Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Decitabine and FR901228 in Treating Patients With Advanced Lung Cancer, Esophageal Cancer, Pleural Mesothelioma, or Lung Metastases

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Active	18 and over	NCI	NCI-02-C-0205 NCI-5270, 5270, NCT00041158

Special Category: NIH Clinical Center trial

Objectives

1. Determine the pharmacokinetics, toxicity, and maximum tolerated dose of decitabine and FR901228 (depsipeptide) in patients with unresectable pulmonary, esophageal, or pleural malignancies.
2. Determine serologic response to NY-ESO-1 in these patients before and after receiving this regimen.
3. Evaluate apoptosis in tumor biopsies of these patients before and after receiving this regimen.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed primary small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), advanced esophageal cancer, or pleural mesothelioma
  • Cancers of non-thoracic origin with metastases to the lungs or pleura eligible
  • Unresectable disease



• Primary or metastatic disease must be accessible for biopsy by endoscopic or percutaneous fine-needle aspiration techniques



• No limited stage SCLC or operable NSCLC



• No active intracranial or leptomeningeal metastases
  • Patients with prior intracranial metastases that have been treated with prior surgery or radiotherapy are eligible provided there is no evidence of active disease and no requirement for anticonvulsant therapy or steroids after treatment

Prior/Concurrent Therapy:

Biologic therapy:

• At least 30 days since prior anticancer biologic therapy

Chemotherapy:

• At least 30 days since prior anticancer chemotherapy
• Prior decitabine or FR901228 (depsipeptide) allowed provided no dose-limiting toxicity was experienced at the scheduled dose

Endocrine therapy:

• See Disease Characteristics

Radiotherapy:

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

Surgery:

• See Disease Characteristics

Other:

• No more than 2 prior systemic cytotoxic treatment regimens
• At least a 5 half-life washout period since and no concurrent medication causing corrected QT interval (QTc) prolongation
• No concurrent medication causing corrected QTc prolongation
• No concurrent anticonvulsants
• No concurrent hydrochlorothiazide diuretics
• No concurrent digitalis

Patient Characteristics:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• At least 3 months

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm³ (without cytokine support)
• Platelet count greater than 100,000/mm³ (without transfusion)

Hepatic:

• Bilirubin less than 1.5 times upper limit of normal
• PT normal

Renal:

• Creatinine no greater than 1.6 mg/dL

  OR

• Creatinine clearance greater than 70 mL/min

Cardiovascular:

• LVEF less than 50% by MUGA scan or echocardiogram
• No New York Heart Association class III or IV heart disease (i.e., decompensated heart failure)
• No myocardial infarction within the past year
• No uncontrolled arrhythmias
• No prior serious ventricular arrhythmias not controlled by coronary artery bypass surgery
• No prosthetic heart valves requiring anticoagulation
• No deep venous thrombosis
• No left ventricular hypertrophy
• No history of sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, or cardiac arrest without currently having an automatic implantable cardioverter defibrillator in place
• No congenital long QT syndrome or QTc > 480 msec
• No Mobitz II second degree block without currently having a pacemaker in place
• No cardiac arrhythmias requiring antiarrhytmic medication except a beta blocker or calcium channel blocker
• No hypertrophic or restrictive cardiomyopathy from prior treatment of other causes
• No uncontrolled hypertension (i.e., blood pressure ≥160/95)
• No clinically significant active myocardial ischemia on the basis of nuclear imaging or angiography
• No history of coronary artery disease (e.g., angina Canadian Class II-IV or positive stress imaging study)
• No evidence of cardiac ischemia (e.g., ST depression greater than or equal to 2 mm) by EKG
• First degree or Mobitz second degree block, bradyarrhythmias, or sick sinus syndrome allowed provided patient undergo Holter monitoring and cardiac evaluation

Pulmonary:

• FEV₁ and DLCO greater than 30% predicted
• Partial pressure of carbon dioxide (pCO₂) less than 50 mm Hg on room air
• Partial pressure of oxygen (pO₂) greater than 60 mm Hg on room air
• No pulmonary embolism

Other:

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

Expected Enrollment

A maximum of 40 patients will be accrued for this study within 10.8-13.5 months.

Outline

This is a dose-escalation study.

Patients receive decitabine IV continuously on days 1-3 and FR901228 (depsipeptide) IV over 4 hours on days 4 and 10. Courses repeat every 33-36 days in the absence of disease progression or unacceptable toxicity.

Sequential dose escalation of decitabine is followed by sequential dose escalation of FR901228. Cohorts of 3-6 patients receive escalating doses of decitabine and then FR901228 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Once the MTD is determined, two additional cohorts (6 lung cancer and 6 mesothelioma patients) receive decitabine and FR901228 as above at the MTD. These patients also receive oral celecoxib twice daily on days 4-34 of each course.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

David Schrump, MD, Protocol chair		Ph: 301-451-1233 Email: david_schrump@nih.gov

U.S.A.
Maryland
	Bethesda
	NCI - Center for Cancer Research
		Tricia Kunst, RN	Ph:  301-451-1233
			Email: tricia_kunst@nih.gov
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937

Related Information

Web site for additional information

Registry Information
Official Title		Phase I Study of Gene Induction Mediated by Sequential Decitabine/Depsipeptide Infusion in Subjects with Pulmonary and Pleural Malignancies
Trial Start Date		2002-05-21
Trial Completion Date		2003-07-15 (estimated)
Registered in ClinicalTrials.gov		NCT00041158
Date Submitted to PDQ		2002-05-16
Information Last Verified		2008-11-30