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Depsipeptide to Treat Patients With Cutaneous T-Cell Lymphoma and Peripheral T-Cell Lymphoma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
James Gulley, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00007345
First received: December 16, 2000
Last updated: April 13, 2017
Last verified: April 2017
December 16, 2000
April 13, 2017
March 8, 2001
January 26, 2015   (Final data collection date for primary outcome measure)
  • Number of Participants With a Response [ Time Frame: up to 56.5 days ]
    A rigorous composite assessment was employed with uni-dimensional measurements of skin and visceral disease sites assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) required clearing of all known disease sites. Partial response (PR) required documented response in skin (≥ 30% per RECIST) or lymph nodes (≥ 50% per the International Working Group (IWG) criteria, with response in both compartments for a determination of PR, IWG guidelines. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive disease (PD) is at least a 20% increase in the sum of the target lesions, or the appearance of one or more new lesions. Lymph node disease was assessed bi-dimensionally using the IWG criteria. Bone marrow involvement, as recommended by IWG criteria, and presence of circulating malignant T-cells ascertained by flow cytometry.
  • Duration of Response (DOR) [ Time Frame: up to 127 months ]
    DOR is defined as the date response was noted until disease was no longer considered to be responding. Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and the International Working Group Criteria (IWG).Complete response (CR) required clearing of all known disease sites. Partial response (PR) required documented response in skin (≥ 30% per RECIST) or lymph nodes (≥ 50% per the International Working Group (IWG) criteria, with response in both compartments for a determination of PR, IWG guidelines. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive disease (PD) is at least a 20% increase in the sum of the target lesions, or the appearance of one or more new lesions. Lymph node disease was assessed bi-dimensionally using the IWG criteria. Bone marrow involvement, as recommended by IWG criteria, and presence of circulating malignant T-cells ascertained by flow cytometry.
Not Provided
Complete list of historical versions of study NCT00007345 on ClinicalTrials.gov Archive Site
  • Number of Participants With Adverse Events [ Time Frame: 147 months and 5 days ]
    Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
  • Median Number of Cycles of Depsipeptide Administered [ Time Frame: 83 cycles (i.e., each cycle is 21 days) ]
    Participants were administered Depsipeptide and cycles (each cycle is 21 days) were monitored from the prescribed dose or higher to determine reductions (if needed) to maintain tolerability.
  • Time to Progression [ Time Frame: Until disease progression, or 30 days following off study date ]
    Time to progression is defined from the first day of therapy until documentation of progressive disease. Progressive disease (PD) is at least a 20% increase in the sum of the target lesions, or the appearance of one or more new lesions. Lymph node disease was assessed bi-dimensionally using the International Working Group (IWG) criteria. Bone marrow involvement, as recommended by IWG criteria, and presence of circulating malignant T-cells ascertained by flow cytometry.
  • Fold Change in Histone Acetylation [ Time Frame: 4 hours, 24 hours, and 48 hours after Romidepsin ]
    Fold change is calculated by dividing the level of histone acetylation in a treated sample (at 4, 24, and 48 hours) measured as intensity on a dot blot immunoassay, divided by the intensity in the pre-treatment sample. We considered a ≥ 2-fold change a measurable difference, and indicative of successful HDAC inhibition by romidepsin (depsipeptide).
  • Multidrug Resistance Protein 1 (MDR1) or ATP-binding Cassette Sub-family B Member 1 (ABCB1) Gene Expression [ Time Frame: 4 hours, 24 hours, and 48 hours after Romidepsin ]
    Total ribonucleic acid (RNA) was isolated from peripheral blood mononuclear cells or patient tissue biopsies and analyzed by quantitative polymerase chain reaction (qPCR). Expression of MDR-1/ABCB1 was determined by qPCR relative to an RNA standard, then normalized to ribosomal RNA (rRNA). Fold change is calculated by dividing the level of MDR-1 in a treated sample (at 4, 24, and 48 hours) measured by qPCR, divided by MDR-1 in the pre-treatment sample. We considered a ≥ 2-fold change a measurable difference, and indicative of successful HDAC inhibition by romidepsin (depsipeptide).
Not Provided
Not Provided
Not Provided
 
Depsipeptide to Treat Patients With Cutaneous T-Cell Lymphoma and Peripheral T-Cell Lymphoma
Phase II Trial of Depsipeptide in Patients With Cutaneous T-Cell Lymphoma and Relapsed Peripheral T-Cell Lymphoma

Background:

NSC630176 is a depsipeptide fermentation product from Chromobacterium violaceum with potent cytotoxic activity against human tumor cell lines and in vivo efficacy against both human tumor xenografts and murine tumors (1-3).

NSC 630176, herein referred to as depsipeptide, shows a lack of cross resistance with several commonly used cytotoxic agents such as vincristine, 5-fluorouracil, mitomycin C and cyclophosphamide (2). However, it has been defined as a P-glycoprotein (Pgp) substrate by COMPARE analysis of the National Cancer Institute (NCI) drug screen cytotoxicity profile (4).

Depsipeptide is a member of a novel class of antineoplastic agents, the histone deacetylase inhibitors.

In the phase I trial conducted at the National Cancer Institute (NCI), responses were observed at the maximum tolerated dose (MTD) in patients with cutaneous and peripheral T-cell lymphoma.

Objectives:

In patients with cutaneous T-cell lymphoma, the primary end points to be examined are overall response rate, complete response rate and duration of response.

In patients with relapsed peripheral T-cell lymphoma, the endpoints to be examined are overall response rate and complete response rate.

To evaluate the tolerability of depsipeptide with extended cycles of therapy.

Eligibility:

Patients with cutaneous T-cell lymphoma (mycosis fungoides or Sezary syndrome) or other peripheral T-cell lymphomas are eligible.

Design:

Depsipeptide will be administered at 14 mg/m^2, over 4 hours on days 1, 8 and 15.

This trial will accrue in six cohorts; Arm 1, patients with cutaneous T-cell lymphoma who have had less than or equal to two prior cytotoxic chemotherapy regimens; Arm 2, patients with peripheral T-cell lymphoma who have had less than or equal to two prior cytotoxic chemotherapy regimens; Arm 3, patients with cutaneous and peripheral T-cell lymphoma who have had more than two prior cytotoxic chemotherapy regimens; Arm 4, patients with other mature T-cell lymphomas; Arm 5, a replicate arm of arm 1; Arm 6, patients with peripheral T-cell lymphoma who have had more than two prior cytotoxic chemotherapy regimens; Arm 7, patients with cutaneous T cell lymphoma who have received vorinostat.

Dose may be adjusted based on toxicities.

Background:

NSC630176 is a depsipeptide fermentation product from Chromobacterium violaceum with potent cytotoxic activity against human tumor cell lines and in vivo efficacy against both human tumor xenografts and murine tumors (1-3).

NSC 630176, herein referred to as depsipeptide, shows a lack of cross resistance with several commonly used cytotoxic agents such as vincristine, 5-fluorouracil, mitomycin C and cyclophosphamide (2). However, it has been defined as a P-glycoprotein (Pgp) substrate by COMPARE analysis of the National Cancer Institute (NCI) drug screen cytotoxicity profile (4).

Depsipeptide is a member of a novel class of antineoplastic agents, the histone deacetylase inhibitors.

In the phase I trial conducted at the NCI, responses were observed at the maximum tolerated dose (MTD) in patients with cutaneous and peripheral T-cell lymphoma.

Objectives:

In patients with cutaneous T-cell lymphoma, the primary end points to be examined are overall response rate, complete response rate and duration of response.

In patients with relapsed peripheral T-cell lymphoma, the endpoints to be examined are overall response rate and complete response rate.

To evaluate the tolerability of depsipeptide with extended cycles of therapy.

Eligibility:

Patients with cutaneous T-cell lymphoma (mycosis fungoides or Sezary syndrome) or other peripheral T-cell lymphomas are eligible.

Design:

Depsipeptide will be administered at 14 mg/m^2, over 4 hours on days 1, 8 and 15.

This trial will accrue in six cohorts; Arm 1, patients with cutaneous T-cell lymphoma who have had less than or equal to two prior cytotoxic chemotherapy regimens; Arm 2, patients with peripheral T-cell lymphoma who have had less than or equal to two prior cytotoxic chemotherapy regimens; Arm 3, patients with cutaneous and peripheral T-cell lymphoma who have had more than two prior cytotoxic chemotherapy regimens; Arm 4, patients with other mature T-cell lymphomas; Arm 5, a replicate arm of arm 1; Arm 6, patients with peripheral T-cell lymphoma who have had more than two prior cytotoxic chemotherapy regimens; Arm 7, patients with cutaneous T cell lymphoma who have received vorinostat.

Dose may be adjusted based on toxicities.

Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
  • Cutaneous T Cell Lymphoma
  • Peripheral T Cell Lymphoma
Drug: Romidepsin
  • Experimental: Peripheral T-cell Lymphoma (PTCL)
    Participants received at least one protocol prescribed dose or higher of Romidepsin intravenously at 14mg/m^2 and at 17.5 mg/m^2 on days 1, 8, and 15 of a 28 day cycle.
    Intervention: Drug: Romidepsin
  • Experimental: Cutaneous T-cell Lymphoma (CTCL)
    Participants received at least one protocol prescribed dose or higher of Romidepsin intravenously at 14mg/m^2 and at 17.5 mg/m^2 on days 1, 8, and 15 of a 28 day cycle.
    Intervention: Drug: Romidepsin

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
131
July 27, 2015
January 26, 2015   (Final data collection date for primary outcome measure)
  • INCLUSION CRITERIA:

Based on the Inclusion Criteria outlined below, patients will accrue to one of the cohorts of the trial.

Cohort- chemotherapy regimens allowed. Cohort Status

Cohort 1

Cutaneous T-cell Lymphoma (mycosis fungoides or Sezary syndrome)-2 or fewer. Closed to accrual

Cohort 2

Peripheral T-cell Lymphoma, unspecified, or Anaplastic large cell lymphoma (T and null cell) Primary Cutaneous Type -2 or fewer. Open and accruing

Cohort 3

Cutaneous T-cell Lymphomas or Peripheral T-cell Lymphoma-More than 2. Closed to accrual

Cohort 4

Other Mature T cell Lymphomas-Any number. Open and accruing

Cohort 5

Cutaneous T-cell Lymphoma (mycosis fungoides or Sezary syndrome)-2 or fewer-Cohort 5 is a replicate cohort, identical to #1

Cohort 6

Peripheral T-cell Lymphoma (PTCL), unspecified, or Anaplastic large cell lymphoma (T and null cell) Primary Cutaneous Type-More than 2. Patients with PTCL in cohort 3 migrated to this cohort

Cohort 7

Cutaneous T-cell Lymphoma (mycosis fungoides or Sezary syndrome) Prior vorinostat required-Any number

Patients with cutaneous T-cell lymphoma [CTCL (mycosis fungoides or Sezary syndrome) stage IB to IVB are eligible. Patients with stage IB and IIA should be refractory to, intolerant to, or have reached a six-month or longer response plateau on at least two prior therapies from the following list: psoralen plus ultraviolet A irradiation (PUVA), ultraviolet B (UVB), electron beam therapy (EBT), photophoresis, interferon, systemic cytotoxic chemotherapy, topical nitrogen mustard, or topical carmustine (BCNU). One qualifying prior treatment must have been topical nitrogen mustard, topical carmustine or a phototherapy (UVB, PUVA or EBT). Topical steroids, systemic retinoids or biologicals do not qualify. Patients with stage IB or IIA who are not candidates for topical nitrogen mustard, topical carmustine or phototherapy (UVB, PUVA or EBT) are eligible for enrollment. Patients may not have received more than two systemic cytotoxic chemotherapy regimens. Steroids, retinoids, and biologic agents, will not be considered as systemic cytotoxic chemotherapy. Radiolabeled monoclonal antibody therapy is considered equivalent to a systemic cytotoxic chemotherapy regimen and must be counted toward the two prior systemic cytotoxic regimens. Patients with stage IIB-IVB who have had no more than 2 prior systemic cytotoxic chemotherapeutic regimens are eligible. There is no restriction regarding number of prior topical therapies, skin irradiation, or non-cytotoxic systemic therapies (i.e. PUVA, retinoids or biologic, with the exception of radiolabeled monoclonal antibody therapy) in this patient group. After 24 patients were enrolled in this arm, the arm was closed, and a replicate arm constituted of this same patient population was opened (Cohort 5).

Patients with peripheral T-cell lymphoma (PTCL), unspecified, or anaplastic large cell lymphoma, T and null cell, primary cutaneous type, as defined by the Revised European American Lymphoma (REAL)/World Health Organization (WHO) classification (16-18), who have experienced disease progression after receiving prior standard treatment and who have had no more than 2 prior systemic cytotoxic chemotherapeutic regimens are eligible.

Patients with cutaneous T cell lymphoma (Mycosis fungoides or Sezary Syndrome) or peripheral T cell lymphoma as defined above who have received more than 2 prior systemic therapies and who have experienced disease progression will be included in a third and independent arm. This arm of the protocol was closed to accrual for CTCL with Amendment H.

Patients with mature T cell lymphomas not included above will be enrolled in a fourth arm. These include but are not exclusively limited to: Enteropathy-type T cell lymphoma; Hepatosplenic T-cell lymphoma; Subcutaneous panniculitis-like T cell lymphoma; Angioimmunoblastic T-cell lymphoma; Anaplastic large cell lymphoma. Patients must have experienced disease progression after receiving prior standard treatment. There will be no limit on the number of prior regimens. Primitive T cell neoplasms and T cell leukemias will not be enrolled.

Patients with peripheral T-cell lymphoma, unspecified, or anaplastic large cell lymphoma, T and null cell, primary cutaneous type, as defined by the REAL/WHO classification (16-18), who have experienced disease progression after receiving prior standard treatment and who have had more than 2 prior systemic cytotoxic chemotherapeutic regimens are eligible for enrollment to a sixth arm of the trial.

Patients with cutaneous T cell lymphoma (Mycosis fungoides or Sezary Syndrome) or peripheral T cell lymphoma as defined in #1 who have received any number of prior systemic therapies and who have previously been treated with vorinostat will be included in a third and independent arm. Patients can be enrolled in this arm if they received prior vorinostat and experienced disease progression, subsequent relapse, or had to discontinue to agent due to toxicity.

Disease that is measurable by radiographic imaging, assessing skin lesions, or by quantitating Sezary cell count.

Patients must:

be age greater than or equal to 18 years

have a performance status of Eastern Cooperative Oncology Group (ECOG) 0-2

have no serious or intercurrent illness and have a life expectancy of greater than 12 weeks

give written informed consent

female patients of childbearing potential must have a negative pregnancy test within 4 weeks and must use effective contraception

sexually active males must use effective contraception

Laboratory values (performed less than or equal to 14 days prior to registration):

absolute neutrophil count greater than or equal to 1000/microliter, platelets greater than or equal to l00,000/microliter, bilirubin (total and direct) less than or equal to 1.5x upper limit of normal, and aspartate aminotransferase (AST) less than or equal to 3x upper limit of normal, unless impairment is due to organ involvement by lymphoma, creatinine less than or equal to 1.5x upper limit of normal, or documented creatinine clearance of greater than or equal to 60mL/min

Cardiac studies (performed within 4 weeks of registration):

Ejection fraction of greater than 50% by Echocardiogram or Cardiac magnetic resonance imaging (MRI), or greater than or equal to 45% by multi-gated acquisition scan (MUGA) Scan.

A stable dose (greater than 1 month) of corticosteroids administered for symptom management will not preclude enrollment. Tapering will be initiated following administration of depsipeptide.

EXCLUSION CRITERIA:

Patients with unconfirmed diagnosis, or with B-cell lymphomas will be excluded.

Prior or concurrent malignancies that have not been curatively treated.

Known central nervous system (CNS) lymphoma.

Chemotherapy within 4 weeks, 6 weeks for nitrosoureas or mitomycin C.

Biologics, Immunotherapy within 2 weeks.

Human Immunodeficiency virus (HIV) seropositivity.

Pregnant or breast-feeding patients.

Major surgery within 21 days.

Uncontrolled infection or uncontrolled medical illness.

Patients having received prior histone deacetylase (HDAC) inhibitor therapy for T cell lymphoma will be excluded except for patients eligible to enroll in cohort 7.

Patients with the following cardiac risk factors will be excluded from the study:

Patients with known cardiac abnormalities such as:

Congenital long QT syndrome

Corrected QT interval (QTc) interval greater than 480 milliseconds

Patients who have had a myocardial infarction within 12 months of study entry.

Patients who have active coronary artery disease as, e.g. angina as defined by Canadian Class II-IV

Patients with an electrocardiography (ECG) recorded at screening showing evidence of cardiac ischemia (ST depression of greater than or equal to 2 mm).

Any patient in whom coronary artery disease is suspected should be referred for a cardiology consultation and if active myocardial ischemia is demonstrated the patient should be excluded. If a noninvasive imaging study is equivocal, it may be necessary to proceed to coronary angiography.

Patients with congestive heart failure that meets New York Heart Association (NYHA) Class II to IV definitions and/or ejection fraction less than 45% by MUGA scan or less than 50% by echocardiogram and/or MRI.

Patients with a history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD). Patients with a history of arrhythmia should have Holter monitoring and evaluation by cardiology.

Patients with dilated, hypertrophic, or restrictive cardiomyopathy from prior treatment or other causes (in doubt, see ejection fraction criteria above). Patients with left ventricular hypertrophy should be discussed with the Principal Investigator or Study Chairman.

Patients with uncontrolled hypertension, i.e., systolic blood pressure (SBP) greater than or equal to 160 mm Hg or diastolic blood pressure (DBP) greater than or equal to 95 mm Hg.

Patients with cardiac arrhythmia requiring anti-arrhythmic medication other than beta blocker or calcium channel blocker. Patients in whom digitalis cannot be discontinued are excluded from study.

Patients with Mobitz II second degree heart block who do not have a pacemaker. Patients with first degree or Mobitz I second degree heart block, bradyarrhythmias or sick sinus syndrome require Holter monitoring and evaluation by cardiology.

Patients with other cardiac disease may be excluded at the discretion of the principal investigator (PI) following consultation with cardiology.

Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
Australia,   United States
 
 
NCT00007345
010049
01-C-0049
No
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Plan to Share IPD: No
James Gulley, M.D., National Institutes of Health Clinical Center (CC)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: James Gulley, M.D. National Cancer Institute (NCI)
National Institutes of Health Clinical Center (CC)
April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP