OBJECTIVES:

Primary

• Determine the maximum tolerated dose and dose-limiting toxic effects of FR901228 (depsipeptide) when administered with flavopiridol in patients with advanced primary lung or esophageal cancer, malignant pleural mesothelioma, or lung or pleural metastases.
• Determine the pharmacokinetics of this regimen in these patients.

Secondary

• Analyze gene expression in laser-captured tumor cells, buccal mucosa, and peripheral blood mononuclear cells of these patients before and after treatment with this regimen.
• Analyze mcl-1 protein expression and apoptosis in tumor biopsies from these patients before and after treatment with this regimen.

OUTLINE: This is a dose-escalation study of FR901228 (depsipeptide).

Patients receive FR901228 IV over 4 hours followed by flavopiridol IV continuously over 72 hours beginning on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of FR901228 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Six additional patients receive treatment at the MTD.

PROJECTED ACCRUAL: A total of 48 patients will be accrued for this study within 1-2 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed advanced malignancy of 1 of the following types:

  • Primary small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC)

    • No limited-stage SCLC or operable NSCLC

  • Esophageal cancer

    • Inoperable disease
  • Malignant pleural mesothelioma
  • Epithelial thymoma

  • Cancer of nonthoracic origin with metastases to the lungs or pleura

    • No potentially treatable pulmonary metastases from lymphomas or germ cell tumors
• Tumor must be amenable to biopsy by endoscopic or percutaneous fine needle aspiration techniques
• Chemonaïve patients allowed provided they refused potentially effective first-line chemotherapy

• Intracranial or leptomeningeal metastases allowed provided the following are true:

  • Treated by surgery or radiotherapy
  • No evidence of active disease
  • No requirement for anticonvulsant therapy or steroids

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 3 months

Hematopoietic

• Platelet count > 100,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3 (transfusion and cytokine independent)

Hepatic

• PT normal
• Bilirubin < 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 1.5 times ULN

Renal

• Creatinine ≤ 1.6 mg/dL OR
• Creatinine clearance > 70 mL/min

Cardiovascular

• No myocardial infarction within the past 6 months
• Ejection fraction ≥ 45%
• QTc ≤ 500 msec
• No unstable angina
• No cardiac ischemia
• No left ventricular hypertrophy
• No deep venous thrombosis requiring anticoagulation within the past 6 months

• No known cardiac abnormalities including any of the following:

  • Uncontrolled arrhythmias
  • History of sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, or cardiac arrest without an automatic implantable cardioverter defibrillator in place
  • Congenital long QT syndrome or QTc > 480 msec
  • Mobitz II second degree block without a pacemaker in place

  • Any cardiac arrhythmia requiring antiarrhythmic medication

    • Beta blockers and calcium channel blockers allowed
  • New York Heart Association class II or IV decompensated heart failure
  • Left ventricular ejection fraction < 50% by MUGA scan or echocardiogram
  • Hypertrophic or restrictive cardiomyopathy from prior treatment or other causes
  • Left ventricular hypertrophy
  • Uncontrolled hypertension (i.e., blood pressure ≥ 160/95)
  • Myocardial infarction within the past year
  • Clinically significant active myocardial ischemia by nuclear imaging or angiography
  • History of coronary artery disease (e.g., Canadian class II-IV angina or positive stress imaging study)

Pulmonary

• FEV_1 and DLCO > 30% of predicted
• pCO_2 < 50 mm Hg by arterial blood gas (ABG) on room air
• pO_2 > 60 mm Hg by ABG on room air
• No pulmonary embolism requiring anticoagulation within the past 6 months

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active infection
• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 30 days since prior biologic therapy for the malignancy
• No concurrent cytokine support

Chemotherapy

• See Disease Characteristics
• Prior FR901228 (depsipeptide) or flavopiridol allowed provided patient did not experience dose-limiting toxicity at the dose they are scheduled to receive on study
• At least 30 days since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) for the malignancy

Endocrine therapy

• See Disease Characteristics

Radiotherapy

• See Disease Characteristics
• At least 30 days since prior radiotherapy for the malignancy
• At least 14 days since prior localized radiotherapy to non-target lesions and recovered

Surgery

• See Disease Characteristics

Other

• No more than 2 prior systemic cytotoxic treatment regimens
• No concurrent hydrochlorothiazide
• No concurrent digoxin