Fludarabine With or Without Cyclophosphamide in Treating Patients With Chronic Lymphocytic Leukemia - Full Text View

Sponsor:	Eastern Cooperative Oncology Group
Collaborators:	National Cancer Institute (NCI) Cancer and Leukemia Group B Southwest Oncology Group
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00003764

Purpose

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known whether combining cyclophosphamide with fludarabine is more effective than fludarabine alone in treating chronic lymphocytic leukemia.

PURPOSE: Randomized phase III trial to study the effectiveness of fludarabine with or without cyclophosphamide in treating patients who have chronic lymphocytic leukemia that has not been treated previously.

Condition	Intervention	Phase
Leukemia	Drug: cyclophosphamide Drug: fludarabine phosphate	Phase III

Study Type:	Interventional
Study Design:	Treatment, Randomized, Active Control
Official Title:	Phase III Randomized Trial of Fludarabine and Cyclophosphamide Versus Fludarabine for Previously Untreated Chronic Lymphocytic Leukemia

Resource links provided by NLM:

MedlinePlus related topics: Cancer Leukemia, Adult Acute Leukemia, Adult Chronic

Drug Information available for: Cyclophosphamide Fludarabine Fludarabine monophosphate

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Estimated Enrollment:	280
Study Start Date:	December 1999

Detailed Description:

OBJECTIVES:

Compare the efficacy of fludarabine with or without cyclophosphamide in terms of complete remission rate and overall survival in patients with previously untreated B cell chronic lymphocytic leukemia (CLL).
Compare the toxicities of these 2 regimens in this patient population.
Determine whether the expression of proteins specifically implicated in the regulation of DNA damage induced apoptosis of lymphoid cells (i.e., p53; mdm2; GST; Bcl-2; Mcl-1; Bax; p27; and caspase-3) correlates with response to chemotherapy in these patients.
Determine whether there is a relationship between clinical response or resistance and differential expression of genes in the CLL cells either at initiation of therapy or following relapse and progression.
Correlate mutations in immunoglobulin heavy chain variable region genes with clinical response or resistance in this patient population.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to stage of disease (O-II vs III-IV). Patients are randomized to one of two treatment arms.

Arm I: Patients receive fludarabine IV over 30 minutes on days 1-5.
Arm II: Patients receive fludarabine as in arm I plus cyclophosphamide IV over 1 hour on day 1.

Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years and then every 6 months until disease progression.

PROJECTED ACCRUAL: A total of 280 patients will be accrued for this study over 2 to 2.5 years.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Diagnosis of chronic lymphocytic leukemia (CLL) of any stage as defined by the following:
- Peripheral blood absolute lymphocyte count greater than 5,000/mm^3 within 14 days prior to study
- Lymphocytes must be small to moderate size with no more than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically
- Phenotypically characterized as B-CLL
Must have one of the following characteristics indicating need for chemotherapy:
- Progressive marrow failure (hemoglobin less than 10 g/dL and/or platelet count less than 100,000/mm^3)
- Progressive lymphocytosis with an increase of more than 50% over a 2 month period or anticipated doubling time of less than 6 months
- Massive (i.e., greater than 6 cm below left costal margin) or progressive splenomegaly
- Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or progressive adenopathy
- At least 10% weight loss within 6 months of study
- Extreme fatigue
- Fevers greater than 100.5 degrees F for 2 weeks without evidence of infection
- Night sweats without evidence of infection
No autoimmune anemia or autoimmune thrombocytopenia

PATIENT CHARACTERISTICS:

Age:

18 and over

Performance status:

ECOG 0-2

Life expectancy:

Not specified

Hematopoietic:

See Disease Characteristics

Hepatic:

Bilirubin no greater than 2 mg/dL unless secondary to tumor

Renal:

Creatinine no greater than 2.0 mg/dL
Creatinine clearance at least 40 mL/min if creatinine is greater than 1.5 mg/dL

Other:

No other prior or concurrent malignancy within the past 2 years except basal cell carcinoma of the skin or carcinoma in situ of the cervix
No active infection requiring oral or intravenous antibiotics
Not pregnant or nursing
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy:

Not specified

Chemotherapy:

No prior cytotoxic chemotherapy

Endocrine therapy:

No prior steroid treatment for CLL

Radiotherapy:

Not specified

Surgery:

Not specified

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00003764

Show 218 Study Locations

Sponsors and Collaborators

Eastern Cooperative Oncology Group

National Cancer Institute (NCI)

Cancer and Leukemia Group B

Southwest Oncology Group

Investigators

Study Chair:	Ian W. Flinn, MD, PhD	Sidney Kimmel Comprehensive Cancer Center
Study Chair:	Michael R. Grever, MD	Arthur G. James Cancer Hospital & Richard J. Solove Research Institute
Study Chair:	Mohamad A. Hussein, MD	The Cleveland Clinic

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Publications:

Flinn IW, Neuberg DS, Grever MR, Dewald GW, Bennett JM, Paietta EM, Hussein MA, Appelbaum FR, Larson RA, Moore DF Jr, Tallman MS. Phase III Trial of Fludarabine Plus Cyclophosphamide Compared With Fludarabine for Patients With Previously Untreated Chronic Lymphocytic Leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007 Feb 5; [Epub ahead of print]

Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S, Flinn IW, Tallman MS, Appelbaum FR, Larson RA, Paietta E, Jelinek DF, Gribben JG, Byrd JC. Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007 Feb 5; [Epub ahead of print]

Grever MR, Dewald GW, Neuberg DS, et al.: Select high risk genetic features predict earlier progression following chemotherapy in chronic lymphocytic leukemia: prospective randomized trial (Intergroup E2997) to evaluate justification for risk-adapted therapy. [Abstract] J Clin Oncol 24 (Suppl 18): A-6521, 342s, 2006.

Flinn IW, Kumm E, Grever MR, et al.: Fludarabine and cyclophosphamide produces a higher complete response rate and more durable remissions than fludarabine in patients with previously untreated CLL: Intergroup trial E2997. [Abstract] Blood 104 (11): A-475, 2004.

Grever MR, Lucas DM, Dewald GW, et al.: Outcome of treatment with fludarabine versus fludarabine and cyclophosphamide in chronic lymphocytic leukemia (CLL) is adversely impacted by high risk genetic features: results from ECOG 2997. [Abstract] Blood 104 (11 Pt 1): A-3487, 2004.

Dewald GW, Paietta E, Goloubeva O, et al.: Correlation of interphase fluorescence in situ hybridization (FISH) anomalies with cell morphology and immunophenotyping in chronic lymphocytic leukemia (B-CLL). [Abstract] Blood 100 (11 pt 1): A-2334, 2002.

Study ID Numbers:	CDR0000066890, ECOG-2997, CALGB-10103, SWOG-E2997
Study First Received:	November 1, 1999
Last Updated:	July 23, 2008
ClinicalTrials.gov Identifier:	NCT00003764 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

stage 0 chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia

stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Leukemia, Lymphoid
Vidarabine
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Cyclophosphamide
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Therapeutic Uses
Alkylating Agents
Immunoproliferative Disorders

Neoplasms by Histologic Type
Immune System Diseases
Fludarabine monophosphate
Antiviral Agents
Immunosuppressive Agents
Pharmacologic Actions
Lymphatic Diseases
Neoplasms
Myeloablative Agonists
Fludarabine
Antineoplastic Agents, Alkylating
Lymphoproliferative Disorders
Leukemia, B-Cell
Antirheumatic Agents

ClinicalTrials.gov processed this record on November 27, 2009