Alemtuzumab and Rituximab in Treating Patients With High-Risk, Early-Stage Chronic Lymphocytic Leukemia

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00436904
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 83
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as alemtuzumab and 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 alemtuzumab together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects and how well giving alemtuzumab together with rituximab works in treating patients with high-risk, early-stage chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Drug: Alemtuzumab; Drug: Rituximab	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the rate of complete and overall response to alemtuzumab and rituximab in patients with high-risk, early-stage chronic lymphocytic leukemia.

• Determine the toxicity of this regimen in these patients. Secondary

• Determine the overall survival and time to progression of patients treated with this regimen.

• Determine time to response and duration of response in patients treated with this regimen.

• Correlate prognostic markers 11q-, 17p-, unmutated VH gene, and CD38+ with clinical outcome.

• Determine response to this regimen using an expanded definition of response that includes minimal residual disease detected by sensitive flow cytometry in patients in complete clinical remission and single rearranged IgVH gene detected by polymerase chain reaction in patients with no monoclonal population on flow cytometry.

• Correlate in vitro response with clinical outcome in patients treated with this regimen.

• Determine if alemtuzumab and rituximab are synergistic in vitro.

• Determine the mechanism of action of this regimen in vitro.

• Determine the effect of this regimen on immune function.

• Monitor T-lymphocyte, natural killer cell, and monocyte number during and after treatment in these patients.

• Serially evaluate T-lymphocyte immunophenotype and function in patients treated with this regimen.

• Monitor recovery of humoral immunity by serial serum protein electrophoresis, immunofixation electrophoresis, and immunoglobulin quantification.

OUTLINE:

• Dose-escalation (week 1): Patients receive rituximab IV on day 1 and escalating doses of alemtuzumab subcutaneously (SC) on days 3-5 in week 1.

• Treatment (weeks 2-5): Patients receive alemtuzumab SC on days 1-3 (at the highest dose administered during week 1) and rituximab IV on day 3 in weeks 2-5 in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection at baseline and periodically during study treatment for pharmacokinetic and prognostic biomarker (11q-, 17p-, unmutated IgVH, and CD38 expression by flow cytometry and fluorescent in-situ hybridization) studies. Immune function (CDR3 T-cell receptor by reverse transcriptase-polymerase chain reaction) and in vitro and in vivo response are also examined.

After completion of study therapy, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Antibody Therapy With Alemtuzumab and Rituximab for Initial Treatment of High Risk Chronic Lymphocytic Leukemia
• Study Start Date: Dec 1, 2004
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alemtuzumab + Rituximab Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)	Drug: Alemtuzumab; 30 mg Monday, Wednesday, and Friday x 5 weeks; Drug: Rituximab; 375mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)

Outcome Measures

Primary Outcome Measures

1. Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months [Up to 6 months]

   Confirmed response is defined as a > 50% decrease in clinical symptoms from baseline and recovery from blood counts.

2. Number of Participants With Treatment Related Adverse Events [Weekly for first 6 weeks, then monthly for 6 months, then at 9 and 12 months post registration]

   Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE.> > Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE

Secondary Outcome Measures

1. Time to Response [Registration to first response (up to 5 years)]

   Calculated from the date of registration until the first date at which the patient's objective status was classified as a response. In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. Response is defined the same way as in the response primary outcome measure.

2. Duration of Response [Up to 5 years]

   Duration of response is calculated from the date of documented response until the date of progression in the subset of patients who respond to treatment. In patients who have not yet progressed, duration of response will be censored at the patient's last evaluation date.

3. Survival [Death or last follow-up (up to 5 years)]

   Survival is calculated from the date of registration to the date of death due to any cause. In patients who are still alive, survival will be censored at the last date when the patient was known to be alive.

4. Time to Disease Progression [Time from registration to progression (up to 5 years)]

   Calculated from date of registration to date of disease progression. In patients that have not progressed, time to disease progression will be censored at the patient's last evaluation date.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL)

• Early-stage, biologically high-risk disease defined by the following criteria:

• Rai stage 0-II (does not meet standard NCI-sponsored Working Group criteria for treatment)

• Clinical and phenotypic features manifested in the peripheral blood, including the following:

• Minimum threshold peripheral blood lymphocyte count of > 5,000/mm³

• Small-to-moderate peripheral blood lymphocytes with ≤ 55% prolymphocytes

• Monoclonality of B lymphocytes by immunophenotypic evaluation, demonstrating co-expression of CD19, CD5, and CD23 antigens, surface expression of CD20 and CD52, and B-cell monoclonal population defined by light-chain exclusions

• Poor prognosis demonstrated by ≥ 1 of the following high-risk parameters:

• Unmutated human immunoglobulin variable region heavy chain (IgVH) gene and CD38 expression (≥ 30% cells positive on flow cytometry) OR unmutated IgVH ZAP-70 expression (≥ 20% cells positive on flow cytometry) = 11q- = 17p-

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Creatinine ≤ 1.5 times upper limit of normal (ULN)

• Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 times ULN

• AST ≤ 3.0 times ULN (unless due to hemolysis or CLL)

• Hemoglobin ≥ 9.0 g/dL

• No New York Heart Association class III-IV heart disease

• No myocardial infarction within the past month

• No uncontrolled infection

• No active HIV infection

• No evidence of autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia

• No other active primary malignancy requiring treatment or limiting survival to less than 2 years

PRIOR CONCURRENT THERAPY:

• No prior treatment for CLL

• Prior corticosteroids allowed

• No prior radiotherapy

• More than 4 weeks since prior major surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Clive S. Zent, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00436904
• Other Study ID Numbers: CDR0000529809; P30CA015083; MC038G; 801-04; 106.G0309; U3023s
• First Posted: Feb 19, 2007
• Last Update Posted: Dec 1, 2011
• Last Verified: Nov 1, 2011

• Keywords provided by Mayo Clinic: stage 0 chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia; B-cell chronic lymphocytic leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Alemtuzumab

Study Results

Participant Flow

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Period Title: Overall Study
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Overall Participants	30
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	10 33.3%
Male	20 66.7%
Region of Enrollment (participants) [Number]
United States	30 100%
Performance Score (participants) [Number]
0 - Fully Active	27 90%
1 - Ambulatory, restricted strenuous activity	3 10%

Outcome Measures

1. Primary Outcome

Title	Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months
Description	Confirmed response is defined as a > 50% decrease in clinical symptoms from baseline and recovery from blood counts.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

Number of patients with a confirmed response out of total patients evaluable for response.

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Measure Participants	30
Number (95% Confidence Interval) [participants]	27 90%

2. Primary Outcome

Title	Number of Participants With Treatment Related Adverse Events
Description	Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE.> > Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE
Time Frame	Weekly for first 6 weeks, then monthly for 6 months, then at 9 and 12 months post registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Measure Participants	30
Grade 3-4 Hematologic	11 36.7%
Grade 3-4 Non-hematologic	3 10%

3. Secondary Outcome

Title	Time to Response
Description	Calculated from the date of registration until the first date at which the patient's objective status was classified as a response. In patients who do not achieve a response, time to response will be censored at the patient's last evaluation date. Response is defined the same way as in the response primary outcome measure.
Time Frame	Registration to first response (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Measure Participants	30
Median (95% Confidence Interval) [Days]	8

4. Secondary Outcome

Title	Duration of Response
Description	Duration of response is calculated from the date of documented response until the date of progression in the subset of patients who respond to treatment. In patients who have not yet progressed, duration of response will be censored at the patient's last evaluation date.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Patients that responded were included in the analysis.

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Measure Participants	27
Median (95% Confidence Interval) [Months]	14.4

5. Secondary Outcome

Title	Survival
Description	Survival is calculated from the date of registration to the date of death due to any cause. In patients who are still alive, survival will be censored at the last date when the patient was known to be alive.
Time Frame	Death or last follow-up (up to 5 years)

Outcome Measure Data

Analysis Population Description

At analysis time, only 1 out of 30 patients had died. Thus, median survival was not attainable.

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Measure Participants	0

6. Secondary Outcome

Title	Time to Disease Progression
Description	Calculated from date of registration to date of disease progression. In patients that have not progressed, time to disease progression will be censored at the patient's last evaluation date.
Time Frame	Time from registration to progression (up to 5 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
Measure Participants	30
Median (95% Confidence Interval) [Months]	12.5

Adverse Events

Arm/Group Title	Alemtuzumab + Rituximab
Arm/Group Description	Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)
All Cause Mortality
	Alemtuzumab + Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alemtuzumab + Rituximab
	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)
Infections and infestations
Skin infection	1/30 (3.3%)	1
Nervous system disorders
Ischemia-Cerebral	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Alemtuzumab + Rituximab
	Affected / at Risk (%)	# Events
Total	29/30 (96.7%)
Blood and lymphatic system disorders
Anemia	3/30 (10%)	4
Gastrointestinal disorders
Diarrhea-No Colostom	6/30 (20%)	8
Dyspepsia	2/30 (6.7%)	2
Dysphagia	1/30 (3.3%)	1
Nausea	1/30 (3.3%)	1
Pain-Abdominal	3/30 (10%)	3
Vomiting	1/30 (3.3%)	1
General disorders
Fever-No ANC	15/30 (50%)	24
Rigors	1/30 (3.3%)	1
Immune system disorders
Hypersensitivity	3/30 (10%)	3
Infections and infestations
Blood Infection	2/30 (6.7%)	2
Bronchial infection	2/30 (6.7%)	2
Bronchus infection	1/30 (3.3%)	1
Pneumonia	3/30 (10%)	4
Respiratory tract infection	6/30 (20%)	6
Skin infection	4/30 (13.3%)	5
Upper airway infection	1/30 (3.3%)	1
Injury, poisoning and procedural complications
Appendix injury	1/30 (3.3%)	1
Investigations
Alanine aminotransferase increased	2/30 (6.7%)	3
Aspartate aminotransferase increased	2/30 (6.7%)	2
Blood bilirubin increased	3/30 (10%)	4
Leukopenia	19/30 (63.3%)	55
Lymphopenia	1/30 (3.3%)	1
Neutropenia	12/30 (40%)	24
Metabolism and nutrition disorders
Anorexia	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/30 (3.3%)	1
Joint effusion	1/30 (3.3%)	1
Nervous system disorders
Olfactory nerve disorder	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary	1/30 (3.3%)	1
Skin and subcutaneous tissue disorders
Rash/Desquamation	24/30 (80%)	57

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.