FR901228 and Flavopiridol in Treating Patients With Advanced Lung, Esophageal, or Pleural Cancer

RATIONALE: Drugs used in chemotherapy, such as FR901228 and flavopiridol, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving FR901228 together with flavopiridol may kill more tumor cells.

Date First Received: December 7, 2004

Last Updated: February 27, 2008

Verified by: National Cancer Institute (NCI), September 2007

Clinical Trial Phase: Phase 1 | Start Date: November 2004

Overall Status: Recruiting

Estimated Enrollment: 48

Brief Summary

Official Title: “Phase I Study Of Sequential Depsipeptide/Flavopiridol Infusion for Malignancies Involving Lungs, Esophagus, Pleura or Mediastinum”

Condition Keyword(s):

• Esophageal Cancer
• Lung Cancer
• Malignant Mesothelioma
• Metastatic Cancer

Intervention(s):

• Drug: alvocidib
• Drug: romidepsin
• Procedure: chemosensitization/potentiation therapy
• Procedure: chemotherapy
• Procedure: enzyme inhibitor therapy

PURPOSE: This phase I trial is studying the side effects and best dose of FR901228 when given together with flavopiridol in treating patients with advanced lung, esophageal, or pleural cancer.

Study Type: Interventional

Study Design: Treatment

Detailed Clinical Trial Description

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.

Criteria for Participation in this Clinical Trial

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 expectancty - 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 <>
• 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 <>
• 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 <>
• 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

Clinical Trials Locations, Contact Details, and Sponsors

Lead Sponsor: National Cancer Institute (NCI)

NCI - Center for Cancer Research

Bethesda Maryland 20892 United States

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office

Bethesda Maryland 20892-1182 United States

Overall Clinical Trial Officials and Contacts

David S. Schrump, MD Study Chair NCI - Surgery Branch

Additional Information

Information obtained from ClinicalTrials.gov on April 29, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00098644

Study ID Number: CDR0000398184

ClinicalTrials.gov Identifier: NCT00098644

Health Authority: Unspecified

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