This study will test the safety and effectiveness of a new anticancer drug called depsipeptide in treating T-cell lymphomas. Depsipeptide has been shown to kill cancer cells in laboratory studies and to shrink various kinds of tumors in animal models. This study will evaluate the response of T-cell lymphomas to depsipeptide and determine how well patients tolerate the drug over a period of several months.

Patients with peripheral T-cell lymphoma and cutaneous T-cell lymphoma (Sezary syndrome and mycosis fungoides) 18 years of age or older may be eligible for this study. Candidates will be screened with a medical history and physical examination, computerized tomography (CT) scans of the chest, abdomen and pelvis, electrocardiogram, blood tests, and possibly a bone marrow biopsy. For the biopsy, the hip area is anesthetized and bone marrow is drawn from the hipbone using a special needle.

Participants will receive an intravenous (through a vein) infusion of depsipeptide on days 1 and 5 of each 21-day treatment cycle. The drug will be infused over 4 hours through an arm vein or through a central line (a catheter placed under the skin of the chest or neck and passed into a major vein). This catheter is used to deliver the chemotherapy and to draw blood samples for tests to measure the effects of the drug on the body and on the cancer cells. Patients will be admitted to the hospital for the first treatment cycle. If medically feasible, subsequent cycles will be administered on an outpatient basis.

Patients may also be asked to undergo additional tumor biopsies before and after treatment and to have a procedure called apheresis, in which immune cells of the blood are collected. For this procedure, whole blood is collected through a needle placed in an arm vein. The blood circulates through a machine that separates it into its components. The white cells are removed, and the red cells, platelets and plasma are returned to the body, either through the same needle used to draw the blood or through a second needle placed in the other arm.

Condition	Treatment or Intervention	Phase
Cutaneous T Cell Lymphoma Peripheral T Cell Lymphoma	Drug: Depsipeptide	Phase II

NSC 630176 is a depsipeptide fermentation product from Chromobacterium violaceum that was first isolated by the Fujisawa Company. It has demonstrated potent cytotoxic activity against human tumor cell lines and in vivo efficacy against both human tumor xenografts and murine tumors. 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. However, it has been defined as a P-glycoprotein (Pgp) substrate by COMPARE analysis of the NCI drug screen cytotoxicity profile. Depsipeptide is a member of a novel class of antineoplastic agents, the histone deacetylase inhibitors.

A phase I trial of depsipeptide was completed at the NCI. The MTD was found to be 17.8 mg/m(2). The major observed toxicities were granulocytopenia, thrombocytopenia, hypocalcemia, fatigue, nausea and vomiting. In that trial, three responses were observed at the MTD in patients with T-cell lymphomas. Two of the patients had cutaneous T-cell lymphoma and one had peripheral T-cell lymphoma. Because of these observed responses, this phase II study will examine the use of depsipeptide in patients with cutaneous T-cell lymphoma and with peripheral T-cell lymphoma. Patients with cutaneous T-cell lymphoma generally demonstrate some response to cytotoxic agents, however they have a short duration of response. Therefore, 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. Patients with peripheral T-cell lymphoma do have some durable responses to cytotoxic agents. Therefore, patients with peripheral T-cell lymphoma will be admitted on study after failure of a conventional therapy. The endpoints to be examined will be overall response rate and complete response rate.

In addition, the molecular effects of depsipeptide and the tolerability of depsipeptide with extended cycles of therapy will be examined. Our ultimate goal is to use depsipeptide for strategies aimed at the reversal of drug resistance. T-cell lymphomas are good models because they demonstrate a high response rate to many different agents that is generally followed by relapse and treatment failure.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Patients with cutaneous T-cell lymphoma (mycosis fungoides or Sezary syndrome) stage IA to IVB. Patients with stage IA, IB, 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: PUVA, UVB, 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 IA, IB, IIA who are ineligible for topical nitrogen mustard, topical carmustine or phototherapy (UVB, PUVA or EBT). Patients may not have received more than two systemic cytotoxic chemotherapy regimens. Steroids, retinoids or biologicals, aside from radiolabeled monoclonal antibodies, do not qualify. Patients with stage IIB-IVB who have had no more than 2 prior systemic cytotoxic chemotherapeutic regimens are eligible. There is no restriction regarding prior topical therapies, skin irradiation, or non-cytotoxic systemic therapies (i.e. PUVA, retinoids or biologicals, with the exception of radiolabeled monoclonal antibody therapy). After 24 patients have been enrolled in this arm, the arm will close, and a replicate arm constituted of this patient population will be opened.
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, 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.
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 pannicultitis-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.
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 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/microliters, platelets greater than or equal to 100,000/microliters, bilirubin (total and direct) less than or equal to 1.5 times upper limit of normal, and AST less than or equal to 3 times the upper limit of normal, unless impairment is due to organ involvement by lymphoma
-creatinine less than or equal to 1.5 times upper limit of normal, or documented creatinine clearance of greater than or equal to 60 mL/min
Cardiac studies (performed within 4 weeks of registration:
-Ejection fraction of greater than or equal to 50% by Echocardiogram or Cardiac MRI or greater than or equal to 45% by 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 CNS lymphoma
Chemotherapy within 4 weeks, 6 weeks for nitrosoureas or mitomycin C.
Biologics, Immunotherapy within 2 weeks.
HIV seropositivity.
Pregnant or breast-feeding patients.
Major surgery within 21 days.
Uncontrolled infection.
Patients with MI within previous 6 months, EF less than 45%, (by MUGA) or (less than 50% by Echocardiogram or Cardiac MRI), QTc greater than 500 ms, unstable angina, or with third degree or Mobitz II second degree heart block that do not have a pacemaker. Patients with first degree or Mobitz I second degree heart block require consultation with cardiology. Patients with other cardiac disease may be excluded at the discretion of the PI following consultation with cardiology.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  010049; 01-C-0049
Record last reviewed:  August 1, 2004
Last Updated:  August 1, 2004
Record first received:  December 16, 2000
ClinicalTrials.gov Identifier:  NCT00007345
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-11-18