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

National Cancer Institute (NCI)

Status and phase: Terminated; Phase 1

Conditions: Stage IV Small Lymphocytic Lymphoma; Contiguous Stage II Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; B-cell Chronic Lymphocytic Leukemia; Noncontiguous Stage II Small Lymphocytic Lymphoma

Treatments: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: alvocidib

Study type: Interventional

Funder types: NIH

Identifiers

NCT00377104

U01CA076576 (U.S. NIH Grant/Contract)

OSU-05116

OSU-IRB-2006C0031

NCI-2009-00161

CDR0000501975

OSU 05116

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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)

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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24 participants in 1 patient group

Treatment (chemotherapy)

Experimental group

Description:

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.

Treatment:

Drug: alvocidib

Other: laboratory biomarker analysis

Other: pharmacological study