Depsipeptide (Romidepsin) in Treating Patients With Metastatic or Unresectable Soft Tissue Sarcoma

PRIMARY OBJECTIVES:

I. To estimate the response rates of metastatic or unresectable soft tissue sarcomas to single-agent depsipeptide.

II. To estimate the time to progression of metastatic or unresectable soft tissue sarcomas to single-agent depsipeptide.

III. To evaluate the scope and extent of acute toxicities associated with single-agent depsipeptide when given to patients with soft tissue sarcomas.

OUTLINE: This is a multicenter study.

Patients receive depsipeptide (romidepsin) intravenously (IV) over 4 hours on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients achieving a complete response (CR) receive 6 additional courses beyond documentation of CR.

After completion of study treatment, patients are followed up every 2 months.

Inclusion criteria

• Histologically or cytologically confirmed soft tissue sarcoma (STS), including, but not limited to, the following histologies:

• Gastrointestinal stromal tumors (GIST)

• Refractory to imatinib mesylate
• Desmoplastic small round cell tumors
• Clear cell sarcoma
• Extraskeletal osteosarcoma*
• Extraskeletal Ewing's sarcoma*
• Extraskeletal (myxoid) chondrosarcoma*
• Secondary STS (e.g., radiation-induced STS or neurofibrosarcoma due to neurofibromatosis) allowed
• Metastatic or unresectable disease
• No standard curative therapy exists
• Patients with GIST must have received and progressed on imatinib mesylate
• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
• No known brain metastases
• Performance status - Eastern Cooperative Oncology Group (ECOG) 0-2
• Performance status - Karnofsky 50-100%
• More than 3 months
• White blood cells (WBC) ⥠3,000/mm^3
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ⤠2.5 times upper limit of normal (ULN)
• Bilirubin normal
• Creatinine < 1.5 times ULN
• Creatinine clearance ≥ 60 mL/min
• QTc ≤ 480 msec

Exclusion criteria

• No cardiac abnormalities (e.g., congenital long QT syndrome)
• No myocardial infarction within the past year
• No history of coronary artery disease (e.g., angina Canadian Class II-IV or positive stress imaging study)
• No cardiac ischemia (ST depression >2 mm) by electrocardiogram (ECG)
• No New York Heart Association Class II-IV congestive heart failure
• Ejection fraction > 50% by multi gated acquisition scan (MUGA) scan or echocardiogram
• No history of sustained ventricular tachycardia, ventricular fibrillation, Torsades de Pointes, or cardiac arrest unless controlled by an automatic implantable cardioverter defibrillator
• No hypertrophic or restrictive cardiomyopathy from prior treatment or other causes
• No significant left ventricular hypertrophy
• No uncontrolled hypertension (i.e., blood pressure ≥ 160/95 mm Hg)
• No cardiac arrhythmia requiring anti-arrhythmic medication

• Beta blocker or calcium channel blocker allowed
• Patients on digitalis that cannot be discontinued not allowed
• No Mobitz II second degree block without a pacemaker (first degree or Mobitz I second degree block, bradyarrhythmias, or sick sinus syndrome require Holter monitoring and evaluation by cardiology)
• No uncontrolled dysrhythmia
• No poorly controlled angina
• No other cardiac disease
• No history of allergic reaction attributed to compounds of similar chemical or biological composition to FR901228
• No ongoing or active infection
• No iatrogenic immune deficiency or immune deficiency secondary to an underlying disorder
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Potassium ≥ 4.0 mmol/L
• Magnesium ≥ 2.0 mg/dL
• No other uncontrolled illness
• No psychiatric illness or social situation that would preclude study compliance
• No concurrent anticancer biologic agents
• No more than 1 prior chemotherapy regimen for sarcoma

• Adjuvant chemotherapy preceding disease relapse is considered 1 prior chemotherapy regimen
• Patients with GIST may have received up to 3 prior chemotherapy regimens comprising imatinib mesylate and/or sunitinib malate provided no other chemotherapy agents were used
• No prior FR901228 (depsipeptide)
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• No prior cumulative doxorubicin dose > 500 mg/m^2
• No other concurrent anticancer chemotherapy
• At least 4 weeks since prior radiotherapy
• No concurrent anticancer radiotherapy
• At least 4 weeks since prior surgery
• No prior organ transplantation
• Recovered from all prior therapy
• No concurrent medications that cause QTc prolongation
• No concurrent combination highly active anti-retroviral therapy for HIV-positive patients
• No other concurrent drugs known to have histone deacetylase inhibitor activity (e.g., sodium valproate)
• No other concurrent investigational agents
• No other concurrent anticancer agents