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

Phase 2

Completed

Conditions: Adult Extraskeletal Osteosarcoma
Adult Malignant Mesenchymoma
Adult Extraskeletal Chondrosarcoma
Adult Fibrosarcoma
Adult Alveolar Soft-part Sarcoma
Adult Angiosarcoma
Adult Leiomyosarcoma
Adult Liposarcoma
Recurrent Adult Soft Tissue Sarcoma
Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

Interventions: Drug: romidepsin

Registration Number: NCT00112463

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (single-agent depsipeptide)	romidepsin	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.

Primary Outcome Measures

Name	Time	Method
Objective Tumor Response (Complete and Partial)	While on treatment - max of 16 months	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
Time to Progression	Until disease progression - max of 48 months	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.
Toxicity as Assessed Using the Expanded Common Toxicity Criteria Version 3	During treatment (max of 16 months) and for 1 month following treatment	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.