Alvocidib in Treating Patients With B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

B-cell Chronic Lymphocytic Leukemia Clinical Trial

Official title:

A Phase I Dose-Escalation Study of Flavopiridol (NSC 649890) Administered as a 30 Minute Loading Dose Followed by a 4-Hour Infusion in Patients With B-Cell Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Following Cytoreduction With Chemotherapy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00377104
• Other study ID #: NCI-2009-00161
• Secondary ID: OSU 05116OSU-IRB
• Status: Terminated
• Phase: Phase 1
• First received: September 13, 2006
• Last updated: July 1, 2013
• Start date: September 2006

Study information

• Verified date: July 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase I trial is studying the side effects and best dose of flavopiridol in treating patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Drugs used in chemotherapy, such as alvocidib, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Description:

PRIMARY OBJECTIVES:

I. Determine the toxicity profile, dose-limiting toxicity, and maximum tolerated dose of flavopiridol (alvocidib) as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics and cellular pharmacodynamics of flavopiridol in these patients.

II. Determine the complete response (CR) and overall response rate (CR and partial response) of patients treated with flavopiridol.

OUTLINE: This is a dose-escalation study. Patients receive alvocidib intravenously (IV) over 30 minutes (loading dose), followed by alvocidib IV over 4 hours on days 1, 8, and 15.

Treatment repeats every 5 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of flavopiridol until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. A total of 12 patients are treated at the MTD (i.e., recommended phase II dose). Patients undergo blood collection at baseline and periodically during study for pharmacokinetic and cytokine studies (levels of tumor necrosis factor-alpha, interleukin [IL]-6, -11, and -16) by enzyme-linked immunosorbent assay (ELISA). Interphase cytogenetics, p53 mutational status, p53/ATM function, V_H mutational status, zeta-chain-associated protein kinase 70 (ZAP-70) overexpression, and single nucleotide polymorphisms are also examined.

After completion of study treatment, patients are followed at 2 months and then every 3 months for 5 years.

Other known NCT identifiers

• NCT01645579

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 24
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of 1 of the following:

• B-cell chronic lymphocytic leukemia (CLL)

• Small lymphocytic lymphoma (SLL)

• Must have received 1-3 prior therapies for CLL

• Completed therapy 2-12 months ago

• Prior therapy must have led to a partial response or greater

• No evidence of progressive disease

• ECOG performance status 0-2

• Absolute neutrophil count = 1,000/mm³

• WBC = 5,000/mm³

• Platelet count = 50,000/mm³

• Cytopenia allowed

• Creatinine < 2.0 mg/dL

• Bilirubin = 1.5 times normal (unless due to Gilbert's disease or hemolysis)

• AST = 2 times normal (unless due to hemolysis)

• No secondary malignancy or other disease that would limit survival to < 2 years

• No history of inflammatory bowel disease unless inactive for > 2 years

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• See Disease Characteristics

• No other concurrent chemotherapy

• No concurrent radiotherapy

• No concurrent dexamethasone or other corticosteroid-based antiemetics

• No concurrent chronic corticosteroid therapy

• No other concurrent hormonal therapy except for the following:

• Steroids for new adrenal failure

• Hormones for nondisease-related conditions (e.g., insulin for diabetes)

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• B-cell Chronic Lymphocytic Leukemia
• Contiguous Stage II Small Lymphocytic Lymphoma
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Noncontiguous Stage II Small Lymphocytic Lymphoma
• Stage I Chronic Lymphocytic Leukemia
• Stage I Small Lymphocytic Lymphoma
• Stage II Chronic Lymphocytic Leukemia
• Stage III Chronic Lymphocytic Leukemia
• Stage III Small Lymphocytic Lymphoma
• Stage IV Chronic Lymphocytic Leukemia
• Stage IV Small Lymphocytic Lymphoma

Intervention

Drug:
• alvocidib
Given IV

Other:
• pharmacological study
Correlative studies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
United States	Ohio State University Medical Center	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Toxicity profile of alvocidib administered as a 30 minute loading dose followed by a 4-hour infusion once weekly for 3 consecutive weeks every 5 weeks as consolidation therapy following cytoreduction chemotherapy	Assessed utilizing the NCI Common Terminology Criteria for Adverse Events version 3.0.	Day 1, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment	Yes
Primary	Dose-limiting toxicity of alvocidib as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma	The National Cancer Institute Common Toxicity Criteria version 3.0 will be used to characterize toxicity. If no patients experience dose-limiting toxicity, dose escalation will occur. If 1 patient has a dose limiting toxicity, 3 additional patients will be enrolled at that dose. If fewer than 2 of 6 patients experiences dose limiting toxicity, then the next highest dose level will be used for the subsequent cohort of 3 patients. If at any dose level two or more of the six patients experience a dose limiting toxicity, 3 additional patients will be treated at the previous dose level.	Course 1	Yes
Secondary	Pharmacokinetics and cellular pharmacodynamics of alvocidib administered in this schedule	Cytokine studies will be examined by standard ELISA assays to determine if increase IL-6 correlates with hypotension, hypoxemia, and tachycardia observed following treatment and to identify the source of production of this cytokine. We will examine interphase cytogenetics, p53 mutational status, p53/ATM functional assay, VH mutational status, and ZAP-70 over-expression.	Baseline and day 1	No
Secondary	Complete response (CR) and overall response rate (CR and partial response) of alvocidib in patients with previously-treated CLL	Criteria for response will utilize the Revised National Cancer Institute-sponsored Working Group Guidelines.	Baseline, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment	No