Lenalidomide and Rituximab as Treatment of Chronic Lymphocytic Leukemia

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00759603
• Collaborator: Celgene Corporation (Industry)
• Enrollment: 60
• Location: 1
• Arm: 1
• Duration (Months): 69.9
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if the combination of lenalidomide and rituximab can help to control Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) in patients who have already received therapy. The safety of this drug combination will also be studied.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma	Drug: Lenalidomide; Drug: Rituximab	Phase 2

Detailed Description

The Study Drugs:

Lenalidomide is designed to change the body's immune system and may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may decrease the growth of cancer cells.

Rituximab is designed to bind to a protein, called cluster of differentiation antigen 20 (CD20), that is on the surface of the leukemia cells, allowing the leukemia cells to be destroyed by the immune system.

Drug Administration:

If you are found to be eligible to take part in this study, you will receive rituximab through a needle into your vein 1 time a week in Cycle 1. You will not receive rituximab during Cycle 2, but you will continue to take lenalidomide.You will receive a dose of rituximab by vein on Day 1 of Cycles 3-12. Your first dose of rituximab will be given over 6-8 hours. If the first dose is well tolerated, you may receive the next doses over 2-4 hours. If the doctor thinks it is needed, the next doses may given over a longer time.

On Day 9 of Cycle 1, you will begin taking lenalidomide by mouth once a day. You will then take lenalidomide once a day, every day.

The dose and schedule of lenalidomide may change depending on the side effects you may experience. You should swallow lenalidomide capsules whole with a glass (8 ounces) water at the same time each day. Do not break, chew, or open the capsules. If you miss a dose of lenalidomide, take it as soon as you remember on the same day. If you miss a dose, it should NOT be made up on another day.

Each study cycle is 4 weeks.

Study Visits:

Once a week during the first 5 weeks, blood (about 1 tablespoon) will be drawn for routine tests.

After the first 5 weeks, blood (about 1 tablespoon) will be drawn for routine tests every 2 weeks until the doctor thinks your dose of lenalidomide will not change. After this, blood (about 1 tablespoon) will then be drawn every 4 weeks for routine tests.

At the end of Cycles 3, 6, and 12, you will have a bone marrow biopsy and aspirate to check the status of the disease. Blood (about 1 tablespoon) will be drawn for routine blood tests.

If you stay on study past 12 cycles, once every 6 cycles (Cycles 18, 24, 30, and so on), you will have a bone marrow biopsy and aspirate to check the status of the disease. Blood (about 1 tablespoon) will be drawn for routine blood tests.

Blood (about 1 tablespoon) will be drawn more often if the dose of lenalidomide needs to be changed or if you experience intolerable side effects.

Pregnancy Testing:

Women who are able to become pregnant must have a negative urine or blood (less than 1 teaspoon) pregnancy test 10-14 days and 24 hours before the first dose of lenalidomide, even if they have not had a menstrual period due to treatment of the disease or had only 1 menstrual period in the past 24 months.

If you have regular or no menstrual cycles, you will then have a urine or blood (less than 1 teaspoon) pregnancy test every week for the first 4 weeks, then every 4 weeks while taking lenalidomide, again as soon as you have been taken off of lenalidomide therapy, and then 28 days after you have stopped taking lenalidomide.

If you have irregular menstrual cycles, you will have urine or blood (less than 1 teaspoon) pregnancy test every week for the first 4 weeks, then every 2 weeks while taking lenalidomide, again as soon as you have been taken off of lenalidomide therapy, and then at 14 days and 28 days after you have stopped taking lenalidomide.

Length of Study:

You will be on study treatment for about 1 year. You will be taken off study early if you experience intolerable side effects or the disease gets worse.

If the doctor thinks you are benefiting, you may be able to continue taking the study treatment. If you continue, you will follow the same schedule of dosing and study visit schedule.

This is an investigational study. Lenalidomide and rituximab are FDA approved and commercially available. Lenalidomide is approved for the treatment of multiple myeloma and some myelodysplastic syndromes. Rituximab is approved for the treatment of chronic lymphoproliferative disorders and non-Hodgkin's lymphoma. The combination of these drugs to treat CLL and SLL is investigational.

Up to 60 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Lenalidomide in Combination With Rituximab as Treatment for Patients With Relapsed Chronic Lymphocytic Leukemia - RV-CLL-PI-0292
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lenalidomide + Rituximab Oral Lenalidomide 10 mg/day started on Day 9 of cycle 1; Rituximab 375 mg/m^2 intravenously on Day 1, Day 8, Day 15 and Day 22 then continued once every four weeks during cycles 3-12 (+ 7 days). Rituximab not given in Cycle 2. Treatment duration twelve cycles.	Drug: Lenalidomide; Started on Day 9 of Cycle 1 at the dose of 10 mg/day and continued daily. Treatment duration will be twelve cycles.; Other Names: Revlimid ® ; Drug: Rituximab; Dose of 375 mg/m^2 given intravenously on Day 1, Day 8, Day 15 and Day 22 then continued once every four weeks during cycles 3-12 (+ 7 days). Rituximab not given in Cycle 2.; Other Names: Rituxan®

Outcome Measures

Primary Outcome Measures

1. Overall Participant Response Rate: Percentage of Participants With Complete + Partial Response According to Revised National Cancer Institute-sponsored Working Group Guidelines [Responses assessed after 12 cycles, up to 48 weeks with interim assessments performed after 3, 6 and 12 cycles.]

   Complete response: Absence lymphadenopathy, hepatomegaly or splenomegaly & constitutional symptoms; Normal complete blood count (CBC) exhibited by polymorphonuclear leukocytes>1500/µL, platelets>100,000/µL, hemoglobin>11.0 g/dL (untransfused); lymphocyte count <5,000/µL; Bone marrow aspirate & biopsy normocellular for age with <30% nucleated cells lymphocytes; Absence Lymphoid nodules. Fulfillment CR criteria after induction with exception of treatment related persistent cytopenia & bone marrow lymphoid nodules both considered partial response; Partial response: Requires 50% decrease in peripheral lymphocytes from pre-treatment, 50% reduction in lymphadenopathy, &/or 50% reduction in splenomegaly/hepatomegaly for 2+ months from therapy completion. Additionally one following from pre-treatment: Polymorphonuclear leukocytes 1,500/µL or 50% improvement; Platelets>100,000/µL or 50% improvement; Hemoglobin>11.0 g/dL (untransfused) or 50% improvement.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with active disease.

2. Patients must be age 18 or over at the signing of consent and must understand and voluntarily sign an informed consent.

3. Prior treatment with purine analog based chemotherapy or chemoimmunotherapy.

4. Eastern Cooperative Oncology Group (ECOG)/World Health Organization (WHO) performance status of 0-2.

5. Adequate renal function indicated by serum creatinine less or equal to 2 mg/dl. Adequate hepatic function indicated as total bilirubin less or equal to 2 mg/dl and ALT less or equal to two times the upper limit of normal.

6. Disease free of prior malignancies for 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast. Patients with malignancies with indolent behavior such as prostate cancer treated with radiation or surgery can be enrolled in the study as long as they have a reasonable expectation to have been cured with the treatment modality received.

7. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test (sensitivity of at least 50 milli-International unit (mIU/mL) 10-14 days prior to starting lenalidomide. A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

8. Continued from Criteria #7. FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts talking lenalidomide. FCBP must also agree to ongoing pregnancy testing.

9. Continued from Criteria #8: Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.

10. Men must agree not to father a child. They must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a vasectomy. They will be warned that sharing study drug is prohibited and will be counseled about pregnancy precautions and potential risks of fetal exposure. They must agree to abstain from donating blood, semen, or sperm during study participation and for at least 28 days after discontinuation from the study.

11. Continued from Criteria #10: Counseling about the requirement for latex condom use during sexual contact with females of childbearing potential and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded not to share study drug and to not donate blood, sperm, or semen (during study participation and for 28 days following discontinuation from the study).

Exclusion Criteria:

1. Known sensitivity to lenalidomide or other thalidomide derivatives or rituximab.

2. Documented prolymphocytic leukemia (prolymphocytes more than 55% in the blood).

3. Known positivity for HIV or active hepatitis (B or C).

4. Pregnant or breast feeding females.

5. History of tuberculosis treated within the last five years or recent exposure to tuberculosis.

6. Any serious medical condition, laboratory abnormality, or psychiatric illness that places the subject at unacceptable risk if he/she were to participate in the study.

7. Patients with a recent history of deep vein thrombosis (DVT) or pulmonary embolus (PE), in the six months prior to enrollment are not eligible for this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Texas M.D. Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Celgene Corporation

Investigators

• Principal Investigator: Alessandra Ferrajoli, M.D., M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00759603
• Other Study ID Numbers: 2007-0208; NCI-2012-01674
• First Posted: Sep 25, 2008
• Last Update Posted: Aug 27, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by M.D. Anderson Cancer Center: Leukemia; CLL; Chronic Lymphocytic Leukemia; SLL; Small Lymphocytic Lymphoma; Lenalidomide; Revlimid; Rituximab; Rituxan
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Lenalidomide

Study Results

Participant Flow

Recruitment Details	Recruitment Period: September 22, 2008 to November 02, 2009. All recruitment done at The University of Texas MD Anderson Cancer Center.
Pre-assignment Detail	One of the 60 participants enrolled was excluded from the trial before any treatment assignment.

Arm/Group Title	Lenalidomide + Rituximab
Arm/Group Description	Oral Lenalidomide 10 mg/day started on Day 9 of cycle 1; Rituximab 375 mg/m^2 intravenously on Day 1, Day 8, Day 15 and Day 22 then continued once every four weeks during cycles 3-12 (+ 7 days). Rituximab not given in Cycle 2. Treatment duration twelve cycles.
Period Title: Overall Study
STARTED	59
COMPLETED	59
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Lenalidomide + Rituximab
Arm/Group Description	Oral Lenalidomide 10 mg/day started on Day 9 of cycle 1; Rituximab 375 mg/m^2 intravenously on Day 1, Day 8, Day 15 and Day 22 then continued once every four weeks during cycles 3-12 (+ 7 days). Rituximab not given in Cycle 2. Treatment duration twelve cycles.
Overall Participants	59
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62
Sex: Female, Male (Count of Participants)
Female	13 22%
Male	46 78%
Region of Enrollment (participants) [Number]
United States	59 100%

Outcome Measures

1. Primary Outcome

Title	Overall Participant Response Rate: Percentage of Participants With Complete + Partial Response According to Revised National Cancer Institute-sponsored Working Group Guidelines
Description	Complete response: Absence lymphadenopathy, hepatomegaly or splenomegaly & constitutional symptoms; Normal complete blood count (CBC) exhibited by polymorphonuclear leukocytes>1500/µL, platelets>100,000/µL, hemoglobin>11.0 g/dL (untransfused); lymphocyte count <5,000/µL; Bone marrow aspirate & biopsy normocellular for age with <30% nucleated cells lymphocytes; Absence Lymphoid nodules. Fulfillment CR criteria after induction with exception of treatment related persistent cytopenia & bone marrow lymphoid nodules both considered partial response; Partial response: Requires 50% decrease in peripheral lymphocytes from pre-treatment, 50% reduction in lymphadenopathy, &/or 50% reduction in splenomegaly/hepatomegaly for 2+ months from therapy completion. Additionally one following from pre-treatment: Polymorphonuclear leukocytes 1,500/µL or 50% improvement; Platelets>100,000/µL or 50% improvement; Hemoglobin>11.0 g/dL (untransfused) or 50% improvement.
Time Frame	Responses assessed after 12 cycles, up to 48 weeks with interim assessments performed after 3, 6 and 12 cycles.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lenalidomide + Rituximab
Arm/Group Description	Oral Lenalidomide 10 mg/day started on Day 9 of cycle 1; Rituximab 375 mg/m^2 intravenously on Day 1, Day 8, Day 15 and Day 22 then continued once every four weeks during cycles 3-12 (+ 7 days). Rituximab not given in Cycle 2. Treatment duration twelve cycles.
Measure Participants	59
Number [Percentage of Participants]	66 111.9%

Adverse Events

Time Frame	Adverse event collected through 12 cycles of 28-days.
Arm/Group Title	Lenalidomide + Rituximab
Arm/Group Description	Oral Lenalidomide 10 mg/day started on Day 9 of cycle 1; Rituximab 375 mg/m^2 intravenously on Day 1, Day 8, Day 15 and Day 22 then continued once every four weeks during cycles 3-12 (+ 7 days). Rituximab not given in Cycle 2. Treatment duration twelve cycles.
All Cause Mortality
	Lenalidomide + Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lenalidomide + Rituximab
	Affected / at Risk (%)	# Events
Total	29/59 (49.2%)
Blood and lymphatic system disorders
Autoimmune hemolytic anemia	1/59 (1.7%)	1
Evan's syndrome	1/59 (1.7%)	1
Left leg swelling	1/59 (1.7%)	1
Cardiac disorders
Acute Myocardial Infarction	1/59 (1.7%)	1
Atrial Fibrillation	2/59 (3.4%)	3
Cardiac arrhythmia	1/59 (1.7%)	1
Cardiac other	1/59 (1.7%)	1
Left ventricular diastolic dysfunction	1/59 (1.7%)	1
Left ventricular systolic dysfunction	1/59 (1.7%)	1
Thrombus	1/59 (1.7%)	1
Gastrointestinal disorders
Abdominal mass	1/59 (1.7%)	1
Constipation	1/59 (1.7%)	1
Diarrhea	1/59 (1.7%)	1
General disorders
Abdominal pain	1/59 (1.7%)	1
Death	2/59 (3.4%)	2
Fever	2/59 (3.4%)	3
Tumor lysis syndrome	1/59 (1.7%)	1
Infections and infestations
Acute bronchitis	1/59 (1.7%)	1
Catheter related infection	1/59 (1.7%)	1
Neutropenic fever	7/59 (11.9%)	8
Perianal infection	1/59 (1.7%)	1
Pulmonary infection RSV	1/59 (1.7%)	1
Skin infection	2/59 (3.4%)	2
Enteritis	2/59 (3.4%)	2
Lung Infection	9/59 (15.3%)	17
Metabolism and nutrition disorders
Hypokalemia	1/59 (1.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary malignancy	3/59 (5.1%)	3
Nervous system disorders
Syncope	1/59 (1.7%)	1
Renal and urinary disorders
Acute renal failure	1/59 (1.7%)	1
Surgical and medical procedures
Elective surgery, right knee	1/59 (1.7%)	1
Other (Not Including Serious) Adverse Events
	Lenalidomide + Rituximab
	Affected / at Risk (%)	# Events
Total	59/59 (100%)
Blood and lymphatic system disorders
Neutropenia	43/59 (72.9%)	43
Thrombocytopenia	20/59 (33.9%)	20
Anemia	9/59 (15.3%)	9
Peripheral edema	6/59 (10.2%)	6
Gastrointestinal disorders
Diarrhea	21/59 (35.6%)	21
Constipation	11/59 (18.6%)	11
Nausea	10/59 (16.9%)	10
Anorexia	9/59 (15.3%)	9
Heartburn	6/59 (10.2%)	6
General disorders
fatigue	32/59 (54.2%)	32
Tumor flare	16/59 (27.1%)	16
Gastrointestinal pain	7/59 (11.9%)	7
Headache	6/59 (10.2%)	6
Infections and infestations
Penumonia/bronchitis	6/59 (10.2%)	6
Neutropenic fever	6/59 (10.2%)	6
Metabolism and nutrition disorders
Metabolic or laboratory	9/59 (15.3%)	9
Hyperglycemia	8/59 (13.6%)	8
Hypomagnesemia	7/59 (11.9%)	7
Hyperbilirubinemia	7/59 (11.9%)	7
Musculoskeletal and connective tissue disorders
Arthralgia	10/59 (16.9%)	10
Nervous system disorders
Sensory neuropathy	14/59 (23.7%)	14
Neurologic other	10/59 (16.9%)	10
Renal and urinary disorders
Elevated serum creatinine	7/59 (11.9%)	7
Respiratory, thoracic and mediastinal disorders
Dyspnea	6/59 (10.2%)	6
Skin and subcutaneous tissue disorders
Rash	13/59 (22%)	13
Pruritus	8/59 (13.6%)	8

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.