria:

• Pathologic evidence of advanced stage IV or recurrent lung adenocarcinoma reviewed at MSKCC
• Somatic activating mutation in EGFR Radiographic progression during treatment with erlotinib.
• Any number of prior chemotherapy regimens is permitted.
• Measurable (RECIST 1.1) indicator lesion not previously irradiated
• KPS >/= 70%
• Age >18 years old
• Must have undergone biopsy after development of acquired resistance to erlotinib with available archived tissue (equivalent of > 10 unstained slides)
• Left ventricular Ejection Fraction >/= the lower limit of normal by ECHO or MUGA
• Adequate organ function:
• AST, ALT </= 2.5 x ULN
• Total bilirubin </= 1.5 x ULN
• Albumin>/=2.6g/dL - Creatinine < 1.5 x ULN OR calculated creatinine clearance >/=50mL/min
• Absolute neutrophil count (ANC) >/= 1,200 cells/mm3
• Hemoglobin>/=9.0 g/dL
• Platelets >/=100,000/mm3

Exclusion Criteria:

• Patients with symptomatic brain metastasis requiring escalating doses of steroids
• Patients with grade 2 or greater diarrhea prior to study initiation despite maximal medical management due to medications or a medical condition such as Crohn's disease or malabsorption
• Pregnant or lactating women
• Any type of systemic therapy (chemotherapy or experimental drugs) within 2 weeks of starting treatment on protocol except for a EGFR TKI
• Patients who have received prior treatment with a MEK inhibitor
• Any major surgery or extensive radiotherapy within 21 days of starting treatment on protocol.
• A history of clinically significant interstitial lung disease or pneumonitis
• Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months from Day 1 of study administration, New York Heart Association Class III or IV congestive heart failure, or symptomatic uncontrolled Arrythmias, prolonged corrected QT interval >480msec, treatment refractory hypertension, presence of a cardiac defibrillator
• History of central serous retinopathy or retinal vein occlusion