Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk 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

Recurrent Small Lymphocytic Lymphoma

Stage I Chronic Lymphocytic Leukemia

Stage I Small Lymphocytic Lymphoma

Stage II Chronic Lymphocytic Leukemia

Stage II Small Lymphocytic Lymphoma

Stage IV Chronic Lymphocytic Leukemia

Refractory Chronic Lymphocytic Leukemia

Stage III Chronic Lymphocytic Leukemia

Stage III Small Lymphocytic Lymphoma

Chronic Lymphocytic Leukemia

Prolymphocytic Leukemia

Treatments

Biological: Rituximab

Drug: Alvocidib Hydrochloride

Drug: Cyclophosphamide

Other: Pharmacological Study

Other: Diagnostic Laboratory Biomarker Analysis

Study type

Interventional

Funder types

NIH

Identifiers

NCT01076556

CDR0000666448

U01CA076576 (U.S. NIH Grant/Contract)

OSU-09089

OSU 09089

8267 (Other Identifier)

NCI-2011-01373 (Registry Identifier)

P30CA016058 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

This phase I trial is studying the side effects and the best dose of alvocidib when given together with cyclophosphamide and rituximab in treating patients with high risk B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Alvocidib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, can also block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Other find cancer cells and help kill them or carry cancer-killing substances to them. Giving cyclophosphamide, alvocidib, and rituximab together may kill more cancer cells.

Full description

PRIMARY OBJECTIVES:

I. To determine the dose-limiting toxicity and maximum-tolerated dose of treatment with cyclophosphamide, alvocidib, and rituximab in patients with high-risk B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.

II. To determine the feasibility of administering this regimen as an outpatient regimen in these patients.

SECONDARY OBJECTIVES:

I. To determine the complete response rate, partial response rate, and minimal-residual disease-negative response rate in patients treated with this regimen.

II. To determine the pharmacokinetics of alvocidib and dexamethasone as part of this regimen.

III. To determine the immunologic effects of this regimen as measured by serial T-cell and NK-cell number, T-cell function, and immunoglobulin levels.

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

Patients receive rituximab IV over 4 hours on days 1 (days 1-3 in course 1), cyclophosphamide IV over 30-60 minutes on days 1-3, and alvocidib IV over 4.5 hours on days 1 and 8 (day 8 only in course 1). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Blood samples are collected periodically for pharmacokinetic and pharmacodynamic studies.

After completion of study treatment, patients are followed up for up to 5 years.

Enrollment

9 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

Histologically confirmed chronic lymphocytic leukemia (CLL) or B-cell prolymphocytic leukemia* (PLL) arising from CLL
- Patients must have documented B-cell lymphocytosis > 5 x 10^9/L at some point since initial diagnosis of CLL
- Patients must have B-cells that co-express CD5 with CD19 or CD20
- Patients who do not have dim sIg or CD23 expression on their leukemia cells should be examined for cyclin D1 over-expression or t(11;14) to rule out mantle cell lymphoma
To be considered high risk, patients must meet the following criteria:
- At least 1 of the following:
  - 17p deletion
  - 11q deletion
  - Un-mutated IgV_H (≥ 98% homology)
  - Age > 70 years
  - B_2M > 4
- AND at least 1 of the following:
  - Progressive or marked splenomegaly and/or lymphadenopathy
  - Anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100,000/mm^3)
  - Weight loss exceeding 10% of body weight over preceding 6 months
  - NCI grade 2 or 3 fatigue
  - Fevers > 100.5° F or night sweats for > 2 weeks without evidence of infection
  - Progressive lymphocytosis, with an increase exceeding 50% over a 2-month period or a doubling time of < 6 months
No other concurrent hormones, chemotherapy, or radiotherapy except for steroids for new adrenal failure or hormones for nondisease-related conditions (e.g., insulin for diabetes)
- No requirement for chronic corticosteroids
ECOG performance status 0-2
Creatinine ≤ 2.0 mg/dL
Bilirubin ≤ 1.5 times normal unless due to Gilbert disease, hemolysis, or disease infiltration of the liver
AST ≤ 2 times normal unless due to hemolysis or disease infiltration of the liver
Negative pregnancy test
Not pregnant or nursing
Fertile patients must use effective contraception
No secondary or other malignancy that will limit survival to < 2 years
No uncontrolled concurrent illness including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situations that would limit compliance with study requirements
No uncompensated HIV without adequate CD4 (> 200/mm^3) and requiring HIV medication
No active hepatitis B infection
No known G6PD deficiency
No history of allergic reactions attributed to compounds of similar chemical or biologic composition to alvocidib, cyclophosphamide, rituximab, or other agents used in this study
No prior alvocidib
No prior purine analog therapy
No more than 1 prior treatment with a biologic or alkylating agent
No other concurrent investigational agents