Clinical trial NCT01013961: Rituximab and Alemtuzumab in Treating Older Patients With Progressive Chronic Lymphocytic Leukemia
Official title: A Phase II Randomized Trial Comparing Standard and Low Dose Rituximab: Initial Treatment of Progressive Chronic Lymphocytic Leukemia in Elderly Patients Using Alemtuzumab and Rituximab
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Keywords: chronic lymphocytic leukemia
small lymphocytic lymphoma
CLL
elderly
low dose rituximab
alemtuzumab
monoclonal antibodies
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-11-16
Enrollment: 31
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Proportion of Patients With Complete Response (CR)
timeFrame: Assessed after 2 cycles of treatment and 2 months after completion of therapy
measure: Proportion of Patients With Overall Response (OR)
timeFrame: Assessed after 2 cycles of treatment and 2 months after completion of therapy
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
measure: Progression-free Survival (PFS)
timeFrame: Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
measure: Time to Response
timeFrame: Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
measure: Duration of Response
timeFrame: Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Fort Lauderdale
country: United States
facility: Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital
state: Florida
city: Jupiter
country: United States
facility: Ella Milbank Foshay Cancer Center at Jupiter Medical Center
state: Florida
city: Miami Beach
country: United States
facility: CCOP - Mount Sinai Medical Center
state: Florida
city: Savannah
country: United States
facility: Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler
state: Georgia
city: Aurora
country: United States
facility: Rush-Copley Cancer Care Center
state: Illinois
city: Bloomington
country: United States
facility: Illinois CancerCare - Bloomington
state: Illinois
city: Bloomington
country: United States
facility: St. Joseph Medical Center
state: Illinois
city: Canton
country: United States
facility: Graham Hospital
state: Illinois
city: Canton
country: United States
facility: Illinois CancerCare - Canton
state: Illinois
city: Carthage
country: United States
facility: Illinois CancerCare - Carthage
state: Illinois
city: Carthage
country: United States
facility: Memorial Hospital
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Eureka
country: United States
facility: Eureka Community Hospital
state: Illinois
city: Eureka
country: United States
facility: Illinois CancerCare - Eureka
state: Illinois
city: Galesburg
country: United States
facility: Galesburg Clinic, PC
state: Illinois
city: Havana
country: United States
facility: Illinois CancerCare - Havana
state: Illinois
city: Kewanee
country: United States
facility: Illinois CancerCare - Kewanee Clinic
state: Illinois
city: Macomb
country: United States
facility: Illinois CancerCare - Macomb
state: Illinois
city: Macomb
country: United States
facility: McDonough District Hospital
state: Illinois
city: Monmouth
country: United States
facility: Illinois CancerCare - Monmouth
state: Illinois
city: Monmouth
country: United States
facility: OSF Holy Family Medical Center
state: Illinois
city: Normal
country: United States
facility: BroMenn Regional Medical Center
state: Illinois
city: Normal
country: United States
facility: Community Cancer Center
state: Illinois
city: Normal
country: United States
facility: Illinois CancerCare - Community Cancer Center
state: Illinois
city: Ottawa
country: United States
facility: Community Hospital of Ottawa
state: Illinois
city: Ottawa
country: United States
facility: Oncology Hematology Associates of Central Illinois, PC - Ottawa
state: Illinois
city: Pekin
country: United States
facility: Cancer Treatment Center at Pekin Hospital
state: Illinois
city: Pekin
country: United States
facility: Illinois CancerCare - Pekin
state: Illinois
city: Peoria
country: United States
facility: Proctor Hospital
state: Illinois
city: Peoria
country: United States
facility: CCOP - Illinois Oncology Research Association
state: Illinois
city: Peoria
country: United States
facility: Oncology Hematology Associates of Central Illinois, PC - Peoria
state: Illinois
city: Peoria
country: United States
facility: Methodist Medical Center of Illinois
state: Illinois
city: Peoria
country: United States
facility: OSF St. Francis Medical Center
state: Illinois
city: Peru
country: United States
facility: Illinois CancerCare - Peru
state: Illinois
city: Peru
country: United States
facility: Illinois Valley Community Hospital
state: Illinois
city: Princeton
country: United States
facility: Illinois CancerCare - Princeton
state: Illinois
city: Rockford
country: United States
facility: Swedish-American Regional Cancer Center
state: Illinois
city: Spring Valley
country: United States
facility: Illinois CancerCare - Spring Valley
state: Illinois
city: Urbana
country: United States
facility: CCOP - Carle Cancer Center
state: Illinois
city: Beech Grove
country: United States
facility: St. Francis Hospital and Health Centers - Beech Grove Campus
state: Indiana
city: Richmond
country: United States
facility: Reid Hospital & Health Care Services
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic, PC
state: Iowa
city: Cedar Rapids
country: United States
facility: Cedar Rapids Oncology Associates
state: Iowa
city: Cedar Rapids
country: United States
facility: Mercy Regional Cancer Center at Mercy Medical Center
state: Iowa
city: Mason City
country: United States
facility: Mercy Cancer Center at Mercy Medical Center - North Iowa
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Hematology-Oncology Associates, LLP
state: Iowa
city: Sioux City
country: United States
facility: Mercy Medical Center - Sioux City
state: Iowa
city: Sioux City
country: United States
facility: St. Luke's Regional Medical Center
state: Iowa
city: Alexandria
country: United States
facility: Tulane Cancer Center Office of Clinical Research
state: Louisiana
city: Baton Rouge
country: United States
facility: Hematology-Oncology Clinic
state: Louisiana
city: Shreveport
country: United States
facility: Feist-Weiller Cancer Center at Louisiana State University Health Sciences
state: Louisiana
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Marquette
country: United States
facility: Upper Michigan Cancer Center at Marquette General Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Bolivar
country: United States
facility: Central Care Cancer Center at Carrie J. Babb Cancer Center
state: Missouri
city: Branson
country: United States
facility: Skaggs Cancer Center at Skaggs Regional Medical Center
state: Missouri
city: Cape Girardeau
country: United States
facility: Southeast Cancer Center
state: Missouri
city: Jefferson City
country: United States
facility: Goldschmidt Cancer Center
state: Missouri
city: Rolla
country: United States
facility: Mercy Clinic Cancer and Hematology - Rolla
state: Missouri
city: Rolla
country: United States
facility: Phelps County Regional Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Cancer Center
state: Missouri
city: Springfield
country: United States
facility: CCOP - Cancer Research for the Ozarks
state: Missouri
city: Springfield
country: United States
facility: St. John's Regional Health Center
state: Missouri
city: Springfield
country: United States
facility: Hulston Cancer Center at Cox Medical Center South
state: Missouri
city: Las Vegas
country: United States
facility: CCOP - Nevada Cancer Research Foundation
state: Nevada
city: Asheboro
country: United States
facility: Randolph Hospital
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital, Incorporated
state: North Carolina
city: Greensboro
country: United States
facility: Moses Cone Regional Cancer Center at Wesley Long Community Hospital
state: North Carolina
city: Hendersonville
country: United States
facility: Pardee Memorial Hospital
state: North Carolina
city: Kinston
country: United States
facility: Kinston Medical Specialists
state: North Carolina
city: Reidsville
country: United States
facility: Annie Penn Cancer Center
state: North Carolina
city: Statesville
country: United States
facility: Iredell Memorial Hospital
state: North Carolina
city: Bismarck
country: United States
facility: Medcenter One Hospital Cancer Care Center
state: North Dakota
city: Bismarck
country: United States
facility: Mid Dakota Clinic, PC
state: North Dakota
city: Bismarck
country: United States
facility: St. Alexius Medical Center Cancer Center
state: North Dakota
city: Canton
country: United States
facility: Aultman Cancer Center at Aultman Hospital
state: Ohio
city: Dayton
country: United States
facility: Grandview Hospital
state: Ohio
city: Dayton
country: United States
facility: Good Samaritan Hospital
state: Ohio
city: Dayton
country: United States
facility: David L. Rike Cancer Center at Miami Valley Hospital
state: Ohio
city: Dayton
country: United States
facility: Samaritan North Cancer Care Center
state: Ohio
city: Dayton
country: United States
facility: CCOP - Dayton
state: Ohio
city: Findlay
country: United States
facility: Blanchard Valley Medical Associates
state: Ohio
city: Franklin
country: United States
facility: Middletown Regional Hospital
state: Ohio
city: Greenville
country: United States
facility: Wayne Hospital
state: Ohio
city: Kettering
country: United States
facility: Charles F. Kettering Memorial Hospital
state: Ohio
city: Lima
country: United States
facility: St. Rita's Medical Center
state: Ohio
city: Troy
country: United States
facility: UVMC Cancer Care Center at Upper Valley Medical Center
state: Ohio
city: Xenia
country: United States
facility: Ruth G. McMillan Cancer Center at Greene Memorial Hospital
state: Ohio
city: Hershey
country: United States
facility: Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center
state: Pennsylvania
city: Lewistown
country: United States
facility: Lewistown Hospital
state: Pennsylvania
city: Scranton
country: United States
facility: Mercy Hospital Cancer Center - Scranton
state: Pennsylvania
city: Scranton
country: United States
facility: Hematology and Oncology Associates of Northeastern Pennsylvania
state: Pennsylvania
city: State College
country: United States
facility: Mount Nittany Medical Center
state: Pennsylvania
city: Knoxville
country: United States
facility: U.T. Medical Center Cancer Institute
state: Tennessee
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
city: Johnson Creek
country: United States
facility: UW Cancer Center Johnson Creek
state: Wisconsin
city: La Crosse
country: United States
facility: Gundersen Lutheran Center for Cancer and Blood
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Paul P. Carbone Comprehensive Cancer Center
state: Wisconsin
city: Wisconsin Rapids
country: United States
facility: Riverview UW Cancer Center at Riverview Hospital
state: Wisconsin
Study officials:
affiliation: University of Rochester
name: Clive S. Zent, MD
role: STUDY_CHAIR
References: