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

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well depsipeptide (romidepsin) works in treating patients with metastatic or unresectable soft tissue sarcoma. Drugs used in chemotherapy, such as depsipeptide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase II Study of Single Agent Depsipeptide (FK228) in Metastatic or Unresectable Soft Tissue Sarcomas

Conditions
-----------------
Adult Alveolar Soft-part Sarcoma, Adult Angiosarcoma, Adult Epithelioid Sarcoma, Adult Extraskeletal Chondrosarcoma, Adult Extraskeletal Osteosarcoma, Adult Fibrosarcoma, Adult Leiomyosarcoma, Adult Liposarcoma, Adult Malignant Fibrous Histiocytoma, Adult Malignant Hemangiopericytoma, Adult Malignant Mesenchymoma, Adult Neurofibrosarcoma, Adult Rhabdomyosarcoma, Adult Synovial Sarcoma, Gastrointestinal Stromal Tumor, Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Recurrent Adult Soft Tissue Sarcoma, Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
-----------------
* Drug: romidepsin


Participation Criteria
=================
Eligibility Criteria
-----------------
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) â¥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) â¤ 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (single-agent depsipeptide)<br>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. | Drug: romidepsin<br>* DEP is administered at a dose of 13 mg/m2 as a 4-hour intravenous infusion in the outpatient setting.<br>* Other names: Istodax;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response (Complete and Partial) | Objective tumor response was evaluated using the criteria proposed by the Response Evaluation Criteria In Solid Tumors (RECIST) Committee (JNCI 92(3):205-216,2000). Changes in only the largest diameter (unidimensional measurement) of the target lesions are used. A sum of the longest diameter (LD) for all target lesions was calculated and reported as the baseline sum LD. The baseline sum LD was used as reference by which to characterize the objective tumor response. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum LD; Overall Response (OR) = CR + PR | While on treatment - max of 16 months | 
| Time to Progression | Progressive disease is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameters (LD) of target lesions, taking as reference the smallest sum LD recorded since treatment started, or a measurable increase in a non-target lesion, or the appearance of new lesions. Time to progression is the number of months from first treatment until the date of progression. | Until disease progression - max of 48 months | 
| Toxicity as Assessed Using the Expanded Common Toxicity Criteria Version 3 | The outcome reported here is the number (%) of participants who experienced grade 3 or greater toxicity while on study. A summary of the individual toxicities can be found in the AE/SAE results. | During treatment (max of 16 months) and for 1 month following treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Months from first treatment until death or the last date of contact | Max of 98 months |