Alvocidib, Fludarabine Phosphate, and Rituximab in Treating Patients With Lymphoproliferative Disorders or Mantle Cell Lymphoma

PRIMARY OBJECTIVES:

I. To determine a safe and tolerated dose of flavopiridol (alvocidib) in combination with standard dose rituximab and fludarabine (fludarabine phosphate) in patients with indolent B-cell lymphoproliferative disorders and mantle cell lymphoma.

II. To assess the toxicity of the combination regimen of flavopiridol, rituximab and fludarabine in patients with indolent B-cell lymphoproliferative disorders and mantle cell lymphoma.

III. To determine the safety, toxicity and efficacy of administering flavopiridol as a 30-minute bolus followed by 4-hour infusion, in combination with rituximab and fludarabine in patients with indolent B-cell lymphoproliferative disorders and mantle cell lymphoma.

SECONDARY OBJECTIVES:

I. To determine pharmacokinetics of the combination regimen of flavopiridol, rituximab and fludarabine in patients with indolent B-cell lymphoproliferative disorders and mantle cell lymphoma.

II. To determine pharmacodynamics of the combination regimen of flavopiridol, rituximab and fludarabine in patients with indolent B-cell lymphoproliferative disorders and mantle cell lymphoma.

OUTLINE: This is a dose-escalation study of alvocidib.

Patients receive fludarabine phosphate intravenously (IV) over 15-30 minutes on days 1-5 and rituximab IV over 3-4 hours on day 1. Alvocidib is administered IV over 60 minutes on day 1 in cohort 1; on days 1 and 2 in cohort 2; and on days 1, 2, and 3 in cohort 3. In cohorts 4 and 5, patients receive fludarabine phosphate and rituximab as above and alvocidib IV over 30 minutes and then IV over 4 hours on day 1 of courses 2-6. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.

Inclusion criteria

• Histologically confirmed mantle cell lymphoma OR indolent B-cell lymphoproliferative disorders of any of the following types:

• Chronic lymphocytic leukemia
• Small lymphocytic lymphoma
• Follicular center cell non-Hodgkin's lymphoma (grade I or II)
• Marginal zone lymphoma
• Waldenstrom's macroglobulinemia
• Hairy cell leukemia
• Previously untreated or relapsed/refractory disease
• No evidence of histological transformation to an intermediate-grade or aggressive lymphoma
• CD20 positive by immunoperoxidase or flow cytometry
• Evaluable disease with presence of 1 of the following criteria:

• Absolute lymphocyte count greater than 5,000/mm^3
• At least 1 measurable node greater than 2 cm by computed tomography (CT) scan OR measurable disease in a lymphoid structure (spleen)
• Bone marrow involvement (greater than 20% of marrow cellularity)
• Performance status - Eastern Cooperative Oncology Group (ECOG) 0-2
• See Disease Characteristics
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 9.0 g/dL
• Bilirubin no greater than 2 times normal
• Aspartate aminotransferase (AST) no greater than 2 times normal
• Creatinine no greater than 2.0 mg/dL
• Creatinine clearance at least 50 mL/min
• No renal dysfunction that would impair tolerance or compliance with study therapy
• No cardiac dysfunction that would impair tolerance or compliance with study therapy
• No pulmonary dysfunction that would impair tolerance or compliance with study therapy
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No chronic gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, short gut syndrome) that would impair tolerability of compliance with therapy
• No neurological or psychiatric dysfunction that would impair tolerability of or compliance with study therapy
• At least 6 weeks since prior nitrosourea or mitomycin
• No more than 6 prior courses of fludarabine
• No concurrent corticosteroids as antiemetics
• At least 4 weeks since prior therapy for disease
• No more than 3 prior treatments for disease (not including steroids alone)