Phase I Study of Sequential Depsipeptide/Flavopiridol Infusion for Malignancies Involving Lungs, Esophagus, Pleura, Thymus or Mediastinum

Inclusion Criteria

- INCLUSION CRITERIA:

1. Patients with histologically or cytologically proven small cell or non-small
cell lung cancers, esophageal cancers, malignant pleural mesotheliomas chest
wall sarcoma, or epithelial thymomas are eligible for evaluation. In addition,
patients with cancers of nonthoracic origin with metastases to the lungs, pleura
or germ cell tumors refractory to standard therapy are eligible for evaluation.

2. Chemo naive patients with inoperable lung and esophageal cancers, pleural
mesotheliomas, sarcoma, thymomas, as well as tumors of non-thoracic origin with
metastasis within the thorax may be eligible for study provided they have been
apprised of, and refused potentially effective first line chemotherapy.

3. Patients with intracranial metastases which have been treated by surgery or
radiation therapy may be eligible for study provided there is no evidence of
active disease and no requirement for anticonvulsant therapy or steroids.

4. Patients with prior Depsipeptide or Flavopiridol exposure are eligible for study
provided they have not experienced dose limiting toxicity at the dose of DP or
FLA that they are scheduled to receive.

5. Patients must have had no chemotherapy, biologic therapy, or radiation therapy
for their malignancy for at least 30 days prior to treatment. At least six
weeks must elapse between mitomycin C or nitrosourea treatment and DP/FLA
therapy. Patients may have received localized radiation therapy to non-target
lesions provided that the radiotherapy is completed 14 days prior to commencing
therapy, and the patient has recovered from any toxicity.

6. Patients must have an ECOG performance status of 0 - 2.

7. Patients must have adequate pulmonary reserve evidenced by FEV1 and DLCO greater
than the 30% predicted, and pCO2 less than 50 mm Hg and pO2 greater than 60 mm
Hg on room air ABG.

8. Patients must be 18 years of age or older due to the unknown effects of HDAC
inhibitors and cdk inhibitors during childhood and adolescent development.

9. Patients must have a platelet count greater than 100,000, an ANC equal to or
greater than 1500 without transfusion or cytokine support, a normal PT, and
adequate hepatic function as evidenced by a total bilirubin of less than 1.5 x
upper limits of normal, and AST/ALT less than or equal to 1.5 times upper limit
of normal. Serum creatinine less than or equal to 1.6 mg/ml or the creatinine
clearance must be greater than 70 ml/min/1.73m(2).

10. Patients must be aware of the neoplastic nature of his/her illness, the
experimental nature of the therapy, alternative treatments, potential benefits,
and risks. The patient must be willing to sign an informed consent.

EXCLUSION CRITERIA:

1. Patients with limited stage SCLC and operable NSCLC or operable esophageal cancer
will be excluded.

2. Patients with potentially treatable pulmonary metastases from lymphomas or germ cell
tumors will be excluded.

3. Patients who have received three or more systemic cytotoxic treatment regimens will
be excluded due to possible cumulative marrow suppression.

4. Cardiac exclusion criteria, patients with known cardiac abnormalities such as:

Uncontrolled arrhythmias

- History of serious ventricular arrhythmias not controlled by coronary artery
bypass surgery.

- Patients with a history of sustained VT, VF, Toursades de Pointes, or cardiac
arrest who do not have an automatic implantable cardioverter defibrillator in
place.

- Congenital Long QT syndrome or QTc greater than 480 msec.

- Patients with Mobitz II second degree block who do not have a pacemaker.

- Patients with any cardiac arrhythmia requiring anti-arrhythmic medication other
than a beta blocker or calcium channel blocker.

- Patients in whom digitalis cannot be discontinued.

Decompensated heart failure (NYHA Class II or IV).

LVEF less than 50% by MUGA scan or echocardiogram.

Hypertrophic or restrictive cardiomyopathy from prior treatment of other causes
and patients with left ventricular hypertrophy.

Uncontrolled hypertension (i.e. greater than or equal to160/95).

Myocardial infarction within one year of study.

Clinically significant active myocardial ischemia on the basis of nuclear imaging or
angiography.

History of coronary artery disease (e.g. angina Canadian Class II-IV or positive
stress imaging study).

Patients with other cardiac disease may be excluded at the discretion of the PI
following consultation with cardiology.

5. Co-medication causing QTc prolongation (information at Appendix A and
http://georgetowncert.org/gqdrugs_torsades.asp) unless a 5 half-life washout period
has elapsed between discontinuing the drug and entering this study.

6. Patients with active intracranial and leptomeningeal metastases, as well as those
requiring anticonvulsant medications or steroids to control cerebral edema will be
excluded.

7. Patients with life expectancy less than three months will be excluded.

8. Patients with pulmonary embolism or deep venous thrombosis requiring anticoagulation
within six months of protocol entry will be excluded.

9. Pregnant patients and nursing mothers will be excluded due to the unknown,
potentially harmful effects of HDAC inhibitors and cdk inhibitors on fetal and early
childhood development.

10. Patients with active infections will be excluded.

11. Patients with HIV infection will be excluded due to the potential risk of
opportunistic infection during DP/FLA-induced myelosuppression and potentially
deleterious activation of viral gene expression.

12. Patients will have a screening 12 lead EKG and those patients with left ventricular
hypertrophy will not be eligible.

13. Patients who are taking hydrochlorothiazide (HCTZ) will have this agent stopped or
switched to a potassium-conserving combination (e.g. Maxide or Dyazide) or other
antihypertensive agent. Patients, who cannot have the agent stopped or switched to a
potassium-conserving combination or other antihypertensive agent, will not be
eligible.