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