Early or Delayed Fludarabine and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia

Phase 3

Terminated

Conditions: Leukemia

Interventions: Biological: rituximab
Drug: fludarabine phosphate

Registration Number: NCT00513747

Lead Sponsor: Alliance for Clinical Trials in Oncology

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 84

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I	rituximab	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 I	fludarabine phosphate	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	rituximab	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.
Arm II	fludarabine phosphate	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.

Primary Outcome Measures

Name	Time	Method
Time to Second Treatment in High Risk Patients	Up to 72 months	Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to second treatment or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.
Disease-Free Survival in High Risk Patients	Up to 72 months	Kaplan-Meier analysis was conducted to estimate disease free survival defined as:\> * Arm A: Time from randomization until Second Treatment (first relapse) or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.\> * Arm B: Time from randomization until First Treatment (first relapse) or death whichever comes first. Events were defined as the start of first treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.
Overall Survival (OS) for High Risk Patients	Up to 72 months	Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to death from any cause. Estimates were not stratified. Patients who did not experience this primary outcome had their survival times censored at their last follow-up.

Secondary Outcome Measures

Name	Time	Method
Number of Patients With Mutated and Unmutated IgVH Genes	Once at baseline	Number of patients with mutated and unmutated IgVH genes are reported below.
Overall Survival in Low Risk Patients	Up to 72 months	Overall survival in low risk patients (registration to first treatment or death)\> • Events were defined as death from any cause. Low risk Patients who were alive were censored at their last known follow-up.
Time to First Treatment Survival in Low Risk Patients	Up to 72 months	Time to First Treatment Survival in low risk patients (registration to first treatment or death)\> • Events were defined as the start of first treatment or death from any cause. Patients who didn't receive their first treatment were censored at their last known follow-up.

Trial Locations

Locations (382): Regional Medical Center
🇺🇸
Anniston, Alabama, United States
Clearview Cancer Institute
🇺🇸
Huntsville, Alabama, United States
Sparks Regional Medical Center
🇺🇸
Fort Smith, Arkansas, United States
Providence Saint Joseph Medical Center - Burbank
🇺🇸
Burbank, California, United States
Virginia K. Crosson Cancer Center at St. Jude Medical Center
🇺🇸
Fullerton, California, United States
Memorial Medical Center
🇺🇸
Modesto, California, United States
Camino Medical Group - Treatment Center
🇺🇸
Mountain View, California, United States
Palo Alto Medical Foundation
🇺🇸
Palo Alto, California, United States
University of California Davis Cancer Center
🇺🇸
Sacramento, California, United States
Kaiser Permanente Medical Office -Vandever Medical Office
🇺🇸
San Diego, California, United States
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Regional Medical Center
🇺🇸Anniston, Alabama, United States