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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00112463
• Collaborator: (none)
• Enrollment: 40
• Arm: 1
• Actual Duration (Months): 45.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: romidepsin	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

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

3. 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 Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Single Agent Depsipeptide (FK228) in Metastatic or Unresectable Soft Tissue Sarcomas
• Actual Study Start Date: Jan 7, 2005
• Actual Primary Completion Date: Oct 23, 2008
• Actual Study Completion Date: Oct 23, 2008

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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

2. 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.

3. 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.

Secondary Outcome Measures

1. Survival [Max of 98 months]

   Months from first treatment until death or the last date of contact

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Paul Savage, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00112463
• Other Study ID Numbers: NCI-2012-01037; NCI-2012-01037; CCCWFU 71103; 6319; U10CA081851; P30CA012197; NCT01645683
• First Posted: Jun 3, 2005
• Last Update Posted: Jun 14, 2017
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Sarcoma; Osteosarcoma; Gastrointestinal Stromal Tumors; Rhabdomyosarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Leiomyosarcoma; Liposarcoma; Chondrosarcoma; Neuroectodermal Tumors, Primitive, Peripheral; Sarcoma, Synovial; Hemangiosarcoma; Fibrosarcoma; Sarcoma, Alveolar Soft Part; Histiocytoma; Hemangiopericytoma; Solitary Fibrous Tumors; Histiocytoma, Benign Fibrous; Histiocytoma, Malignant Fibrous; Mesenchymoma; Neurofibrosarcoma; Recurrence; Romidepsin

Study Results

Participant Flow

Arm/Group Title	Treatment (Single-agent Depsipeptide)
Arm/Group Description	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.
Period Title: Overall Study
STARTED	40
COMPLETED	1
NOT COMPLETED	39

Baseline Characteristics

Arm/Group Title	Treatment (Single-agent Depsipeptide)
Arm/Group Description	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.
Overall Participants	40
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 60%
>=65 years	16 40%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	19 47.5%
Male	21 52.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	40 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	5 12.5%
White	32 80%
More than one race	0 0%
Unknown or Not Reported	2 5%
Region of Enrollment (participants) [Number]
United States	40 100%

Outcome Measures

1. Primary Outcome

Title	Objective Tumor Response (Complete and Partial)
Description	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 Frame	While on treatment - max of 16 months

Outcome Measure Data

Analysis Population Description

Participants who were evaluable for response

Arm/Group Title	Treatment (Single-agent Depsipeptide)
Arm/Group Description	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.
Measure Participants	35
Count of Participants [Participants]	2 5%

2. Primary Outcome

Title	Time to Progression
Description	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.
Time Frame	Until disease progression - max of 48 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Treatment (Single-agent Depsipeptide)
Arm/Group Description	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.
Measure Participants	38
Median (95% Confidence Interval) [months]	1.9

3. Primary Outcome

Title	Toxicity as Assessed Using the Expanded Common Toxicity Criteria Version 3
Description	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.
Time Frame	During treatment (max of 16 months) and for 1 month following treatment

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Treatment (Single-agent Depsipeptide)
Arm/Group Description	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. romidepsin: DEP is administered at a dose of 13 mg/m2 as a 4-hour intravenous infusion in the outpatient setting.
Measure Participants	38
Count of Participants [Participants]	13 32.5%

4. Secondary Outcome

Title	Survival
Description	Months from first treatment until death or the last date of contact
Time Frame	Max of 98 months

Outcome Measure Data

Analysis Population Description

All treated participants

Arm/Group Title	Treatment (Single-agent Depsipeptide)
Arm/Group Description	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.
Measure Participants	38
Median (95% Confidence Interval) [months]	12.2

Adverse Events

Time Frame	During treatment (max of 16 months) and for 1 month following treatment
Adverse Event Reporting Description	Toxicities were evaluated weekly while the participant was on treatment
Arm/Group Title	Treatment (Single-agent Depsipeptide)
Arm/Group Description	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.
All Cause Mortality
	Treatment (Single-agent Depsipeptide)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Single-agent Depsipeptide)
	Affected / at Risk (%)	# Events
Total	13/38 (34.2%)
Blood and lymphatic system disorders
Coagulation - Other	1/38 (2.6%)	1
Cardiac disorders
Cardiac Arrhythmia - Other	3/38 (7.9%)	4
Cardiac Dysrhythmia	1/38 (2.6%)	1
Cardiac General - Other	2/38 (5.3%)	2
Endocrine disorders
Hyperglycemia	2/38 (5.3%)	3
Gastrointestinal disorders
Constipation	2/38 (5.3%)	2
GI - Other	1/38 (2.6%)	1
Nausea	3/38 (7.9%)	5
Vomiting	4/38 (10.5%)	5
Infections and infestations
Infection - Other	1/38 (2.6%)	1
Metabolism and nutrition disorders
Anorexia	2/38 (5.3%)	2
Dehydration	3/38 (7.9%)	4
Malise/Fatigue	1/38 (2.6%)	1
Metabolic - Other	3/38 (7.9%)	4
Weight Loss	1/38 (2.6%)	1
Nervous system disorders
Pain - Other	1/38 (2.6%)	2
Other (Not Including Serious) Adverse Events
	Treatment (Single-agent Depsipeptide)
	Affected / at Risk (%)	# Events
Total	38/38 (100%)
Blood and lymphatic system disorders
Coagulation - Other	3/38 (7.9%)	5
Hemoglobin	11/38 (28.9%)	84
Cardiac disorders
Cardiac Arrhythmia	5/38 (13.2%)	9
Caridac General - Other	4/38 (10.5%)	4
Endocrine disorders
Hot flashes/flushes	3/38 (7.9%)	19
Hyperglycemia	5/38 (13.2%)	14
Gastrointestinal disorders
Constipation	19/38 (50%)	82
Constitutional Symptioms - Other	13/38 (34.2%)	51
Diarrhea	8/38 (21.1%)	9
Dyspepsia/Heartburn	4/38 (10.5%)	20
GI - Other	25/38 (65.8%)	65
Nausea	26/38 (68.4%)	150
Vomiting	15/38 (39.5%)	42
Immune system disorders
AGC/ANC	3/38 (7.9%)	5
Infections and infestations
Fever in the absence of neutropenia	3/38 (7.9%)	4
Infection - Other	6/38 (15.8%)	10
Mucositis/stomatitis	4/38 (10.5%)	6
WBC	4/38 (10.5%)	11
Metabolism and nutrition disorders
Anorexia	9/38 (23.7%)	55
Malise/Fatigue	32/38 (84.2%)	198
Metabolic - Other	9/38 (23.7%)	21
Weight Gain	3/38 (7.9%)	3
Weight Loss	11/38 (28.9%)	18
Musculoskeletal and connective tissue disorders
Muscle weakness	5/38 (13.2%)	8
Musculoskeletal/Soft Tissue - Other	11/38 (28.9%)	23
Nervous system disorders
Dizziness	3/38 (7.9%)	16
Neurologic - Other	14/38 (36.8%)	59
Pain - Other	22/38 (57.9%)	123
Pain: Abdomen NOS	3/38 (7.9%)	8
Pain: Back	4/38 (10.5%)	5
Pain: Extremity-limb	4/38 (10.5%)	15
Pain: Head/Headache	4/38 (10.5%)	5
Pain: NOS	7/38 (18.4%)	22
Taste Alteration	7/38 (18.4%)	49
Renal and urinary disorders
Creatinine	3/38 (7.9%)	3
Renal/Genitourinary - Other	5/38 (13.2%)	7
Respiratory, thoracic and mediastinal disorders
Dyspnea/SOB	14/38 (36.8%)	26
Pulmonary Other	7/38 (18.4%)	18
Skin and subcutaneous tissue disorders
Dermatology/Skin	6/38 (15.8%)	11

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.