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

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

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.

Study Overview

• Status: Completed
• Conditions: Gastrointestinal Stromal Tumor; Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Adult Rhabdomyosarcoma; Metastatic Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Synovial Sarcoma; Adult Alveolar Soft-part Sarcoma; Adult Extraskeletal Chondrosarcoma; Adult Malignant Fibrous Histiocytoma; Adult Malignant Hemangiopericytoma; Adult Neurofibrosarcoma
• Intervention / Treatment: Drug: romidepsin

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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (single-agent depsipeptide); 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; DEP is administered at a dose of 13 mg/m2 as a 4-hour intravenous infusion in the outpatient setting.; Other Names: FK228; FR901228; 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

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Paul Savage, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): January 7, 2005
• Primary Completion (Actual): October 23, 2008
• Study Completion (Actual): October 23, 2008

Study Registration Dates

• First Submitted: June 2, 2005
• First Submitted That Met QC Criteria: June 2, 2005
• First Posted (Estimate): June 3, 2005

Study Record Updates

• Last Update Posted (Actual): June 14, 2017
• Last Update Submitted That Met QC Criteria: May 18, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Neuromuscular Diseases; Neoplasms, Neuroepithelial; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Neoplasms, Complex and Mixed; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Vascular Tissue; Neoplasms, Muscle Tissue; Nerve Sheath Neoplasms; Peripheral Nervous System Neoplasms; Neoplasms, Adipose Tissue; Myosarcoma; Neoplasms, Fibrous Tissue; Neurofibroma; Sarcoma; Recurrence; Sarcoma, Ewing; Gastrointestinal Stromal Tumors; Osteosarcoma; Leiomyosarcoma; Liposarcoma; Rhabdomyosarcoma; Chondrosarcoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Hemangiosarcoma; Neurofibrosarcoma; Sarcoma, Synovial; Hemangiopericytoma; Solitary Fibrous Tumors; Sarcoma, Alveolar Soft Part; Histiocytoma, Malignant Fibrous; Fibrosarcoma; Histiocytoma; Histiocytoma, Benign Fibrous; Mesenchymoma; Antineoplastic Agents; Antibiotics, Antineoplastic; Romidepsin
• Other Study ID Numbers: NCI-2012-01037 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA012197 (U.S. NIH Grant/Contract); U10CA081851 (U.S. NIH Grant/Contract); CCCWFU 71103 (Other Identifier: Wake Forest University Health Sciences); 6319 (CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No