Early or Delayed Fludarabine and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia - Full Text View

Sponsors and Collaborators:	Cancer and Leukemia Group B National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00513747

Purpose

RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving fludarabine together with rituximab may kill more cancer cells. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving fludarabine together with rituximab early is more effective than giving fludarabine and rituximab after observation in treating chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying fludarabine and rituximab to compare how well they work when given early or after observation in treating patients with previously untreated chronic lymphocytic leukemia.

Condition	Intervention	Phase
Leukemia	Biological: rituximab Drug: fludarabine phosphate	Phase III

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

Drug Information available for: Fludarabine Fludarabine monophosphate Rituximab

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized
Official Title:	A Phase III Intergroup CLL Study of Asymptomatic Patients With Untreated Chronic Lymphocytic Leukemia Randomized to Early Intervention Versus Observation With Later Treatment in the High Risk Genetic Subset With IGVH Unmutated Disease

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

Primary Outcome Measures:

Time to second treatment (TT2T) [ Designated as safety issue: No ]

Secondary Outcome Measures:

Proportion of patients with mutated and unmutated IgVH genes [ Designated as safety issue: No ]
Toxicity [ Designated as safety issue: Yes ]
Correlation of pretreatment clinical and biological characteristics with response, TT2T, and overall survival (OS) in high-risk patients [ Designated as safety issue: No ]
Correlation of pretreatment clinical and biological characteristics with time to first treatment (as measured from study registration date) in low-risk patients [ Designated as safety issue: No ]
Distribution of time to first treatment (as measured from study registration date) and OS in low-risk patients [ Designated as safety issue: No ]
Description of patterns of resistance (in terms of clonal evolution) in relapsed patients [ Designated as safety issue: No ]
PCR status (positive/negative) at end of treatment as a predictor of TT2T and OS [ Designated as safety issue: No ]

Estimated Enrollment:	1750
Study Start Date:	January 2008
Estimated Primary Completion Date:	February 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Arm I: Experimental Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Biological: rituximab Given IV over 4 hours Drug: fludarabine phosphate Given IV over 30 minutes
Arm II: Active Comparator Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Biological: rituximab Given IV over 4 hours Drug: fludarabine phosphate Given IV over 30 minutes

Arms

Assigned Interventions

Arm I: Experimental

Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.

Biological: rituximab

Given IV over 4 hours

Drug: fludarabine phosphate

Given IV over 30 minutes

Arm II: Active Comparator

Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.

Biological: rituximab

Given IV over 4 hours

Drug: fludarabine phosphate

Given IV over 30 minutes

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Detailed Description:

OBJECTIVES:

Primary

To determine if early treatment with chemoimmunotherapy comprising fludarabine phosphate and rituximab extends the time to second treatment in patients with genetically high-risk (unmutated IgV_H), asymptomatic, previously untreated chronic lymphocytic leukemia (CLL).
To determine the time to disease progression that would warrant second treatment.
To determine overall survival.

Secondary

To measure the proportion of patients with asymptomatic, previously untreated CLL who have mutated and unmutated IgV_H genes.
To determine the differences in acute and chronic toxicity of administering chemoimmunotherapy early to patients with genetically high-risk CLL compared to waiting until symptoms develop.
To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction [primary and secondary]) on response, time to second treatment, and overall survival of patients with genetically high-risk CLL randomized to early treatment.
To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction) on response, time to first and second treatments, and overall survival of patients with genetically high-risk CLL randomized to standard treatment (observation until symptoms occur).
To describe the natural history of patients with genetically low-risk (mutated IgV_H genes), asymptomatic, previously untreated CLL, in terms of time to initial treatment, response, progression, and survival.
To determine the effect of select pretreatment characteristics on time to first treatment, response, progression, and survival of patients with genetically low-risk CLL.
To correlate patterns of resistance that emerge in patients with unmutated IgV_H genes who have relapsing or refractory CLL following receipt of chemoimmunotherapy with clonal evolution, including acquisition of high-risk karyotype abnormalities, p53 mutations, p53 dysfunction (primary and secondary), altered mRNA and protein expression related to treatment resistance, DNA mutations, microRNA gene expression, and methylation changes.
To determine whether highly sensitive flow cytometry negativity at completion of therapy in patients randomized to early treatment is an effective surrogate marker for prolonged time to second treatment, overall survival, and other clinical benefits.
To collect demographic data on familial CLL in newly diagnosed patients participating on this study.

OUTLINE: This is a multicenter study.

Genetically high-risk disease: Patients are stratified according to age (< 50 years vs 50 to 70 years vs > 70 years) and presence of the high-risk genetic feature [del(11)(q22.3) or del(17)(p13.1)] by FISH (yes vs no). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.
- Arm II: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
Genetically low-risk disease: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.

Patients undergo blood sample collection periodically for correlative studies.

After finishing treatment, patients are followed periodically for up to 25 years.

Eligibility

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

Criteria

DISEASE CHARACTERISTICS:

Clinical and immunophenotypic evidence of B-cell chronic lymphocytic leukemia (CLL) diagnosed within the past 6 months AND meets the following criteria:
- An absolute lymphocytosis of > 5,000/μL
- Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes
- Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers
  - B-cells must be monoclonal with regard to expression of either κ or λ and have surface immunoglobulin expression of low density
  - Patients with bright surface immunoglobulin levels must have CD23 coexpression and absence of t(11;14) on interphase cytogenetics or have negative tumor protein staining for cyclin D1
Low-risk category (i.e., only stages 0 or I) of the modified three-stage Rai staging system
No evidence of active or progressive disease as demonstrated by any of the following:
- Massive or progressive splenomegaly and/or lymphadenopathy that requires therapy
- Progressive lymphocytosis with an increase of > 50% over a 2-month period or an anticipated doubling time of less than 6 months
- Presence of weight loss > 10% over the preceding 6-month period
- Grade 2 or 3 fatigue
- Fevers > 100.5°F and/or night sweats for greater than 2 weeks without evidence of infection
- Development of anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100,000/μL)
Must have undergone IgV_H mutation testing and be classified according to the following:
- Genetically low-risk disease
  - IgV_H mutated
  - Less than 98% IgV_H homology
- Genetically high-risk disease
  - IgV_H unmutated
  - At least 98% IgV_H homology
Registration on leukemia correlative substudy CALGB-20601 required

PATIENT CHARACTERISTICS:

Performance status 0-1
Creatinine ≤ 1.5 times upper limit of normal
No HIV disease
Not pregnant or nursing
Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

No prior therapy for CLL, including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL
No concurrent hormones or other chemotherapy except for steroids for hypersensitivity reactions or new adrenal failure (chronic requirement for steroids is an exclusion criterion for this study) or hormones for non-disease-related conditions (e.g., insulin for diabetes)
No concurrent palliative radiotherapy
Concurrent enrollment on CALGB-9665 allowed

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00513747

Show 314 Study Locations

Sponsors and Collaborators

Cancer and Leukemia Group B

National Cancer Institute (NCI)

Investigators

Study Chair:

John C. Byrd, MD

Arthur G. James Cancer Hospital & Richard J. Solove Research Institute

More Information

Additional Information:

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

No publications provided

Study ID Numbers:	CDR0000537685, CALGB-10501
Study First Received:	August 8, 2007
Last Updated:	February 12, 2009
ClinicalTrials.gov Identifier:	NCT00513747
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

B-cell chronic lymphocytic leukemia
stage 0 chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia

Study placed in the following topic categories:

Chronic lymphocytic leukemia
Lymphatic Diseases
Leukemia
Leukemia, Lymphoid
Immunoproliferative Disorders
Rituximab

Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-cell, chronic
Fludarabine
Fludarabine monophosphate
Lymphoproliferative Disorders
Leukemia, B-Cell

Additional relevant MeSH terms:

Antimetabolites
Neoplasms by Histologic Type
Antimetabolites, Antineoplastic
Immune System Diseases
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents

Physiological Effects of Drugs
Immunosuppressive Agents
Pharmacologic Actions
Neoplasms
Therapeutic Uses
Antirheumatic Agents

ClinicalTrials.gov processed this record on February 12, 2009