UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas
UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas
This study will examine the effects of an experimental drug called UCN-01
 (7-hydroxystaurosporine) on T-cell lymphomas. UCN-01 inhibits the growth of several different
 tumor cells, and, in laboratory studies, it has worked particularly well on tumor cells taken
 from patients with T cell lymphomas.

 Patients 9 years of age and older with T cell lymphoma that has relapsed or is not responding
 to chemotherapy may be eligible for this study. Candidates will be screened with a medical
 histories and physical examinations, blood and urine tests, electrocardiograms, chest x-rays,
 and computed tomography (CT) scans of the chest, abdomen and pelvis. Additional tests may be
 done if clinically indicated, such as positron emission tomography (PET) scans, bone marrow
 aspirations and biopsies, lumbar punctures (spinal taps) and CT's or magnetic resonance
 imaging (MRI) scans if there is evidence of central nervous system disease.

 Participants are given UCN-01 in 28-day treatment cycles. The drug is given by vein in a
 continuous 72-hour infusion on the first cycle and in 36-hour infusions on subsequent cycles.
 The total number of cycles patients receive depends on how well the tumor responds to the
 drug and how well the patient tolerates drug side effects. Patients who do well may receive
 treatment for up to 1 year. Patients whose disease worsens with treatment or who do not
 tolerate the therapy are taken off the study.

 Some or all of the screening tests are repeated periodically during the course of treatment
 to monitor safety and treatment response. X-rays and scans are done every other treatment
 cycle for the first 6 cycles and then, if the cancer is stable or improving, the interval
 between these imaging studies is lengthened to every 4 cycles. Patients whose tumors can be
 safely biopsied undergo this procedure before entering the study and 3 to 5 days after
 completing the first UCN-01 treatment. Biopsies requiring open surgery (e.g., in the chest or
 abdomen) are done only if absolutely necessary for medical care. Biopsy tissue, blood, and
 other fluids are analyzed for gene and protein studies related to lymphoma research.
Background:

 -  UCN-01 (7-hydroxystaurosporine), a non-specific protein kinase C (PKC) inhibitor appears
 to have several mechanisms of action including protein kinase C (PKC) isoenzyme
 inhibition and cyclin dependent kinase activation and inhibition.

 -  We have demonstrated that cell lines derived from T-cell lymphomas, including those with
 the t (2; 5) translocation, are very sensitive to UCN-01. The t (2; 5) translocation,
 associated with three quarters of cases of anaplastic large cell lymphomas (ALCL), is an
 oncogenic fusion protein - nucleophosmin-anaplastic lymphoma kinase (NPM-ALK).

 -  Anaplastic lymphoma receptor tyrosine kinase (ALK) is one potential target for UCN-01
 action, and anaplastic large cell lymphoma (ALCL) derived SUDHL-1 cells containing the
 NPM-ALK protein have been shown to be very sensitive to UCN-01.

 Objectives:

 -  To assess the clinical response to UCN-01 and progression-free and overall survival in
 patients with relapsed or refractory systemic Anaplastic Large Cell and other mature
 T-cell Lymphomas.

 -  To assess the effect of UCN-01 on ALK expression in ALCL cells.

 -  To assess the effect of UCN-01 on soluble tetrameric antibody complexes (TAC) (CD25).

 -  To evaluate mature T-cell lymphoma malignant cells by complimentary deoxyribonucleic
 acid (cDNA) microarray.

 Eligibility:

 -  Relapsed or refractory systemic Anaplastic Large Cell Lymphoma (ALCL) with T or Null
 phenotype or relapsed or refractory mature T-cell lymphomas.

 -  All patients should have evaluable or measurable disease on entry to study.

 -  Requires systemic therapy

 -  Performance Status Eastern Cooperative Oncology Group (ECOG) less than or equal to 2

 -  Age 7 years or older

 -  Human immunodeficiency virus (HIV) negative

 -  Patients should not have received systemic cytotoxic chemotherapy within 3 weeks of
 study entry.

 Design:

 -  The study will be a Phase II study.

 -  Patients will receive the first cycle of UCN-01 over 72 hours on days 1-3 and subsequent
 cycles over 36 hours. Patients with stable disease may receive UCN-01 for up to 1 year
 beyond achieving maximum response or stable disease, and restaging will be done every 2
 cycles for the first 6 cycles and every 4 cycles thereafter.

 -  Two sequential biopsies will be performed to investigate complimentary deoxyribonucleic
 acid (cDNA) expression by microarray. Soluble Tac (CD25) will be serially followed in
 patients.

 -  For each of the two histologies, this study will be conducted using a Simon two-stage
 optimal design. Up to 37 patients will be treated.
-  INCLUSION CRITERIA:

 Relapsed or refractory systemic Anaplastic Large Cell Lymphoma (ALCL).

 Relapsed or refractory mature T-cell lymphoma to include peripheral T-cell lymphoma
 unspecified and the following "specified" mature T-cell lymphomas:

 Adult T-cell lymphoma; Extranodal natural killer (NK)/T-cell lymphoma,

 nasal type; Enteropathy-type T-cell lymphoma;

 Hepatosplenic T-cell lymphoma;

 Subcutaneous panniculitis-like T-cell lymphoma;

 Angioimmunoblastic T-cell lymphoma.

 All patients should have evaluable or measurable disease on entry to study.

 Histology confirmed by Laboratory of Pathology, National Cancer Institute (NCI).

 Performance Status Eastern Cooperative Oncology Group (ECOG) less than or equal to 2.

 Age 7 years or older.

 Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than 50 ml/min
 for patients at least 18 years.

 Pediatric patients should have maximum serum creatinine by age as follows:

 -  Less than age 7 and less than or equal to age 10 may have a Maximum Serum Creatinine
 of 1.0 mg/dl

 -  Less than age10 and less than or equal to age 15 may have a Maximum Serum Creatinine
 of 1.2 mg/dl

 -  Age 15 years or older may have a Maximum Serum Creatinine of 1.5 mg/dl

 Alternatively, pediatric patients should have a creatinine clearance of greater than 50
 m1/min/1.73m^2.

 Total bilirubin less than 1.5 x upper limit of normal (ULN) (patients with elevation of
 total bilirubin consistent with Gilbert's disease are eligible providing they have a normal
 direct bilirubin);

 aspartate aminotransferase (AST) less than or equal to 2.5 x ULN;

 absolute neutrophil count (ANC) greater than 500/mm^3;

 and platelet greater than or equal to 50,000/mm^3;

 unless hematological impairment due to organ involvement by lymphoma.

 Provides signed informed consent.

 Not pregnant or nursing. This drug has unknown effects in pregnancy and on young
 infants/children.

 Human immunodeficiency virus (HIV) negative.

 Willing to use contraception and continue for at least 8 weeks following the last
 treatment.

 No active central nervous system (CNS) lymphoma.

 Patients should not have received systemic cytotoxic chemotherapy within 3 weeks of study
 entry.

 Have recovered from the toxic effects of prior therapy to a grade less than or equal to 1.

 No history of diabetes mellitus requiring insulin treatment.

 No symptomatic pulmonary disease.

 No evidence of symptomatic cardiac disease (e.g. symptomatic congestive heart failure,
 unstable angina pectoris, exertional angina pectoris, cardiac arrhythmia).

 Patients may not be concurrently receiving any other investigational agents.

 Not a candidate for potentially curative (i.e. transplant) treatment at the time of study
 entry or the patient has a window of opportunity to receive UCN-01 before a transplant.
 Patients are required to have considered a transplant. If, having done this, they refuse
 it, decide against it or decide to wait, they would be eligible for this study.