Rituximab and Alemtuzumab in Treating Older Patients With Progressive Chronic Lymphocytic Leukemia
- Conditions
- Chronic Lymphocytic Leukemia
- Interventions
- Biological: alemtuzumabBiological: rituximab
- Registration Number
- NCT01013961
- Lead Sponsor
- ECOG-ACRIN Cancer Research Group
- Brief Summary
RATIONALE: Monoclonal antibodies, such as rituximab and alemtuzumab, 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 rituximab together with alemtuzumab may kill more cancer cells.
PURPOSE: This randomized phase II trial is studying two different doses of rituximab to compare how well they work when given together with alemtuzumab in treating older patients with progressive chronic lymphocytic leukemia.
- Detailed Description
OBJECTIVES:
Primary
* To compare the rate of complete and overall response in elderly patients with progressive chronic lymphocytic leukemia (CLL) treated with one of two doses of rituximab combined with alemtuzumab to determine if the use of modified-dose rituximab significantly affects outcome.
Secondary
* To monitor and assess toxicity of these regimens.
* To determine the overall and progression-free survival, time to clinical response, time to next treatment, and duration of response in patients treated with these regimens
* To assess the correlation between risk stratification prognostic markers (i.e., CD38, ZAP-70, fluorescent in situ hybridization (FISH), and IgVH mutation) and clinical outcome.
* To assess response to these regimens using both the 1996 National Cancer Institute Working Group (NCI-WG 96) criteria and an expanded definition of response for patients in complete remission, including immunohistochemical examination of the bone marrow and sensitive flow cytometry (4-6 color) of blood for minimal residual disease and computed tomography (CT) scans for residual adenopathy.
* To determine the mechanism of action of rituximab and alemtuzumab and to determine mechanisms of resistance of a subpopulation of CLL cells to these drugs.
OUTLINE: This is a multicenter study. Patients are stratified according to FISH risk (low \[13q14-\] vs intermediate \[12+, no abnormality, all other abnormalities\] vs high \[17p13-,11q22-\]). Patients are randomized to 1 of 2 treatment arms.
* Arm A: Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles.
* Arm B: Patients receive alemtuzumab as in arm A. Patients also receive low-dose rituximab IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 and on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in cycless 2 and 3. Treatment repeats every 28 days for up to 3 cycles.
Blood and bone marrow samples are collected periodically for cytogenetic and biomarker analysis.
Alemtuzumab dose for Cycle 1 Week 1 of both Arms A and B requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1).
After completion of study therapy, patients are followed up periodically for 5 years.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 31
-
Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:
-
Minimum threshold peripheral lymphocyte count of 5 x 10^9/L (CLL variant) OR palpable adenopathy > 1 cm or palpable splenomegaly 9small lymphocytic lymphoma [SLL] variant)
-
Immunophenotypic demonstrations of a population of B-lymphocytes (as defined by CD19+) that are monoclonal (by light-chain exclusion) AND have ≥ 3 of the following characteristics:
- CD5+
- CD23+
- Dim surface light chain expression
- Dim surface CD20 expression
-
FISH analysis is negative for immunoglobulin heavy chain/cyclin D1 gene (IGH/CCND1) and/or immunostaining is negative for cyclin D1 expression (to exclude mantle cell lymphoma)
-
-
Progressive, symptomatic CLL, defined by at least one of the following:
-
Weight loss > 10% within the past 6 months attributable to progressive CLL (grade 2 or higher)
-
Extreme fatigue attributable to progressive CLL (grade 3 or higher)
-
Fevers > 100.5° F for 2 weeks without evidence of infection (grade 1 or higher)
-
Night sweats without evidence of infection (drenching)
-
Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet count < 100 x 10^9/L
-
Rapidly progressive lymphadenopathy for which the largest node is ≤ 5 cm in any dimension
- Largest lymph nodes involved in the neck, axilla, and groin need to be measured and followed for response
-
-
Prior treatment for CLL
-
Massive splenomegaly > 6 cm below left costal margin, at rest, on clinical examination
-
Lymphadenopathy > 5 cm in any diameter
-
New York Heart Association class III or IV heart disease
-
Recent myocardial infarction (within the past month)
-
Uncontrolled infection
-
Infection with the human immunodeficiency virus (HIV/AIDS)
-
Serological evidence of active hepatitis B infection (HBsAg or HBeAg positive)
-
Positive hepatitis C serology
-
Evidence of active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia
-
Other active primary malignancy requiring treatment or that limits survival to ≤ 2 years, except for in situ carcinoma of the cervix or breast or non-metastatic basal cell or squamous cell carcinoma of the skin
-
Major surgery within 4 weeks prior to pre-registration
-
Concomitant use of continuous systemic corticosteroids
- Prior corticosteroids are allowed but not at time of pre-registration to the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm A (standard dose) alemtuzumab Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m\^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week. Arm B (low dose) alemtuzumab Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m\^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week. Arm B (low dose) rituximab Patients receive alemtuzumab SC on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and low-dose rituximab at 20 mg/m\^2 IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC and low-dose rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week. Arm A (standard dose) rituximab Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab 375 mg/m\^2/week intravenously (IV) on days 8, 15, 22, and 29 in cycle 1 (33-day cycle). In cycle 2 and subsequent cycles (28-day cycle), patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 cycles. Alemtuzumab dose for cycle 1 week 1 requires a 'dose ramp' (3 mg day 1, 10 mg day2, and 30 mg day 3 of cycle 1) and then is 30 mg 3 times a week.
- Primary Outcome Measures
Name Time Method Proportion of Patients With Complete Response (CR) Assessed after 2 cycles of treatment and 2 months after completion of therapy Response was evaluated using NCI-WG96 criteria.
A CR requires all of the following for \>= 2 months:
* Absence of lymphadenopathy \> 1 cm in diameter by physical examination
* No hepatomegaly or splenomegaly on physical exam
* No constitutional symptoms
* Normal complete blood count (CBC)
* Patients achieving a clinical CR with negative CT scan after 2 cycles of therapy are re-evaluated using immunohistochemical examination of bone marrow biopsy for residual CLL cells. Patients with no evidence of residual disease and no radiological evidence of residual CLL on CT scan of chest-abdomen-pelvis and no clinical evidence of CLL on clinical evaluation after completion of 2 cycles of therapy will be considered to have a CR with no evidence of residual diseaseProportion of Patients With Overall Response (OR) Assessed after 2 cycles of treatment and 2 months after completion of therapy OR is defined as either CR, clinical CR, or partial response (PR) evaluated by NCI-WG96 criteria. CR has been defined in the other primary endpoint.
A clinical CR requires all of the following:
* Absence of lymphadenopathy by physical examination
* No hepatomegaly or splenomegaly. Spleen and/or liver, if considered enlarged at baseline, should not be palpable, due to disease, on physical exam
* Absence of constitutional symptoms
* Normal CBC as exhibited by:
A PR requires all the following for ≥2 months:
* ≥50% decrease in peripheral blood lymphocyte count from baseline
* ≥50% reduction in lymphadenopathy
* ≥50% reduction in size of liver and/or spleen
* Polymorphonuclear leukocytes ≥1.5x10\^9/L or 50% improvement over baseline
* Platelets \>100x10\^9/L or 50% improvement over baseline
* Hemoglobin \>11.0 gm/dl or 50% improvement over baseline without transfusions
* Any constitutional symptoms
- Secondary Outcome Measures
Name Time Method Progression-free Survival (PFS) Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years PFS is defined to be time from randomization to progression (PD) or to death without documentation of progression. For patients without PD, follow-up is censored at the date of last disease assessment without PD, unless death occurs within three months following the date last known progression free.
PD is characterized by at least one of the following:
* ≥50% increase in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart (at least 1 node must be \>2 cm). Appearance of new palpable lymph nodes (\>1 cm in diameter).
* ≥50% increase in the size of liver and/or spleen as determined by measurement below the respective costal margin; appearance of palpable hepatomegaly or splenomegaly which was not previously present.
* Absolute number of circulating lymphocytes with a count of \>5x10\^9/L
* Transformation to a more aggressive histologyOverall Survival (OS) Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years OS is defined to be time from randomization to death from any cause. Those still alive are censored at the date of last contact.
Time to Response Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years Time to response is defined to be time from randomization to first confirmed CR, PR or clinical CR. Those without confirmed CR, PR or clinical CR are censored at the date of last disease assessment.
Duration of Response Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years Duration of response is defined to be time from first confirmed CR, PR or clinical CR to progression or to death without documentation of progression. Patients without confirmed CR, PR or clinical CR are censored at time 0. Those without documentation of progression are censored at the date of last disease assessment without progression, unless death occurs within three months following the date last known progression free.
Trial Locations
- Locations (102)
McDonough District Hospital
🇺🇸Macomb, Illinois, United States
Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital
🇺🇸Fort Lauderdale, Florida, United States
Ella Milbank Foshay Cancer Center at Jupiter Medical Center
🇺🇸Jupiter, Florida, United States
CCOP - Mount Sinai Medical Center
🇺🇸Miami Beach, Florida, United States
Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler
🇺🇸Savannah, Georgia, United States
Rush-Copley Cancer Care Center
🇺🇸Aurora, Illinois, United States
Illinois CancerCare - Bloomington
🇺🇸Bloomington, Illinois, United States
St. Joseph Medical Center
🇺🇸Bloomington, Illinois, United States
Illinois CancerCare - Carthage
🇺🇸Carthage, Illinois, United States
Illinois CancerCare - Canton
🇺🇸Canton, Illinois, United States
Memorial Hospital
🇺🇸Carthage, Illinois, United States
Eureka Community Hospital
🇺🇸Eureka, Illinois, United States
University of Chicago Cancer Research Center
🇺🇸Chicago, Illinois, United States
Illinois CancerCare - Eureka
🇺🇸Eureka, Illinois, United States
Galesburg Clinic, PC
🇺🇸Galesburg, Illinois, United States
Illinois CancerCare - Havana
🇺🇸Havana, Illinois, United States
Illinois CancerCare - Kewanee Clinic
🇺🇸Kewanee, Illinois, United States
Illinois CancerCare - Macomb
🇺🇸Macomb, Illinois, United States
BroMenn Regional Medical Center
🇺🇸Normal, Illinois, United States
Illinois CancerCare - Monmouth
🇺🇸Monmouth, Illinois, United States
Illinois CancerCare - Community Cancer Center
🇺🇸Normal, Illinois, United States
Community Cancer Center
🇺🇸Normal, Illinois, United States
Oncology Hematology Associates of Central Illinois, PC - Ottawa
🇺🇸Ottawa, Illinois, United States
Community Hospital of Ottawa
🇺🇸Ottawa, Illinois, United States
Illinois CancerCare - Pekin
🇺🇸Pekin, Illinois, United States
Cancer Treatment Center at Pekin Hospital
🇺🇸Pekin, Illinois, United States
Proctor Hospital
🇺🇸Peoria, Illinois, United States
CCOP - Illinois Oncology Research Association
🇺🇸Peoria, Illinois, United States
Oncology Hematology Associates of Central Illinois, PC - Peoria
🇺🇸Peoria, Illinois, United States
Methodist Medical Center of Illinois
🇺🇸Peoria, Illinois, United States
Illinois Valley Community Hospital
🇺🇸Peru, Illinois, United States
OSF St. Francis Medical Center
🇺🇸Peoria, Illinois, United States
Illinois CancerCare - Peru
🇺🇸Peru, Illinois, United States
Illinois CancerCare - Princeton
🇺🇸Princeton, Illinois, United States
Swedish-American Regional Cancer Center
🇺🇸Rockford, Illinois, United States
CCOP - Carle Cancer Center
🇺🇸Urbana, Illinois, United States
Illinois CancerCare - Spring Valley
🇺🇸Spring Valley, Illinois, United States
Reid Hospital & Health Care Services
🇺🇸Richmond, Indiana, United States
St. Francis Hospital and Health Centers - Beech Grove Campus
🇺🇸Beech Grove, Indiana, United States
McFarland Clinic, PC
🇺🇸Ames, Iowa, United States
Cedar Rapids Oncology Associates
🇺🇸Cedar Rapids, Iowa, United States
Mercy Regional Cancer Center at Mercy Medical Center
🇺🇸Cedar Rapids, Iowa, United States
Mercy Cancer Center at Mercy Medical Center - North Iowa
🇺🇸Mason City, Iowa, United States
Siouxland Hematology-Oncology Associates, LLP
🇺🇸Sioux City, Iowa, United States
Mercy Medical Center - Sioux City
🇺🇸Sioux City, Iowa, United States
St. Luke's Regional Medical Center
🇺🇸Sioux City, Iowa, United States
Central Care Cancer Center at Carrie J. Babb Cancer Center
🇺🇸Bolivar, Missouri, United States
Southeast Cancer Center
🇺🇸Cape Girardeau, Missouri, United States
Skaggs Cancer Center at Skaggs Regional Medical Center
🇺🇸Branson, Missouri, United States
Goldschmidt Cancer Center
🇺🇸Jefferson City, Missouri, United States
Mercy Clinic Cancer and Hematology - Rolla
🇺🇸Rolla, Missouri, United States
Phelps County Regional Medical Center
🇺🇸Rolla, Missouri, United States
Missouri Baptist Cancer Center
🇺🇸Saint Louis, Missouri, United States
CCOP - Cancer Research for the Ozarks
🇺🇸Springfield, Missouri, United States
Hulston Cancer Center at Cox Medical Center South
🇺🇸Springfield, Missouri, United States
St. John's Regional Health Center
🇺🇸Springfield, Missouri, United States
CCOP - Nevada Cancer Research Foundation
🇺🇸Las Vegas, Nevada, United States
Randolph Hospital
🇺🇸Asheboro, North Carolina, United States
Wayne Memorial Hospital, Incorporated
🇺🇸Goldsboro, North Carolina, United States
Moses Cone Regional Cancer Center at Wesley Long Community Hospital
🇺🇸Greensboro, North Carolina, United States
Pardee Memorial Hospital
🇺🇸Hendersonville, North Carolina, United States
Kinston Medical Specialists
🇺🇸Kinston, North Carolina, United States
Annie Penn Cancer Center
🇺🇸Reidsville, North Carolina, United States
Iredell Memorial Hospital
🇺🇸Statesville, North Carolina, United States
St. Alexius Medical Center Cancer Center
🇺🇸Bismarck, North Dakota, United States
Aultman Cancer Center at Aultman Hospital
🇺🇸Canton, Ohio, United States
Grandview Hospital
🇺🇸Dayton, Ohio, United States
Good Samaritan Hospital
🇺🇸Dayton, Ohio, United States
Samaritan North Cancer Care Center
🇺🇸Dayton, Ohio, United States
CCOP - Dayton
🇺🇸Dayton, Ohio, United States
David L. Rike Cancer Center at Miami Valley Hospital
🇺🇸Dayton, Ohio, United States
Middletown Regional Hospital
🇺🇸Franklin, Ohio, United States
Blanchard Valley Medical Associates
🇺🇸Findlay, Ohio, United States
Wayne Hospital
🇺🇸Greenville, Ohio, United States
UVMC Cancer Care Center at Upper Valley Medical Center
🇺🇸Troy, Ohio, United States
Charles F. Kettering Memorial Hospital
🇺🇸Kettering, Ohio, United States
Ruth G. McMillan Cancer Center at Greene Memorial Hospital
🇺🇸Xenia, Ohio, United States
Mount Nittany Medical Center
🇺🇸State College, Pennsylvania, United States
Mercy Hospital Cancer Center - Scranton
🇺🇸Scranton, Pennsylvania, United States
Lewistown Hospital
🇺🇸Lewistown, Pennsylvania, United States
Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Hematology and Oncology Associates of Northeastern Pennsylvania
🇺🇸Scranton, Pennsylvania, United States
Danville Regional Medical Center
🇺🇸Danville, Virginia, United States
UW Cancer Center Johnson Creek
🇺🇸Johnson Creek, Wisconsin, United States
University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
🇺🇸Madison, Wisconsin, United States
Mayo Clinic Cancer Center
🇺🇸Rochester, Minnesota, United States
Medcenter One Hospital Cancer Care Center
🇺🇸Bismarck, North Dakota, United States
Mid Dakota Clinic, PC
🇺🇸Bismarck, North Dakota, United States
Graham Hospital
🇺🇸Canton, Illinois, United States
Borgess Medical Center
🇺🇸Kalamazoo, Michigan, United States
West Michigan Cancer Center
🇺🇸Kalamazoo, Michigan, United States
Mayo Clinic Scottsdale
🇺🇸Scottsdale, Arizona, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
Gundersen Lutheran Center for Cancer and Blood
🇺🇸La Crosse, Wisconsin, United States
Riverview UW Cancer Center at Riverview Hospital
🇺🇸Wisconsin Rapids, Wisconsin, United States
Upper Michigan Cancer Center at Marquette General Hospital
🇺🇸Marquette, Michigan, United States
U.T. Medical Center Cancer Institute
🇺🇸Knoxville, Tennessee, United States
Tulane Cancer Center Office of Clinical Research
🇺🇸Alexandria, Louisiana, United States
Hematology-Oncology Clinic
🇺🇸Baton Rouge, Louisiana, United States
OSF Holy Family Medical Center
🇺🇸Monmouth, Illinois, United States
St. Rita's Medical Center
🇺🇸Lima, Ohio, United States
Feist-Weiller Cancer Center at Louisiana State University Health Sciences
🇺🇸Shreveport, Louisiana, United States