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

July 1, 2013 updated by: National Cancer Institute (NCI)

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Ohio
      • Columbus, Ohio, United States, 43210
        • Ohio State University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (chemotherapy)
Patients receive alvocidib 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.
Other: laboratory biomarker analysis
Correlative studies
Drug: alvocidib
Given IV
Other Names:
  • FLAVO
  • flavopiridol
  • HMR 1275
  • L-868275
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Time Frame: Day 1, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment
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
Dose-limiting toxicity of alvocidib as consolidation chemotherapy after cytoreduction chemotherapy in patients with B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma
Time Frame: Course 1
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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pharmacokinetics and cellular pharmacodynamics of alvocidib administered in this schedule
Time Frame: Baseline and day 1
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
Complete response (CR) and overall response rate (CR and partial response) of alvocidib in patients with previously-treated CLL
Time Frame: Baseline, every 2 courses, at 2 months and then every 3 months for 5 years after completion of study treatment
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Leslie Andritsos, Ohio State University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2006

Primary Completion (Actual)

November 1, 2012

Study Registration Dates

First Submitted

September 13, 2006

First Submitted That Met QC Criteria

September 13, 2006

First Posted (Estimate)

September 15, 2006

Study Record Updates

Last Update Posted (Estimate)

July 2, 2013

Last Update Submitted That Met QC Criteria

July 1, 2013

Last Verified

July 1, 2013

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NCI-2009-00161
  • U01CA076576 (U.S. NIH Grant/Contract)
  • OSU 05116
  • OSU-IRB-2006C0031
  • CDR0000501975
  • OSU-05116

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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