Rituximab and Alemtuzumab in Treating Older Patients With Progressive Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01013961
• Other study ID #: E1908
• Secondary ID: E1908U10CA180794
• Status: Terminated
• Phase: Phase 2
• Start date: April 27, 2011
• Est. completion date: April 14, 2015

Study information

• Verified date: June 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 31
• Est. completion date: April 14, 2015
• Est. primary completion date: April 14, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Biological:
• alemtuzumab
Given IV
• rituximab
Given IV

Locations

Country	Name	City	State
United States	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana
United States	McFarland Clinic, PC	Ames	Iowa
United States	Randolph Hospital	Asheboro	North Carolina
United States	Rush-Copley Cancer Care Center	Aurora	Illinois
United States	Hematology-Oncology Clinic	Baton Rouge	Louisiana
United States	St. Francis Hospital and Health Centers - Beech Grove Campus	Beech Grove	Indiana
United States	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota
United States	Mid Dakota Clinic, PC	Bismarck	North Dakota
United States	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota
United States	Illinois CancerCare - Bloomington	Bloomington	Illinois
United States	St. Joseph Medical Center	Bloomington	Illinois
United States	Central Care Cancer Center at Carrie J. Babb Cancer Center	Bolivar	Missouri
United States	Skaggs Cancer Center at Skaggs Regional Medical Center	Branson	Missouri
United States	Aultman Cancer Center at Aultman Hospital	Canton	Ohio
United States	Graham Hospital	Canton	Illinois
United States	Illinois CancerCare - Canton	Canton	Illinois
United States	Southeast Cancer Center	Cape Girardeau	Missouri
United States	Illinois CancerCare - Carthage	Carthage	Illinois
United States	Memorial Hospital	Carthage	Illinois
United States	Cedar Rapids Oncology Associates	Cedar Rapids	Iowa
United States	Mercy Regional Cancer Center at Mercy Medical Center	Cedar Rapids	Iowa
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Danville Regional Medical Center	Danville	Virginia
United States	CCOP - Dayton	Dayton	Ohio
United States	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio
United States	Good Samaritan Hospital	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Samaritan North Cancer Care Center	Dayton	Ohio
United States	Eureka Community Hospital	Eureka	Illinois
United States	Illinois CancerCare - Eureka	Eureka	Illinois
United States	Blanchard Valley Medical Associates	Findlay	Ohio
United States	Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital	Fort Lauderdale	Florida
United States	Middletown Regional Hospital	Franklin	Ohio
United States	Galesburg Clinic, PC	Galesburg	Illinois
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	Wayne Hospital	Greenville	Ohio
United States	Illinois CancerCare - Havana	Havana	Illinois
United States	Pardee Memorial Hospital	Hendersonville	North Carolina
United States	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Goldschmidt Cancer Center	Jefferson City	Missouri
United States	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin
United States	Ella Milbank Foshay Cancer Center at Jupiter Medical Center	Jupiter	Florida
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Charles F. Kettering Memorial Hospital	Kettering	Ohio
United States	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois
United States	Kinston Medical Specialists	Kinston	North Carolina
United States	U.T. Medical Center Cancer Institute	Knoxville	Tennessee
United States	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin
United States	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	St. Rita's Medical Center	Lima	Ohio
United States	Illinois CancerCare - Macomb	Macomb	Illinois
United States	McDonough District Hospital	Macomb	Illinois
United States	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin
United States	Upper Michigan Cancer Center at Marquette General Hospital	Marquette	Michigan
United States	Mercy Cancer Center at Mercy Medical Center - North Iowa	Mason City	Iowa
United States	CCOP - Mount Sinai Medical Center	Miami Beach	Florida
United States	Illinois CancerCare - Monmouth	Monmouth	Illinois
United States	OSF Holy Family Medical Center	Monmouth	Illinois
United States	BroMenn Regional Medical Center	Normal	Illinois
United States	Community Cancer Center	Normal	Illinois
United States	Illinois CancerCare - Community Cancer Center	Normal	Illinois
United States	Community Hospital of Ottawa	Ottawa	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois
United States	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois
United States	Illinois CancerCare - Pekin	Pekin	Illinois
United States	CCOP - Illinois Oncology Research Association	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois
United States	OSF St. Francis Medical Center	Peoria	Illinois
United States	Proctor Hospital	Peoria	Illinois
United States	Illinois CancerCare - Peru	Peru	Illinois
United States	Illinois Valley Community Hospital	Peru	Illinois
United States	Illinois CancerCare - Princeton	Princeton	Illinois
United States	Annie Penn Cancer Center	Reidsville	North Carolina
United States	Reid Hospital & Health Care Services	Richmond	Indiana
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Swedish-American Regional Cancer Center	Rockford	Illinois
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	Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler	Savannah	Georgia
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	Hematology and Oncology Associates of Northeastern Pennsylvania	Scranton	Pennsylvania
United States	Mercy Hospital Cancer Center - Scranton	Scranton	Pennsylvania
United States	Feist-Weiller Cancer Center at Louisiana State University Health Sciences	Shreveport	Louisiana
United States	Mercy Medical Center - Sioux City	Sioux City	Iowa
United States	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa
United States	St. Luke's Regional Medical Center	Sioux City	Iowa
United States	Illinois CancerCare - Spring Valley	Spring Valley	Illinois
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	Mount Nittany Medical Center	State College	Pennsylvania
United States	Iredell Memorial Hospital	Statesville	North Carolina
United States	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio
United States	CCOP - Carle Cancer Center	Urbana	Illinois
United States	Riverview UW Cancer Center at Riverview Hospital	Wisconsin Rapids	Wisconsin
United States	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
ECOG-ACRIN Cancer Research Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Patients With Complete Response (CR)	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 disease	Assessed after 2 cycles of treatment and 2 months after completion of therapy
Primary	Proportion of Patients With Overall Response (OR)	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	Assessed after 2 cycles of treatment and 2 months after completion of therapy
Secondary	Overall Survival (OS)	OS is defined to be time from randomization to death from any cause. Those still alive are censored at the date of last contact.	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
Secondary	Progression-free Survival (PFS)	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 histology	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
Secondary	Time to Response	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.	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years
Secondary	Duration of Response	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.	Assessed after 2 cycles of treatment, 2 months after completion of therapy and then yearly up to 5 years