This study will test the safety and effectiveness of UCN-01, an experimental drug, together with fludarabine, a standard treatment for low-grade lymphomas and leukemias, in treating these cancers. Laboratory studies have shown that UCN-01 inhibits (slows or prevents) tumor cell growth and may also destroy some cells. Laboratory studies have also shown that when UCN-01 was combined with fludarabine, it increased fludarabine's effectiveness as much as 10 times.

Patients with low-grade relapsed lymphoma or leukemia who are candidates for this study will undergo various tests. These may include blood tests, X rays, CT and MRI scans, nuclear medicine scans, and bone marrow biopsy and aspiration to determine the extent of the patient's disease. For those accepted to the study, some or all of these tests will be repeated at various times during the study, for up to two years after treatment is completed.

Treatment will consist of up to six courses, or cycles, of UCN-01 and fludarabine given in combination. Each patient will first receive UCN-01 alone to determine if it is safe for that patient. Then, UCN-01 and fludarabine will be given together. UCN-01 will be infused through a vein over a period of 36 hours (except for the first course, which will take 72 hours) and fludarabine will be infused over 30 minutes. Fludarabine will be given from one to five days, starting the same day the UCN-01infusion begins. The cycle is repeated at four-week intervals.

Patients may also be asked to undergo additional bone marrow biopsy and aspirations and apheresis-a procedure to remove white blood cells-for research purposes, but these tests are not required to participate in the study.

Condition	Treatment or Intervention	Phase
Chronic Lymphocytic Leukemia Hairy Cell Leukemia Leukemia Lymphoma Waldenstrom Macroglobulinemia	Drug: UCN-01	Phase I

Further Study Details: 

Expected Total Enrollment:  20

We are interested in identifying agent(s) that may decrease the threshold for cytotoxic-induced apoptosis. The novel staurosporine analog, 7-hydroxystaurosporine (UCN-01: NSC 638850), appears to increase cytotoxic-induce apoptosis, and thus may decrease the threshold for apoptosis. UCN-01 is a non-specific protein and tyrosine kinase inhibitor that regulates signal transduction, and is synergistic in vitro with a number of chemotherapy agents. Thus, UCN-01 may augment the activity of chemotherapy in drug resistant patients. To begin to assess this, we wish to assess the tolerance of UCN-01 and fludarabine in patients with relapsed indolent lymphoid malignancies. We have selected indolent lymphomas based on the clinical evidence that as a group, they are responsive to fludarabine. The study will be a phase I and pharmacokinetic study. Patients will initially receive 1 cycle of UCN-01 alone to allow measurement of PK and other scientific endpoints. Leukopheresis for normal T-cells in patients without leukemias and for circulating tumor cells in patients with leukemias will be performed and analyzed by gene chip technology for alterations in mRNA expression and kinase activity. Furthermore, FACS analysis for CD4, CD8, CD45RO, CD4RA will be performed before and after 1 cycle of UCN-01 to assess effects on T-cell number and distribution. Following 1 cycle of UCN-01 alone, patients will crossover to receive UCN-01 and fludarabine beginning on cycle 2. PK of UCN-01 and fludarabine will be repeated when the combination is administered. Furthermore, gene chip and FACS analysis would be performed during the combination cycles as well.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
Relapsed or refractory low-grade lymphoid malignancies (follicular small cleaved-grade I/II subtypes; marginal zone-nodal/extranodal/ splenic subtypes; small lymphocytic-lymphoma/leukemia subtypes (CLL); Waldenstrom's macroglobulinemia, mantle cell; lymphoplasmacytoid; Hairy cell leukemia.
Patients with transformed indolent subtypes are eligible providing they have previously received a doxorubicin-containing regimen or do not have rapidly progressive disease that threatens vital functions.
Histology confirmed by Laboratory of Pathology, NCI.
Requires systemic therapy.
Performance Status greater than or equal to 60%.
Age 18 years or older.
Creatinine less than 1.5 mg/dl or creatinine clearance greater than 60 ml/min; total bilirubin less than 2.0 mg/dl (patients with elevation of total bilirubin consistent with Gilbert's disease are eligible providing they have a normal direct bilirubin); ANC greater than or equal to 1000/mm(3); and platelet greater than or equal to 80,000/mm(3).
Measurable disease.
Recovered from acute effects of prior therapy.
Provides signed informed consent.
EXCLUSION CRITERIA:
HIV positive serology.
Pregnant or nursing. The effects of these agents on an unborn or breastfeeding child are unknown. Because there is a risk of detrimental effects on an unborn or breastfeeding child, pregnant or nursing women will be excluded fpr the study. Both male and female patients must be willing to use adequate contraception.
Active leptomeningeal or parenchymal CNS lymphoma.
Active Coombs + hemolytic anemia.
Systemic chemotherapy or systemic steroids within 3 weeks of study entry.
Diabetes mellitus requiring insulin treatment.
History of active coronary artery disease (defined by angina, congestive heart failure or myocardial infarction with 6 months).

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

Study ID Numbers:  990127; 99-C-0127
Record last reviewed:  June 1, 2004
Last Updated:  November 23, 2004
Record first received:  November 3, 1999
ClinicalTrials.gov Identifier:  NCT00001822
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08