Romidepsin and Erlotinib Hydrochloride in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer

To be eligible for study participation, patients must fulfill all of the following criteria:

• Histologically confirmed locally advanced or metastatic (stage IIIB pleural effusion or stage IV) NSCLC;
• Age ≥ 18 years;
• Written informed consent;
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST);
• ECOG (Eastern Cooperative Oncology Group ) performance status 0 to 1;
• Serum potassium and magnesium greater than or equal to the lower limit of institutional normal range (electrolyte abnormalities may be corrected with supplementation to meet inclusion criteria);
• Negative urine or serum pregnancy test on females of childbearing potential;
• All women of childbearing potential must use an effective barrier method of contraception (an intrauterine contraceptive device [IUCD] or double barrier method using condoms or a diaphragm plus spermicide) during the treatment period and for at least 1 month thereafter. Male patients should use a barrier method of contraception during the treatment period and for at least 1 month thereafter. Hormonal methods of contraception such as the contraceptive pill or patch (particularly those containing ethinyl-estradiol) should be avoided due to a potential drug interaction (see Appendix D).
• Adequate bone marrow, liver, and renal function as evidenced by
• Hemoglobin ≥10 g/dL (transfusions and/or erythropoietin-stimulating agents are permitted)
• Absolute neutrophil count (ANC) ≥1.5 x 109 cells/L • Platelet count ≥100 x 109 cells/L
• Total bilirubin <1.5 x upper limit of normal (ULN)
• (Aspartate amino transferase) AST/SGOT(serum glutamic-oxaloacetic transaminase) and (amino alanine transferase) ALT/SGPT (serum glutamic-pyruvic transaminase) <2.0 x upper limit of normal (ULN) or <3.0 x ULN in the presence of demonstrable liver metastases
• Serum creatinine <2.0 x ULN
• Clinically stable brain metastases are permitted

Phase I study:

• Prior erlotinib therapy is permitted (with a 3-week washout period)
• Patients may have received prior anti-cancer therapy (with a 3-week washout period) or, at the discretion of the investigator, may be treatment-naïve

Phase II study:

• Patients must have received at least one and no more than two prior chemotherapy regimens for their advanced NSCLC
• Patients may not have received prior erlotinib

Patients are ineligible for entry if any of the following criteria are met:

• Chemotherapy for NSCLC within 3 weeks prior to study entry;
• Concomitant use of any other anti-cancer therapy;
• Concomitant use of any investigational agent;
• Use of any investigational agent within 4 weeks prior to study entry;
• Any known cardiac abnormalities such as:
• Congenital long QT syndrome;
• QTc interval (corrected QT interval) Myocardial infarction within 12 months prior to study entry;
• Other significant ECG abnormalities including type II second-degree atrio ventricular (AV) block, third-degree AV block, or bradycardia (ventricular rate < 50 beats/min); o A history of coronary artery disease (CAD); eg, angina Canadian Class II-IV. In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
• An ECG recorded at screening showing significant ST depression (ST depression of ≥2 mm, measured from isoelectric line to the ST segment at a point 60 msec from the end of the QRS complex). If there is any doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present;
• Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction < 40% by MUGA ( multiple gated acquisition) scan or <50% by echocardiogram and/or MRI;
• A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsades de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardiac defibrillator (AICD);
• Hypertrophic cardiomyopathy or restrictive cardiomyopathy from prior treatment or other causes (if there is any doubt, see ejection fraction criteria above);
• Uncontrolled hypertension (defined as blood pressure [BP] ≥160/95; or
• Any cardiac arrhythmia requiring anti-arrhythmic medication;
• Serum potassium or serum magnesium below lower limit of institutional normal range (electrolyte abnormalities may be corrected with supplementation to meet inclusion criteria)
• Concomitant use of drugs that may cause a prolongation of the QTc interval .
• Concomitant use of CYP3A4 inhibitors
• Concomitant use of warfarin (due to a potential drug interaction);
• Clinically significant active infection (including known infection with human immunodeficiency virus [HIV], hepatitis B, or hepatitis C); l >480 milliseconds (msec);
• Major surgery or radiation within 2 weeks prior to study entry;
• Patients who are pregnant or breast-feeding;
• Any significant medical or psychiatric condition that might prevent the patient from complying with all study procedures;
• Prior exposure to romidepsin