Fludarabine and Rituximab With or Without Lenalidomide or Cyclophosphamide in Treating Patients With Symptomatic Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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This randomized phase II trial studies how well fludarabine (fludarabine phosphate) and rituximab with or without lenalidomide or cyclophosphamide work in treating patients with symptomatic chronic lymphocytic leukemia. Drugs used in chemotherapy, such as fludarabine phosphate and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Giving fludarabine phosphate and rituximab together with lenalidomide or cyclophosphamide may be an effective treatment for chronic lymphocytic leukemia.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the two-year progression-free survival (PFS) after remission induction with four different chemo-immunotherapy combinations for patients with untreated, symptomatic, lower-risk and high-risk chronic lymphocytic leukemia (CLL) to decide which of the four arms, if any, to take forward into a randomized phase III trial. II. To determine the induction response to fludarabine phosphate and rituximab (FR) and fludarabine phosphate, cyclophosphamide, and rituximab (FCR) in each of these arms, along with the consolidation response to lenalidomide in patients with CLL. III. To determine the toxicity from these four chemoimmunotherapy combinations and that of consolidation therapy with lenalidomide. IV. To determine the induction response and toxicity of FCR in patients with deletion (del) (11q22.3) along with consolidation response, 2-year PFS and toxicity of lenalidomide in this specific genetic group. V. To determine the effect of pretreatment biologic characteristics on clinical outcomes, such as attaining a complete response to induction therapy and progression-free survival. VI. To collect relapse samples to determine the frequency of clonal evolution among patients with immunoglobulin heavy chain variable region (IgVH) mutated and unmutated disease and to study mechanisms of resistance to chemoimmunotherapy. VII. To determine if flow cytometry-negative status immediately post-therapy and at 24 months after study entry is an effective surrogate marker for prolonged progression-free survival and overall survival. OUTLINE: Patients are randomized to 1 of 3 treatment arms (Arms A, B, or C). Patients on Arm A or B who are found to be del (11q22.3) positive are assigned to Arm D beginning with course 2 of induction therapy. ARM A (remission-induction [RI] therapy with fludarabine phosphate and rituximab): Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab intravenously (IV) over 1-4 hours on days 1 (50 mg/m^2), 3 (325 mg/m^2), and 5 (375 mg/m^2) of course 1 and on day 1 (375 mg/m^2) of all subsequent courses. Patients also receive fludarabine phosphate 25 mg/m^2/day IV over 30 minutes or orally (PO) on days 1-5. ARM B (RI therapy with fludarabine phosphate and rituximab followed by remission-consolidation [RC] therapy with lenalidomide): Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab IV over 1-4 hours on days 1 (50 mg/m^2), 3 (325 mg/m^2), and 5 (375 mg/m^2) of course 1 and on day 1 (375 mg/m^2) of all subsequent courses. Patients also receive fludarabine phosphate 25 mg/m^2/day IV over 30 minutes or PO on days 1-5. Participants without progression receive consolidation therapy: lenalidomide 5mg/day cycle 1, 10 mg/day cycles 2-6 PO once daily (QD) on days 1-21 of 28 day cycle. ARM C (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide): Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab IV over 4 hours on days 1 (50mg/m^2) and 3 (325 mg/m^2) of course 1 and on day 1 (500 mg/m^2) of all subsequent courses. Patients then receive fludarabine phosphate (age < 70: 25 mg/m^2/day; age >= 70: 20 mg/m^2/day) IV piggyback over 30 minutes or PO (32 mg/m^2/day) followed by cyclophosphamide (age < 70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) IV piggyback over 30 minutes on days 1-3. ARM D (RI therapy with fludarabine phosphate, rituximab, and cyclophosphamide followed by RC therapy with lenalidomide): Patients receive the first course of induction therapy as in Arm A or B before being re-assigned to Arm D. Beginning in course 2, patients receive rituximab IV (500 mg/m^2) on day 1 and fludarabine phosphate (age < 70: 25 mg/m^2/day; age >= 70: 20 mg/m^2/day) IV piggyback over 30 minutes or PO (32 mg/m^2/day) and cyclophosphamide IV (age < 70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) piggyback over 30 minutes on days 1-3. Participants without progression receive consolidation therapy: lenalidomide 5mg/day cycle 1, 10 mg/day cycles 2-6 PO QD on days 1-21 of 28 day cycle. After completion of study therapy, patients are followed up every 3 months for 1 year and then every 6 months for up to 15 years.

Official Title
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A Genetic Risk-Stratified, Randomized Phase II Study of Four Fludarabine/Antibody Combinations for Patients With Symptomatic, Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Stage I Chronic Lymphocytic Leukemia, Stage II Chronic Lymphocytic Leukemia, Stage III Chronic Lymphocytic Leukemia, Stage IV Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide
* Biological: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Specific diagnosis of B-cell CLL: An absolute lymphocytosis of > 5,000/uL Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes Bone marrow examination must include at least a unilateral aspirate and biopsy; the aspirate smear must show > 30% of all nucleated cells to be lymphoid or the bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL; overall cellularity must be normocellular or hypercellular Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (cluster of differentiation [CD]19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers; additionally, the B-cells must be monoclonal with regard to expression of either kappa or lambda and have surface immunoglobulin expression of low density; patients with bright surface immunoglobulin levels must have CD23 co-expression Patients must have symptomatic and active intermediate or high-risk categories of the modified three-stage Rai staging system: Not eligible: low risk, Rai stage 0, lymphocytes (L) in blood (> 5000/uL) and marrow (> 30%) only Intermediate risk, Rai stage I, L + enlarged lymph nodes (LN) Intermediate risk, Rai stage II, L + spleen and/or liver (LN + or -) High risk, Rai stage III, L + anemia (hemoglobin < 11 gm/dL) High risk, Rai stage IV, L + thrombocytopenia (platelets < 100,000/uL) Patients in the intermediate-risk group must have evidence of active disease as demonstrated by at least one of the following criteria: Massive or progressive splenomegaly, hepatomegaly and/or lymphadenopathy Presence of weight loss > 10% over the preceding 6 month period Grade 2 or 3 fatigue Fevers > 100.5 degrees Fahrenheit (°F) or night sweats for greater than 2 weeks without evidence of infection Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months No prior therapy for CLL, including no corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL No medical condition requiring chronic use of oral corticosteroids Performance status 0 - 2 Patients with human immunodeficiency virus (HIV) infection may be eligible provided they meet the following criteria: no evidence of infection with hepatitis B or C; CD4+ cell count > 350/mm^3; no evidence of resistant strains of HIV; if not on anti-HIV therapy, an HIV viral load < 10,000 copies HIV ribonucleic acid (RNA)/mL; if on HIV therapy, HIV viral load < 50 copies HIV RNA/mL; and no history of acquired immune deficiency syndrome (AIDS)-defining condition; patients receiving concurrent zidovudine or stavudine may not be enrolled Non-pregnant and non-nursing In females of child-bearing potential randomized to Arm B or assigned to Arm D, a negative urine or serum pregnancy test with a sensitivity of at least 25 mIU/mL will be required: 1) 10-14 days prior to beginning lenalidomide consolidation therapy; and 2) within 24 hours prior to the first dose of lenalidomide consolidation therapy; in addition, females of childbearing potential in Arm B and Arm D with regular menses must have a pregnancy test performed weekly during the first 28 days of treatment, and then every 28 days while taking lenalidomide (including breaks in lenalidomide), at discontinuation of lenalidomide, and then 28 days following discontinuation of lenalidomide; if menses are irregular, a pregnancy test must be performed weekly during the first 28 days of treatment, and then every 14 days while taking lenalidomide, at discontinuation of lenalidomide, and at 14 and 28 days after discontinuation of lenalidomide; additionally, females of childbearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO reliable methods of birth control - one highly effective method (intrauterine device [IUD], hormonal [birth control pills, injections, or implants], tubal ligation, or partner's vasectomy), and one additional effective method (latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least 4 weeks before she begins lenalidomide therapy, while participating in the study, and for at least 4 weeks after completing lenalidomide therapy; females of childbearing potential is defined as a sexually mature woman who has not undergone a hysterectomy or bilateral oophorectomy, or who has had menses at any time in the preceding 24 consecutive months (not been naturally postmenopausal for at least 24 consecutive months) Male patients randomized to Arm B or reassigned to Arm D must agree not to father a child and to use a latex condom during any sexual contact with females of childbearing potential while taking lenalidomide and for at least 4 weeks following completion of lenalidomide therapy, even if the patient have undergone a successful vasectomy All patients randomized to Arm B or reassigned to Arm D must be counseled by a trained counselor every 28 days during consolidation therapy about pregnancy precautions and risks of fetal exposure Creatinine =< 1.5 x upper limit of normal

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A (rituximab, fludarabine phosphate)<br>Participants receive induction therapy (every 28 days for up to 6 cycles) of: Patients receive rituximab IV over 1-4 hours on days 1 (50 mg/m^2), 3 (325 mg/m^2), and 5 (375 mg/m^2) of course 1 and on day 1 (375 mg/m^2) of all subsequent courses. Patients also receive fludarabine phosphate 25 mg/m^2/day IV over 30 minutes or PO on days 1-5. | Drug: Fludarabine Phosphate<br>* Given IV or PO<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Arm B (rituximab, fludarabine phosphate, lenalidomide)<br>Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab IV over 1-4 hours on days 1 (50 mg/m^2), 3 (325 mg/m^2), and 5 (375 mg/m^2) of course 1 and on day 1 (375 mg/m^2) of all subsequent courses. Patients also receive fludarabine phosphate 25 mg/m^2/day IV over 30 minutes or PO on days 1-5. Participants without progression receive consolidation therapy lenalidomide 5mg/day cycle 1, 10 mg/day cycles 2-6 PO QD on days 1-21 of 28 day cycle. | Drug: Fludarabine Phosphate<br>* Given IV or PO<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Arm C (rituximab, fludarabine phosphate, cyclophosphamide)<br>Participants receive induction therapy (every 28 days for up to 6 cycles) of: rituximab IV over 4 hours on days 1 (50mg/m^2) and 3 (325 mg/m^2) of course 1 and on day 1 (500 mg/m^2) of all subsequent courses. Patients then receive fludarabine phosphate (age < 70: 25 mg/m^2/day; age >= 70: 20 mg/m^2/day) IV piggyback over 30 minutes or PO (32 mg/m^2/day) followed by cyclophosphamide (age < 70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) IV piggyback over 30 minutes on days 1-3. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV or PO<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|
| Experimental: Arm D (rituximab, fludarabine, cyclophosphamide, lenalidomide)<br>Patients receive the first course of induction therapy as in Arm A or B before being re-assigned to Arm D. Beginning in course 2, patients receive rituximab IV (500 mg/m^2) on day 1 and fludarabine phosphate (age < 70: 25 mg/m^2/day; age >= 70: 20 mg/m^2/day) IV piggyback over 30 minutes or PO (32 mg/m^2/day) and cyclophosphamide IV (age < 70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) piggyback over 30 minutes on days 1-3. Participants without progression receive consolidation therapy: lenalidomide 5mg/day cycle 1, 10 mg/day cycles 2-6PO QD on days 1-21 of 28 day cycle. | Drug: Cyclophosphamide<br>* Given IV<br>* Other names: WR- 138719;Drug: Fludarabine Phosphate<br>* Given IV or PO<br>* Other names: SH T 586;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Biological: Rituximab<br>* Given IV<br>* Other names: Truxima;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 2-Year Progression Free Survival (PFS) Rate | Proportion of participants who were alive and progression free at 2 years. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate in Patients Without Del(11q22.3) | Percentage of non-del(11q22.3) participants with a complete response (CR) or partial response (PR). CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus >= 1 of the following: >= 1500/uL polymorphonuclear leukocytes, > 100,000/uL platelets, > 11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions. | Up to 15 years | 
| Overall Response Rates in Patients With Del(11q22.3) | Percentage of del(11q22.3) participants with a complete response (CR) or partial response (PR). CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus >= 1 of the following: >= 1500/uL polymorphonuclear leukocytes, > 100,000/uL platelets, > 11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions. | Up to 15 years | 
| PFS Rate of Patients With Del(11q22.3) | Proportion of del (11q22.3) participants who were alive and progression free at 2 years. | 2 years | 
| Time-to-progression in Patients Without Del(11q22.3) | Time to progression (TTP) was defined as the registration date to date of progression or death due to any cause, whichever occurs first. TTP was estimated using the Kaplan Meier method. Progressive disease (PD) required at least one of the following: >= 50% increase in the absolute number of lymphocytes, appearance of new palpable lymph nodes, >= 50% increase in the product of at least two lymphnodes, >= 50% increase in the enlargement of the liver and/or spleen. | Up to 15 years | 
| Time-to-progression in Patients With Del(11q22.3) | Time to progression (TTP) in del(11q22.3) participants was defined as the registration date to date of progression or death due to any cause, whichever occurs first. TTP was estimated using the Kaplan Meier method. | Up to 15 years |