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

OBJECTIVES:

Primary

- To characterize the toxicity and determine the maximum-tolerated dose (MTD) of erlotinib
hydrochloride plus romidepsin. (Phase I)

- To obtain preliminary data regarding efficacy, including response rate and
progression-free survival. (Phase II)

Secondary

- To characterize the pharmacokinetic profile of romidepsin in combination with erlotinib
hydrochloride.

- To evaluate the impact of erlotinib hydrochloride on the biologic activity of romidepsin
by analyzing peripheral blood mononuclear cell (PBMC) histone acetylation status and
histone acetylase activity. (Exploratory)

- To evaluate the effect of romidepsin and erlotinib hydrochloride on components of the
EGFR-signaling pathway in skin biopsies, particularly downstream mediators such as MAPK.
(Exploratory)

OUTLINE: This is a dose-escalation study of romidepsin followed by a phase II study.

Patients receive romidepsin IV on days 1, 8, and 15 and erlotinib hydrochloride orally (PO)
once daily beginning on day 3 of course 1 and on days 1-28 of all subsequent courses. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection at baseline and periodically during study for
pharmacokinetic studies. Additional samples of peripheral blood mononuclear cells and skin
biopsies may be also collected for correlative studies.

After completion of study therapy, patients are followed up for 30 days.

PROJECTED ACCRUAL: A total of 39 patients (15 patients for phase I and 24 patients for phase
II) will be accrued for this study.

DISEASE CHARACTERISTICS:

- Histologically confirmed locally advanced or metastatic (stage IIIB pleural effusion
or stage IV) non-small cell lung cancer (NSCLC), including the following cell types:

- Squamous cell carcinoma

- Adenocarcinoma

- Adenosquamous carcinoma

- Large cell carcinoma

- Large cell neuroendocrine

- Carcinoma not otherwise specified

- Measurable disease as defined by RECIST

- Clinically stable brain metastases are permitted

PATIENT CHARACTERISTICS:

- ECOG performance status 0-1

- Serum potassium ≥ 3.8 mmol/L and magnesium ≥ 2.0 mg/dL

- Electrolyte abnormalities may be corrected with supplementation

- Hemoglobin ≥ 10 g/dL (transfusions and/or erythropoietin-stimulating agents are
permitted)

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Total bilirubin < 1.5 times upper limit of normal (ULN)

- AST and ALT < 2.0 times ULN (< 3 times ULN in the presence of demonstrable liver
metastases)

- Serum creatinine < 2.0 times ULN

- Not pregnant or nursing

- Negative urine or serum pregnancy test

- Women of childbearing potential and men must use an effective barrier method of
contraception (e.g., an intrauterine contraception device [IUCD], double-barrier
method using condoms, or a diaphragm plus spermicide) during the treatment period and
for at least 1 month thereafter

- No known cardiac abnormalities, including any of the following:

- Congenital long QT syndrome

- QTc interval > 480 msec

- Myocardial infarction within 12 months prior to study entry

- Other significant electrocardiogram (ECG) abnormalities, including type II
second- or third-degree atrio-ventricular (AV) block, or bradycardia (ventricular
rate < 50 beats/min)

- History of coronary artery disease (CAD) (e.g., angina Canadian class II-IV)

- For any patients in whom there is doubt, a stress-imaging study should be
performed and if abnormal, an angiography should also be performed 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)

- NYHA class II to IV congestive heart failure (CHF), and/or ejection fraction (EF)
< 40% by MUGA scan or < 50% by ECG and/or MRI

- 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

- Uncontrolled hypertension defined as blood pressure ≥ 160/95 mm Hg

- Any cardiac arrhythmia requiring anti-arrhythmia medication

- No clinically significant active systemic, pulmonary, or pericardial infection,
including known HIV infection and hepatitis B or C

- No significant medical or psychiatric condition that might prevent the patient from
complying with all study procedures

PRIOR CONCURRENT THERAPY:

- At least 3 weeks since prior erlotinib hydrochloride (phase I)

- At least 3 weeks since prior anti-cancer therapy or, at the discretion of the
investigator, may be treatment-naive (phase I)

- At least 1 and no more than 2 prior chemotherapy regimens for advanced NSCLC (phase
II)

- At least 3 weeks since prior chemotherapy for NSCLC

- At least 2 weeks since prior major surgery or radiation therapy

- No prior erlotinib hydrochloride (phase II)

- No prior romidepsin

- No other concurrent anti-cancer therapy

- No prior or concurrent investigational agent within 4 weeks prior to study entry

- No concurrent drugs that may cause a prolongation of the QTc interval

- No concurrent CYP3A4 inhibitors

- No concurrent warfarin