UCN-01 (7-Hydroxystaurosporine) to Treat Relapsed T-Cell Lymphomas

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

Study Overview

• Status: Terminated
• Conditions: Lymphoma, T-Cell; Lymphoma, Large-Cell, Ki-1
• Intervention / Treatment: Drug: UCN-01 (7-hydroxystaurosporine)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UCN-01 for T-cell lymphomas - Cohort 1 - Every 28 days; Cycle 1: 45 mg/m^2/day continuous intravenous infusion 1 to 3 days (72 hours) for total dose of 135 mg/m^2 Cycle 2: 45 mg/m^2/day continuous intravenous infusion 1 to 2 days (36 hours) for total dose of 68 mg/m^2; Repeat cycles every 28 days.	Drug: UCN-01 (7-hydroxystaurosporine); UCN-01 for relapsed or refractory T-cell lymphomas - Cohort 1, Cycle 1: 45 mg/m^2/day continuous intravenous infusion 1 to 3 days (72 hours) for total dose of 135 mg/m^2 Cycle 2: 45 mg/m^2/day continuous intravenous infusion 1 to 2 days (36 hours) for total dose of 68 mg/m^2; Repeat cycles every 28 days. UCN-01 for relapsed or refractory T-cell lymphomas - Cohort 2, Cycle 1: 45 mg/m^2/day continuous intravenous infusion 1 to 3 days (72 hours) for total dose of 135 mg/m^2 Cycle 2: 45 mg/m^2/day continuous intravenous infusion 1 to 2 days (36 hours) for total dose of 68 mg/m^2; Repeat cycles every 21 days.; Other Names: UCN-01
Experimental: UCN-01 for T-cell lymphomas - Cohort 2 -Every 21 days; Cycle 1: 45 mg/m^2/day continuous intravenous infusion 1 to 3 days (72 hours) for total dose of 135 mg/m^2 Cycle 2: 45 mg/m^2/day continuous intravenous infusion 1 to 2 days (36 hours) for total dose of 68 mg/m^2; Repeat cycles every 21 days.	Drug: UCN-01 (7-hydroxystaurosporine); UCN-01 for relapsed or refractory T-cell lymphomas - Cohort 1, Cycle 1: 45 mg/m^2/day continuous intravenous infusion 1 to 3 days (72 hours) for total dose of 135 mg/m^2 Cycle 2: 45 mg/m^2/day continuous intravenous infusion 1 to 2 days (36 hours) for total dose of 68 mg/m^2; Repeat cycles every 28 days. UCN-01 for relapsed or refractory T-cell lymphomas - Cohort 2, Cycle 1: 45 mg/m^2/day continuous intravenous infusion 1 to 3 days (72 hours) for total dose of 135 mg/m^2 Cycle 2: 45 mg/m^2/day continuous intravenous infusion 1 to 2 days (36 hours) for total dose of 68 mg/m^2; Repeat cycles every 21 days.; Other Names: UCN-01

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Response Rate	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	74.5 months
Progression Free Survival (PFS)	PFS is defined as the time interval from start of treatment to documented evidence of disease progression. Disease progression is assessed by the International Workshop to Standardize Response Criteria for non-Hodgkin's Lymphomas and is defined as a ≥50% increase from nadir in the sum of the products of the greatest diameters of any previously identified abnormal node for partial response's or non-responders or appearance of any new lesion during or at the end of therapy.	3.6 months
Overall Survival (OS)	OS is defined as the date of on-study to the date of death from any cause or last follow up.	55 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.	76 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of UCN-01 on Soluble TAC Cluster of Differentiation 25 (CD25)	Soluble TAC (CD25) levels will be assessed in patients with anaplastic large cell lymphoma.	Day 3-5 after drug administration
Evaluation of Mature T-cell Lymphoma Cells by Complementary Double-Stranded Deoxyribonucleic Acid (cDNA) Microarray	Mature T-cells will be analyzed to identify gene expression changes that correlate with loss of a tumor suppressor gene in a human melanoma cell line.	Day 3-5 after drug administration
Effect of UCN-01 on Anaplastic Lymphoma Kinase (ALK) Expression in ALCL	Gene expression patterns in participants ALK positive tumors will be assessed.	Day 3-5 after drug administration

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Wyndham Wilson, M.D., National Cancer Institute, National Institutes of Health

Publications and helpful links

General Publications

• Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol. 1998 Aug;16(8):2780-95. doi: 10.1200/JCO.1998.16.8.2780.
• Stein H, Mason DY, Gerdes J, O'Connor N, Wainscoat J, Pallesen G, Gatter K, Falini B, Delsol G, Lemke H, et al. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985 Oct;66(4):848-58.
• Falini B, Pileri S, Zinzani PL, Carbone A, Zagonel V, Wolf-Peeters C, Verhoef G, Menestrina F, Todeschini G, Paulli M, Lazzarino M, Giardini R, Aiello A, Foss HD, Araujo I, Fizzotti M, Pelicci PG, Flenghi L, Martelli MF, Santucci A. ALK+ lymphoma: clinico-pathological findings and outcome. Blood. 1999 Apr 15;93(8):2697-706.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2004
• Primary Completion (Actual): September 27, 2011
• Study Completion (Actual): September 27, 2011

Study Registration Dates

• First Submitted: April 28, 2004
• First Submitted That Met QC Criteria: April 27, 2004
• First Posted (Estimate): April 28, 2004

Study Record Updates

• Last Update Posted (Actual): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 1, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Lymphoma; Gene Expression Profiling; Anaplastic Large Cell Lymphoma; ALCL; Apoptosis; T-Cell Lymphoma; Protein Kinase Inhibition; Soluble Tac; ALK Expression
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Lymphoma, Large-Cell, Anaplastic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; 7-hydroxystaurosporine
• Other Study ID Numbers: 040173; 04-C-0173

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes