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

NCT00007345 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 01004901-C-0049
• Study Type: interventional
• Target: 131
• Locations: 2 countries
• Sites: 13

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.

Conditions

Cutaneous T Cell Lymphoma; Peripheral T Cell Lymphoma

Keywords

Histone Acetylase; Differentiation; Sezary Syndrome; Mycosis Fungoides; CD 30 Lymphoma

Outcome Measures

Primary Outcomes (2)

• Number of Participants With a Response

  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.

  up to 56.5 days

• Duration of Response (DOR)

  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.

  up to 127 months

Secondary Outcomes (5)

• Number of Participants With Adverse Events

  147 months and 5 days

• Median Number of Cycles of Depsipeptide Administered

  83 cycles (i.e., each cycle is 21 days)

• Time to Progression

  Until disease progression, or 30 days following off study date

• Fold Change in Histone Acetylation

  4 hours, 24 hours, and 48 hours after Romidepsin

• 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

Study Arms (2)

Peripheral T-cell Lymphoma (PTCL)

EXPERIMENTAL

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.

Drug: Romidepsin

Cutaneous T-cell Lymphoma (CTCL)

EXPERIMENTAL

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.

Drug: Romidepsin

Interventions

Romidepsin DRUG

Cutaneous T-cell Lymphoma (CTCL); Peripheral T-cell Lymphoma (PTCL)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (13)

Mayo Clinic Scottsdale

Scottsdale, Arizona, 85259, United States

Location

University of Arkansas

Little Rock, Arkansas, 72205, United States

Location

City of Hope National Cancer Center

Duarte, California, 91010, United States

Location

Mercy General Hospital

Sacramento, California, 95819, United States

Location

Georgetown University

Washington D.C., District of Columbia, 20007-2197, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

North Shore University Hospital

Manhasset, New York, 11030, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

West Virginia University

Morgantown, West Virginia, 26506, United States

Location

Royal Adelaide Hospital

Adelaide, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Australia

Location

Sir Charles Gairdner Hospital

Perth, Australia

Location

Related Publications (10)

• Piekarz RL, Frye AR, Wright JJ, Steinberg SM, Liewehr DJ, Rosing DR, Sachdev V, Fojo T, Bates SE. Cardiac studies in patients treated with depsipeptide, FK228, in a phase II trial for T-cell lymphoma. Clin Cancer Res. 2006 Jun 15;12(12):3762-73. doi: 10.1158/1078-0432.CCR-05-2095.

  PMID: 16778104 BACKGROUND

• Woo S, Gardner ER, Chen X, Ockers SB, Baum CE, Sissung TM, Price DK, Frye R, Piekarz RL, Bates SE, Figg WD. Population pharmacokinetics of romidepsin in patients with cutaneous T-cell lymphoma and relapsed peripheral T-cell lymphoma. Clin Cancer Res. 2009 Feb 15;15(4):1496-503. doi: 10.1158/1078-0432.CCR-08-1215.

  PMID: 19228751 BACKGROUND

• Ritchie D, Piekarz RL, Blombery P, Karai LJ, Pittaluga S, Jaffe ES, Raffeld M, Janik JE, Prince HM, Bates SE. Reactivation of DNA viruses in association with histone deacetylase inhibitor therapy: a case series report. Haematologica. 2009 Nov;94(11):1618-22. doi: 10.3324/haematol.2009.008607. Epub 2009 Jul 16.

  PMID: 19608677 BACKGROUND

• Bates SE, Zhan Z, Steadman K, Obrzut T, Luchenko V, Frye R, Robey RW, Turner M, Gardner ER, Figg WD, Steinberg SM, Ling A, Fojo T, To KW, Piekarz RL. Laboratory correlates for a phase II trial of romidepsin in cutaneous and peripheral T-cell lymphoma. Br J Haematol. 2010 Jan;148(2):256-67. doi: 10.1111/j.1365-2141.2009.07954.x. Epub 2009 Oct 28.

  PMID: 19874311 BACKGROUND

• Akilov OE, Grant C, Frye R, Bates S, Piekarz R, Geskin LJ. Low-dose electron beam radiation and romidepsin therapy for symptomatic cutaneous T-cell lymphoma lesions. Br J Dermatol. 2012 Jul;167(1):194-7. doi: 10.1111/j.1365-2133.2012.10905.x.

  PMID: 22372971 BACKGROUND

• Noonan AM, Eisch RA, Liewehr DJ, Sissung TM, Venzon DJ, Flagg TP, Haigney MC, Steinberg SM, Figg WD, Piekarz RL, Bates SE. Electrocardiographic studies of romidepsin demonstrate its safety and identify a potential role for K(ATP) channel. Clin Cancer Res. 2013 Jun 1;19(11):3095-104. doi: 10.1158/1078-0432.CCR-13-0109. Epub 2013 Apr 15.

  PMID: 23589175 BACKGROUND

• Bates SE, Eisch R, Ling A, Rosing D, Turner M, Pittaluga S, Prince HM, Kirschbaum MH, Allen SL, Zain J, Geskin LJ, Joske D, Popplewell L, Cowen EW, Jaffe ES, Nichols J, Kennedy S, Steinberg SM, Liewehr DJ, Showe LC, Steakley C, Wright J, Fojo T, Litman T, Piekarz RL. Romidepsin in peripheral and cutaneous T-cell lymphoma: mechanistic implications from clinical and correlative data. Br J Haematol. 2015 Jul;170(1):96-109. doi: 10.1111/bjh.13400. Epub 2015 Apr 19.

  PMID: 25891346 RESULT

• Piekarz RL, Frye R, Turner M, Wright JJ, Allen SL, Kirschbaum MH, Zain J, Prince HM, Leonard JP, Geskin LJ, Reeder C, Joske D, Figg WD, Gardner ER, Steinberg SM, Jaffe ES, Stetler-Stevenson M, Lade S, Fojo AT, Bates SE. Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol. 2009 Nov 10;27(32):5410-7. doi: 10.1200/JCO.2008.21.6150. Epub 2009 Oct 13.

  PMID: 19826128 RESULT

• Piekarz RL, Frye R, Prince HM, Kirschbaum MH, Zain J, Allen SL, Jaffe ES, Ling A, Turner M, Peer CJ, Figg WD, Steinberg SM, Smith S, Joske D, Lewis I, Hutchins L, Craig M, Fojo AT, Wright JJ, Bates SE. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood. 2011 Jun 2;117(22):5827-34. doi: 10.1182/blood-2010-10-312603. Epub 2011 Feb 25.

  PMID: 21355097 RESULT

• Shustov A, Coiffier B, Horwitz S, Sokol L, Pro B, Wolfson J, Balser B, Eisch R, Popplewell L, Prince HM, Allen SL, Piekarz R, Bates S. Romidepsin is effective and well tolerated in older patients with peripheral T-cell lymphoma: analysis of two phase II trials. Leuk Lymphoma. 2017 Oct;58(10):2335-2341. doi: 10.1080/10428194.2017.1295143. Epub 2017 Mar 7.

  PMID: 28264616 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Sezary Syndrome; Mycosis Fungoides

Interventions

romidepsin

Condition Hierarchy (Ancestors)

Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Limitations and Caveats

7 cohorts were consolidated for submission to the Food and Drug Administration (FDA) into the peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) groups, thus they are presented in this format.

Results Point of Contact

• Title: Dr. Kieron Dunleavy
• Organization: National Cancer Institute

DunleavK@mail.nih.gov

301-435-1007

Study Officials

• James Gulley, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 16, 2000
• First Posted: December 18, 2000
• Study Start: March 8, 2001
• Primary Completion: January 26, 2015
• Study Completion: July 27, 2015
• Last Updated: May 16, 2017
• Results First Posted: February 12, 2016

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3); US (10)