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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT00007345




Registration number
NCT00007345
Ethics application status
Date submitted
16/12/2000
Date registered
18/12/2000
Date last updated
16/05/2017

Titles & IDs
Public title
Depsipeptide to Treat Patients With Cutaneous T-Cell Lymphoma and Peripheral T-Cell Lymphoma
Scientific title
Phase II Trial of Depsipeptide in Patients With Cutaneous T-Cell Lymphoma and Relapsed Peripheral T-Cell Lymphoma
Secondary ID [1] 0 0
01-C-0049
Secondary ID [2] 0 0
010049
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cutaneous T Cell Lymphoma 0 0
Peripheral T Cell Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - 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.

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.


Treatment: Drugs: Romidepsin


Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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.
Timepoint [1] 0 0
up to 56.5 days
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
up to 127 months
Secondary outcome [1] 0 0
Number of Participants With Adverse Events - Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Timepoint [1] 0 0
147 months and 5 days
Secondary outcome [2] 0 0
Median Number of Cycles of Depsipeptide Administered - 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.
Timepoint [2] 0 0
83 cycles (i.e., each cycle is 21 days)
Secondary outcome [3] 0 0
Time to Progression - 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.
Timepoint [3] 0 0
Until disease progression, or 30 days following off study date
Secondary outcome [4] 0 0
Fold Change in Histone Acetylation - 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).
Timepoint [4] 0 0
4 hours, 24 hours, and 48 hours after Romidepsin
Secondary outcome [5] 0 0
Multidrug Resistance Protein 1 (MDR1) or ATP-binding Cassette Sub-family B Member 1 (ABCB1) Gene Expression - 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).
Timepoint [5] 0 0
4 hours, 24 hours, and 48 hours after Romidepsin

Eligibility
Key inclusion criteria
- 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 0 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 0 0
Sir Charles Gairdner Hospital - Perth
Recruitment postcode(s) [1] 0 0
- Adelaide
Recruitment postcode(s) [2] 0 0
- Melbourne
Recruitment postcode(s) [3] 0 0
- Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
Arkansas
Country [3] 0 0
United States of America
State/province [3] 0 0
California
Country [4] 0 0
United States of America
State/province [4] 0 0
District of Columbia
Country [5] 0 0
United States of America
State/province [5] 0 0
Illinois
Country [6] 0 0
United States of America
State/province [6] 0 0
Maryland
Country [7] 0 0
United States of America
State/province [7] 0 0
New York
Country [8] 0 0
United States of America
State/province [8] 0 0
Pennsylvania
Country [9] 0 0
United States of America
State/province [9] 0 0
West Virginia

Funding & Sponsors
Primary sponsor type
Government body
Name
National Cancer Institute (NCI)
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/show/NCT00007345
Trial related presentations / publications
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.
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.
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.
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.
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.
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.
Public notes

Contacts
Principal investigator
Name 0 0
James Gulley, M.D.
Address 0 0
National Cancer Institute (NCI)
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications