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Phase II Study of UCN-01 in Relapsed or Refractory Systemic Anaplastic Large Cell and Mature T-Cell Lymphomas


Phase 2
12 Years
N/A
Not Enrolling
Both
Lymphoma, Large-Cell, Ki-1, Lymphoma, T-Cell

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Trial Information

Phase II Study of UCN-01 in Relapsed or Refractory Systemic Anaplastic Large Cell and Mature T-Cell Lymphomas


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


- 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.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical Response Rate

Outcome Description:

Clinical Response Rate is the percentage of participants with a response assessed by the International Workshop to Standardize Response Criteria. Complete response (CR) is complete disappearance of all detectable clinical and radiographic evidence of disease. Complete response unconfirmed (CRu) is per CR criteria except that if a residual node is >1.5cm, it must have regressed by >75%. Partial response (PR) is no increase in size of nodes, liver or spleen. Progressive disease (PD) is a greater than or equal to 50% increase from nadir. Details re: response criteria, see the protocol link module

Outcome Time Frame:

74.5 months

Safety Issue:

No

Principal Investigator

Wyndham Wilson, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health

Authority:

United States: Federal Government

Study ID:

040173

NCT ID:

NCT00082017

Start Date:

April 2004

Completion Date:

September 2011

Related Keywords:

  • Lymphoma, Large-Cell, Ki-1
  • Lymphoma, T-Cell
  • Protein Kinase Inhibition
  • Soluble Tac
  • Gene Expression Profiling
  • ALK Expression
  • Apoptosis
  • Lymphoma
  • Anaplastic Large Cell Lymphoma
  • ALCL
  • T-Cell Lymphoma
  • Lymphoma
  • Lymphoma, Large B-Cell, Diffuse
  • Lymphoma, T-Cell
  • Lymphoma, Large-Cell, Anaplastic

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892