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

Study Description

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Brief 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.

Condition or disease	Intervention/treatment	Phase
B-cell Chronic Lymphocytic Leukemia; Contiguous Stage II Small Lymphocytic 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	Drug: alvocidib; Other: pharmacological study; Other: laboratory biomarker analysis	Phase 1

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	24 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Study Start Date :	September 2006
Actual Primary Completion Date :	November 2012

Arms and Interventions

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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.	Drug: alvocidib; Given IV; Other Names: FLAVO; flavopiridol; HMR 1275; L-868275 Other: pharmacological study; Correlative studies; Other Name: pharmacological studies Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

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Primary Outcome Measures :

1. 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.
2. 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.

Secondary Outcome Measures :

1. 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.
2. 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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)

Contacts and Locations

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Locations

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

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Leslie Andritsos	Ohio State University

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Awan FT, Jones JA, Maddocks K, Poi M, Grever MR, Johnson A, Byrd JC, Andritsos LA. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy. Ann Hematol. 2016 Jun;95(7):1137-43. doi: 10.1007/s00277-016-2683-1. Epub 2016 Apr 27.

Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00377104 History of Changes
Obsolete Identifiers:	NCT01645579
Other Study ID Numbers:	NCI-2009-00161; OSU 05116; OSU-IRB-2006C0031; CDR0000501975; OSU-05116; U01CA076576 ( U.S. NIH Grant/Contract )
First Posted:	September 15, 2006
Last Update Posted:	July 2, 2013
Last Verified:	July 2013

Additional relevant MeSH terms:

Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Leukemia; Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases	Leukemia, B-Cell; Alvocidib; Antineoplastic Agents; Growth Inhibitors; Growth Substances; Physiological Effects of Drugs; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action