Clinical trial NCT00007345: Depsipeptide to Treat Patients With Cutaneous T-Cell Lymphoma and Peripheral T-Cell Lymphoma
Official title: Phase II Trial of Depsipeptide in Patients With Cutaneous T-Cell Lymphoma and Relapsed Peripheral T-Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cutaneous T Cell Lymphoma
Peripheral T Cell Lymphoma
Keywords: Histone Acetylase
Differentiation
Sezary Syndrome
Mycosis Fungoides
CD 30 Lymphoma
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2000-12-18
Enrollment: 131
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Number of Participants With a Response
timeFrame: up to 56.5 days
measure: Duration of Response (DOR)
timeFrame: up to 127 months
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 147 months and 5 days
measure: Median Number of Cycles of Depsipeptide Administered
timeFrame: 83 cycles (i.e., each cycle is 21 days)
measure: Time to Progression
timeFrame: Until disease progression, or 30 days following off study date
measure: Fold Change in Histone Acetylation
timeFrame: 4 hours, 24 hours, and 48 hours after Romidepsin
measure: Multidrug Resistance Protein 1 (MDR1) or ATP-binding Cassette Sub-family B Member 1 (ABCB1) Gene Expression
timeFrame: 4 hours, 24 hours, and 48 hours after Romidepsin
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Little Rock
country: United States
facility: University of Arkansas
state: Arkansas
city: Duarte
country: United States
facility: City of Hope National Cancer Center
state: California
city: Sacramento
country: United States
facility: Mercy General Hospital
state: California
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Morgantown
country: United States
facility: West Virginia University
state: West Virginia
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
Study officials:
affiliation: National Cancer Institute (NCI)
name: James Gulley, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.