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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Lung Cancer Stage IV, Lung Adenocarcinoma, Lung Cancer, Lung Cancer Metastatic, Recurrent Lung Adenocarcinoma, Recurrent Lung Cancer

Intervention / Treatment
-----------------
* Drug: Trametinib
* Drug: Erlotinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Trametinib 1.5mg + Erlotinib 75mg
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trametinib 1.5mg + Erlotinib 75mg<br>Phase 1: Accrue 6 patients on Trametinib 1.5mg + Erlotinib 75mg by mouth once daily Phase 2: Accrue 24 patients (including 6 patients treated during Phase 1) on Trametinib 1.5mg + Erlotinib 75mg by mouth once daily or Trametinib 1.0mg + Erlotinib 100mg by mouth once daily. | Drug: Trametinib<br>* Trametinib 1.5mg once daily by mouth<br>Drug: Erlotinib<br>* Erlotinib 75mg once daily by mouth<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants Response Rate | Response and progression of disease will be evaluated in this study using interval imaging every 8 weeks with CT scan of the chest and imaging of any other target lesion with response evaluated by RECIST 1.1. | 2 years | 
| Number of Participants Evaluated for Toxicities | Safety and tolerability will be evaluated by systematic and regular toxicity evaluations. Toxicity will be graded according to NCI CTCAE version 4.0. | 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
erlotinib, trametinib, 15-098