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
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.
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.
Inclusion Criteria:
Diagnosis of 1 of the following:
Must have received 1-3 prior therapies for CLL
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: