This study will examine the effects of an experimental drug called UCN-01 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
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 CT scans of the chest, abdomen and pelvis. Additional tests may be done if
clinically indicated, such as PET scans, bone marrow aspirations and biopsies, lumbar
punctures (spinal taps) and CTs or MRI scans if there is evidence of central nervous system
Participants are given UNC-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.
- UCN-01, a non-specific protein kinase C (PKC) inhibitor appears to have several
mechanisms of action including 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
- ALK is one potential target for UCN-01 action, and ALCL derived SUDHL-1 cells
containing the NPM-ALK protein have been shown to be very sensitive to UCN-01.
- 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
- To assess the effect of UCN-01 on ALK expression in ALCL cells.
- To assess the effect of UCN-01 on soluble TAC (CD25).
- To evaluate mature T-cell lymphoma malignant cells by cDNA microarray.
- 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 ECOG less than or equal to 2
- Age 7 years or older
- HIV negative
- Patients should not have received systemic cytotoxic chemotherapy within 3 weeks of
- 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 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 NK/T-cell lymphoma, nasal type; Enteropathy-type T-cell lymphoma; Hepatosplenic
T-cell lymphoma; Subcutaneous panniculitis-like T-cell lymphoma; Angioimmunoblastic T-cell
All patients should have evaluable or measurable disease on entry to study.
Histology confirmed by Laboratory of Pathology, NCI.
Performance Status 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
Total bilirubin less than 1.5 x ULN (patients with elevation of total bilirubin consistent
with Gilbert's disease are eligible providing they have a normal direct bilirubin); AST
less than or equal to 2.5 x ULN; 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
Provides signed informed consent.
Not pregnant or nursing. This drug has unknown effects in pregnancy and on young
Willing to use contraception and continue for at least 8 weeks following the last
No active CNS lymphoma.
Patients should not have received systemic cytotoxic chemotherapy within 3 weeks of study
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.