Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

NCT ID: NCT01076556

Last Updated: 2015-11-11

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30

Brief Summary

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.

Detailed 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.

Conditions

Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (rituximab, cyclophosphamide, 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).

Group Type: EXPERIMENTAL

Alvocidib Hydrochloride

Intervention Type: DRUG

Given IV

Cyclophosphamide

Intervention Type: DRUG

Given IV

Diagnostic Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Rituximab

Intervention Type: BIOLOGICAL

Given IV

Interventions

Alvocidib Hydrochloride

Given IV

Intervention Type: DRUG

Cyclophosphamide

Given IV

Intervention Type: DRUG

Diagnostic Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Rituximab

Given IV

Intervention Type: BIOLOGICAL

Other Intervention Names

4H-1-Benzopyran-4-one, 2-(2-chlorophenyl)-5, 7-dihydroxy-8-(3-hydroxy-1-methyl-4-piperidinyl)-, hydrochloride, (-)-cis-; Flavopiridol Hydrochloride; HL-275; HMR 1275; L-86-8275; L-868275; MDL 107,826A; MDL-107826A; (-)-Cyclophosphamide; 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate; Carloxan; Ciclofosfamida; Ciclofosfamide; Cicloxal; Clafen; Claphene; CP monohydrate; CTX; CYCLO-cell; Cycloblastin; Cycloblastine; Cyclophospham; Cyclophosphamid monohydrate; Cyclophosphamidum; Cyclophosphan; Cyclophosphane; Cyclophosphanum; Cyclostin; Cyclostine; Cytophosphan; Cytophosphane; Cytoxan; Fosfaseron; Genoxal; Genuxal; Ledoxina; Mitoxan; Neosar; Revimmune; Syklofosfamid; WR- 138719; BI 695500; C2B8 Monoclonal Antibody; Chimeric Anti-CD20 Antibody; IDEC-102; IDEC-C2B8; IDEC-C2B8 Monoclonal Antibody; MabThera; Monoclonal Antibody IDEC-C2B8; PF-05280586; Rituxan; Rituximab Biosimilar BI 695500; Rituximab Biosimilar PF-05280586; Rituximab Biosimilar RTXM83; RTXM83

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Joseph Flynn

Role: PRINCIPAL_INVESTIGATOR

Ohio State University Comprehensive Cancer Center

Locations

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States

Countries

United States

Other Identifiers

NCI-2011-01373

Identifier Type: REGISTRY

Identifier Source: secondary_id

OSU 09089

Identifier Type: -

Identifier Source: secondary_id

CDR0000666448

Identifier Type: -

Identifier Source: secondary_id

OSU-09089

Identifier Type: -

Identifier Source: secondary_id

OSU 09089

Identifier Type: OTHER

Identifier Source: secondary_id

8267

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA016058

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01CA076576

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2011-01373

Identifier Type: -

Identifier Source: org_study_id