Depsipeptide to Treat Patients With Cutaneous T-Cell Lymphoma and Peripheral T-Cell Lymphoma
- Conditions
- Peripheral T Cell LymphomaCutaneous T Cell Lymphoma
- Interventions
- Registration Number
- NCT00007345
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 131
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Peripheral T-cell Lymphoma (PTCL) Romidepsin 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. Cutaneous T-cell Lymphoma (CTCL) Romidepsin 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.
- Primary Outcome Measures
Name Time Method Number of Participants With a Response 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) 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Adverse Events 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 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 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 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 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).
Trial Locations
- Locations (13)
City of Hope National Cancer Center
🇺🇸Duarte, California, United States
Royal Adelaide Hospital
🇦🇺Adelaide, Australia
Peter MacCallum Cancer Centre
🇦🇺Melbourne, Australia
Sir Charles Gairdner Hospital
🇦🇺Perth, Australia
Mayo Clinic Scottsdale
🇺🇸Scottsdale, Arizona, United States
University of Arkansas
🇺🇸Little Rock, Arkansas, United States
Mercy General Hospital
🇺🇸Sacramento, California, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States
North Shore University Hospital
🇺🇸Manhasset, New York, United States
West Virginia University
🇺🇸Morgantown, West Virginia, United States
Georgetown University
🇺🇸Washington, District of Columbia, United States