Depsipeptide/Flavopiridol Infusion for Cancers of the Lungs, Esophagus, Pleura, Thymus or Mediastinum

Background:

In preclinical studies we have demonstrated that the histone deacetylase (HDAC) inhibitor
Depsipeptide FR901228 (DP) mediates cell cycle arrest and apoptosis in cultured lung and
esophageal cancer, and malignant pleural mesothelioma cells.

We have observed that the cdk inhibitor Flavopiridol (FLA) markedly potentiates
Depsipeptide-mediated apoptosis in cultured cancer cells, but not cultured normal epithelial
cells.

Patients with advanced malignancies involving lungs, esophagus, or pleura will receive 4-hour
Depsipeptide infusion followed by 72-hour FLA infusion using a phase I study design.

Tumor and buccal mucosa biopsies as well as PBMC may be obtained prior to, and after therapy
to evaluate gene expression using cDNA array long-oligo and protein lysate array techniques,
and determine if sequential DP/FLA mediates apoptosis in target tissues.

Results of these studies may provide the rationale for phase II evaluation of sequential
DP/FLA infusion in thoracic oncology patients.

Objectives:

Primary objectives:

To define the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of sequential 4
hour Depsipeptide(DP)/72 hour Flavopiridol (FLA)

To evaluate the pharmacokinetics of sequential DP/FLA infusion

Secondary objectives

To analyze gene expression profiles in laser-captured tumor cells, buccal mucosa, and PBMC
before and after sequential DP/FLA exposure.

To analyze mcl-1 protein expression and apoptosis in tumor biopsies before and after
sequential DP/FLA treatment.

Tertiary objectives:

The development of tissue and serum proteomic techniques to assess treatment response in
patients receiving sequential DP/FLA infusions.

Eligibility:

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

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

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

Patients must be 18 years of age or older.

Adequate organ function as evidenced by standard laboratory parameters.

The patient must be willing to sign an informed consent.

Design:

A phase 1 study where patient cohorts will receive escalating doses of Depsipeptide,
administered on day 1 and day 21, and a dose of flavopiridol (either 40 mg/m2/d or 50
mg/m2/d) administered on days 1-3, and 21-24 of a 42-day course.

Pharmacokinetics, systemic toxicity, and response to therapy will be recorded.

Two cycles of therapy (one course) will be administered, following which treatment evaluation
will be performed using standard clinical criteria.

48 patients will be enrolled over a period of 2-4 years.

- 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.