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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00602459
• Collaborator: Eastern Cooperative Oncology Group (Other), NCIC Clinical Trials Group (Other), Southwest Oncology Group (Other)
• Enrollment: 418
• Locations: 364
• Arms: 4
• Patients Per Site: 1.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Stage I Chronic Lymphocytic Leukemia; Stage II Chronic Lymphocytic Leukemia; Stage III Chronic Lymphocytic Leukemia; Stage IV Chronic Lymphocytic Leukemia	Drug: Cyclophosphamide; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Lenalidomide; Biological: Rituximab	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. 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.

3. To determine the toxicity from these four chemoimmunotherapy combinations and that of consolidation therapy with lenalidomide.

4. 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.

5. To determine the effect of pretreatment biologic characteristics on clinical outcomes, such as attaining a complete response to induction therapy and progression-free survival.

6. 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.

7. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 418 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Genetic Risk-Stratified, Randomized Phase II Study of Four Fludarabine/Antibody Combinations for Patients With Symptomatic, Previously Untreated Chronic Lymphocytic Leukemia
• Actual Study Start Date: Jan 15, 2008
• Actual Primary Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A (rituximab, fludarabine phosphate) 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; Given IV or PO; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Rituximab; Given IV; Other Names: ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Riabni Rituxan Rituximab ABBS Rituximab ARRX Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar JHL1101 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 Rituximab PVVR rituximab-abbs Rituximab-arrx Rituximab-pvvr RTXM83 Ruxience Truxima
Experimental: Arm B (rituximab, fludarabine phosphate, 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 QD on days 1-21 of 28 day cycle.	Drug: Fludarabine Phosphate; Given IV or PO; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Lenalidomide; Given PO; Other Names: CC-5013 CC5013 CDC 501 Revlimid ; Biological: Rituximab; Given IV; Other Names: ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Riabni Rituxan Rituximab ABBS Rituximab ARRX Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar JHL1101 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 Rituximab PVVR rituximab-abbs Rituximab-arrx Rituximab-pvvr RTXM83 Ruxience Truxima
Experimental: Arm C (rituximab, fludarabine phosphate, 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.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Fludarabine Phosphate; Given IV or PO; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Rituximab; Given IV; Other Names: ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Riabni Rituxan Rituximab ABBS Rituximab ARRX Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar JHL1101 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 Rituximab PVVR rituximab-abbs Rituximab-arrx Rituximab-pvvr RTXM83 Ruxience Truxima
Experimental: Arm D (rituximab, fludarabine, cyclophosphamide, 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 2-6PO QD on days 1-21 of 28 day cycle.	Drug: Cyclophosphamide; Given IV; Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 ; Drug: Fludarabine Phosphate; Given IV or PO; Other Names: 2-F-ara-AMP 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)- Beneflur Fludara SH T 586 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Lenalidomide; Given PO; Other Names: CC-5013 CC5013 CDC 501 Revlimid ; Biological: Rituximab; Given IV; Other Names: ABP 798 BI 695500 C2B8 Monoclonal Antibody Chimeric Anti-CD20 Antibody CT-P10 IDEC-102 IDEC-C2B8 IDEC-C2B8 Monoclonal Antibody MabThera Monoclonal Antibody IDEC-C2B8 PF-05280586 Riabni Rituxan Rituximab ABBS Rituximab ARRX Rituximab Biosimilar ABP 798 Rituximab Biosimilar BI 695500 Rituximab Biosimilar CT-P10 Rituximab Biosimilar GB241 Rituximab Biosimilar IBI301 Rituximab Biosimilar JHL1101 Rituximab Biosimilar PF-05280586 Rituximab Biosimilar RTXM83 Rituximab Biosimilar SAIT101 Rituximab Biosimilar SIBP-02 rituximab biosimilar TQB2303 Rituximab PVVR rituximab-abbs Rituximab-arrx Rituximab-pvvr RTXM83 Ruxience Truxima

Outcome Measures

Primary Outcome Measures

1. 2-Year Progression Free Survival (PFS) Rate [2 years]

   Proportion of participants who were alive and progression free at 2 years.

Secondary Outcome Measures

1. Overall Response Rate in Patients Without Del(11q22.3) [Up to 15 years]

   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.

2. Overall Response Rates in Patients With Del(11q22.3) [Up to 15 years]

   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.

3. PFS Rate of Patients With Del(11q22.3) [2 years]

   Proportion of del (11q22.3) participants who were alive and progression free at 2 years.

4. Time-to-progression in Patients Without Del(11q22.3) [Up to 15 years]

   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.

5. Time-to-progression in Patients With Del(11q22.3) [Up to 15 years]

   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.

Eligibility Criteria

Criteria

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

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

1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	PCR Oncology	Arroyo Grande	California	United States	93420
3	Providence Saint Joseph Medical Center/Disney Family Cancer Center	Burbank	California	United States	91505
4	Palo Alto Medical Foundation-Camino Division	Mountain View	California	United States	94040
5	Palo Alto Medical Foundation Health Care	Palo Alto	California	United States	94301
6	UCSF Medical Center-Mount Zion	San Francisco	California	United States	94115
7	Hartford Hospital	Hartford	Connecticut	United States	06102
8	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
9	Norwalk Hospital	Norwalk	Connecticut	United States	06856
10	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut	United States	06790
11	Beebe Medical Center	Lewes	Delaware	United States	19958
12	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
13	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
14	Sibley Memorial Hospital	Washington	District of Columbia	United States	20016
15	Jupiter Medical Center	Jupiter	Florida	United States	33458
16	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
17	Orlando Health Cancer Institute	Orlando	Florida	United States	32806
18	Saint Anthony's Health	Alton	Illinois	United States	62002
19	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
20	MacNeal Hospital and Cancer Center	Berwyn	Illinois	United States	60402
21	Saint Joseph Medical Center	Bloomington	Illinois	United States	61701
22	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
23	Graham Hospital Association	Canton	Illinois	United States	61520
24	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
25	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
26	Memorial Hospital	Carthage	Illinois	United States	62321
27	Hematology and Oncology Associates	Chicago	Illinois	United States	60611
28	Northwestern University	Chicago	Illinois	United States	60611
29	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
30	Weiss Memorial Hospital	Chicago	Illinois	United States	60640
31	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
32	Heartland Cancer Research NCORP	Decatur	Illinois	United States	62526
33	AMITA Health Alexian Brothers Medical Center	Elk Grove Village	Illinois	United States	60007
34	Eureka Hospital	Eureka	Illinois	United States	61530
35	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
36	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
37	Galesburg Cottage Hospital	Galesburg	Illinois	United States	61401
38	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
39	Illinois CancerCare-Havana	Havana	Illinois	United States	62644
40	Mason District Hospital	Havana	Illinois	United States	62644
41	Hematology Oncology Associates of Illinois-Highland Park	Highland Park	Illinois	United States	60035
42	Hopedale Medical Complex - Hospital	Hopedale	Illinois	United States	61747
43	Midwest Center for Hematology Oncology	Joliet	Illinois	United States	60432
44	Duly Health and Care Joliet	Joliet	Illinois	United States	60435
45	Presence Saint Mary's Hospital	Kankakee	Illinois	United States	60901
46	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
47	AMG Libertyville - Oncology	Libertyville	Illinois	United States	60048
48	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
49	Mcdonough District Hospital	Macomb	Illinois	United States	61455
50	Loyola University Medical Center	Maywood	Illinois	United States	60153
51	Holy Family Medical Center	Monmouth	Illinois	United States	61462
52	Illinois CancerCare-Monmouth	Monmouth	Illinois	United States	61462
53	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
54	DuPage Medical Group-Ogden	Naperville	Illinois	United States	60563
55	Illinois Cancer Specialists-Niles	Niles	Illinois	United States	60714
56	Bromenn Regional Medical Center	Normal	Illinois	United States	61761
57	Carle Cancer Institute Normal	Normal	Illinois	United States	61761
58	Illinois CancerCare-Community Cancer Center	Normal	Illinois	United States	61761
59	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
60	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois	United States	61350
61	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
62	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
63	Pekin Hospital	Pekin	Illinois	United States	61554
64	Proctor Hospital	Peoria	Illinois	United States	61614
65	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
66	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
67	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
68	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
69	Illinois Valley Hospital	Peru	Illinois	United States	61354
70	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
71	Perry Memorial Hospital	Princeton	Illinois	United States	61356
72	Swedish American Hospital	Rockford	Illinois	United States	61104
73	OSF Saint Anthony Medical Center	Rockford	Illinois	United States	61108
74	Hematology Oncology Associates of Illinois - Skokie	Skokie	Illinois	United States	60076
75	Illinois CancerCare-Spring Valley	Spring Valley	Illinois	United States	61362
76	Saint Margaret's Hospital	Spring Valley	Illinois	United States	61362
77	Memorial Medical Center	Springfield	Illinois	United States	62781
78	Carle Cancer Center	Urbana	Illinois	United States	61801
79	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois	United States	60555
80	Franciscan Saint Francis Health-Beech Grove	Beech Grove	Indiana	United States	46107
81	Elkhart Clinic	Elkhart	Indiana	United States	46514-2098
82	Michiana Hematology Oncology PC-Elkhart	Elkhart	Indiana	United States	46514
83	Elkhart General Hospital	Elkhart	Indiana	United States	46515
84	Fort Wayne Medical Oncology and Hematology Inc-Parkview	Fort Wayne	Indiana	United States	46845
85	Community Howard Regional Health	Kokomo	Indiana	United States	46904
86	IU Health La Porte Hospital	La Porte	Indiana	United States	46350
87	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
88	Michiana Hematology Oncology PC-Mishawaka	Mishawaka	Indiana	United States	46545
89	Saint Joseph Regional Medical Center-Mishawaka	Mishawaka	Indiana	United States	46545
90	Michiana Hematology Oncology PC-Plymouth	Plymouth	Indiana	United States	46563
91	Reid Health	Richmond	Indiana	United States	47374
92	Memorial Hospital of South Bend	South Bend	Indiana	United States	46601
93	Michiana Hematology Oncology PC-South Bend	South Bend	Indiana	United States	46601
94	South Bend Clinic	South Bend	Indiana	United States	46617
95	Northern Indiana Cancer Research Consortium	South Bend	Indiana	United States	46628
96	Michiana Hematology Oncology PC-Westville	Westville	Indiana	United States	46391
97	McFarland Clinic PC - Ames	Ames	Iowa	United States	50010
98	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
99	Mercy Capitol	Des Moines	Iowa	United States	50307
100	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
101	Iowa-Wide Oncology Research Coalition NCORP	Des Moines	Iowa	United States	50309
102	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa	United States	50309
103	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
104	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
105	Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
106	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa	United States	52242
107	Iowa City VA Healthcare System	Iowa City	Iowa	United States	52246
108	Ottumwa Regional Health Center	Ottumwa	Iowa	United States	52501
109	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
110	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51102
111	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
112	HaysMed University of Kansas Health System	Hays	Kansas	United States	67601
113	Hutchinson Regional Medical Center	Hutchinson	Kansas	United States	67502
114	Providence Medical Center	Kansas City	Kansas	United States	66112
115	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
116	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
117	Olathe Cancer Center	Olathe	Kansas	United States	66061
118	Menorah Medical Center	Overland Park	Kansas	United States	66209
119	Radiation Oncology Practice Corporation Southwest	Overland Park	Kansas	United States	66210
120	Saint Luke's South Hospital	Overland Park	Kansas	United States	66213
121	Ascension Via Christi - Pittsburg	Pittsburg	Kansas	United States	66762
122	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas	United States	66208
123	Salina Regional Health Center	Salina	Kansas	United States	67401
124	Advent Health - Shawnee Mission Medical Center	Shawnee Mission	Kansas	United States	66204
125	Cotton O'Neil Cancer Center / Stormont Vail Health	Topeka	Kansas	United States	66606
126	University of Kansas Health System Saint Francis Campus	Topeka	Kansas	United States	66606
127	Wesley Medical Center	Wichita	Kansas	United States	67214
128	Doctors Carrol, Sheth, Raghavan	Louisville	Kentucky	United States	40215
129	Harold Alfond Center for Cancer Care	Augusta	Maine	United States	04330
130	Eastern Maine Medical Center	Bangor	Maine	United States	04401
131	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
132	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
133	Christiana Care - Union Hospital	Elkton	Maryland	United States	21921
134	Unspecified Site	Rockville	Maryland	United States	20852
135	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
136	Henry Ford Hospital	Detroit	Michigan	United States	48202
137	Green Bay Oncology - Escanaba	Escanaba	Michigan	United States	49829
138	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan	United States	49503
139	Green Bay Oncology - Iron Mountain	Iron Mountain	Michigan	United States	49801
140	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
141	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
142	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
143	Lakeland Hospital Niles	Niles	Michigan	United States	49120
144	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan	United States	49085
145	Marie Yeager Cancer Center	Saint Joseph	Michigan	United States	49085
146	Munson Medical Center	Traverse City	Michigan	United States	49684
147	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
148	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
149	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
150	Unity Hospital	Fridley	Minnesota	United States	55432
151	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
152	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
153	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
154	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
155	Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
156	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
157	Minneapolis VA Medical Center	Minneapolis	Minnesota	United States	55417
158	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
159	Mayo Clinic in Rochester	Rochester	Minnesota	United States	55905
160	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
161	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
162	Regions Hospital	Saint Paul	Minnesota	United States	55101
163	United Hospital	Saint Paul	Minnesota	United States	55102
164	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
165	Lakeview Hospital	Stillwater	Minnesota	United States	55082
166	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
167	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
168	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
169	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
170	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
171	University of Missouri - Ellis Fischel	Columbia	Missouri	United States	65212
172	Centerpoint Medical Center LLC	Independence	Missouri	United States	64057
173	Capital Region Southwest Campus	Jefferson City	Missouri	United States	65109
174	Truman Medical Centers	Kansas City	Missouri	United States	64108
175	Saint Luke's Hospital of Kansas City	Kansas City	Missouri	United States	64111
176	Radiation Oncology Practice Corporation South	Kansas City	Missouri	United States	64114
177	Saint Joseph Health Center	Kansas City	Missouri	United States	64114
178	North Kansas City Hospital	Kansas City	Missouri	United States	64116
179	Heartland Hematology and Oncology Associates Incorporated	Kansas City	Missouri	United States	64118
180	Research Medical Center	Kansas City	Missouri	United States	64132
181	Radiation Oncology Practice Corporation - North	Kansas City	Missouri	United States	64154
182	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
183	Liberty Radiation Oncology Center	Liberty	Missouri	United States	64068
184	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
185	Saint Joseph Oncology Inc	Saint Joseph	Missouri	United States	64507
186	SSM Health Saint Louis University Hospital	Saint Louis	Missouri	United States	63104
187	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
188	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
189	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
190	Center for Cancer Care and Research	Saint Louis	Missouri	United States	63141
191	Comprehensive Cancer Care PC	Saint Louis	Missouri	United States	63141
192	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
193	Saint Louis-Cape Girardeau CCOP	Saint Louis	Missouri	United States	63141
194	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
195	CoxHealth South Hospital	Springfield	Missouri	United States	65807
196	Billings Clinic Cancer Center	Billings	Montana	United States	59101
197	Saint Vincent Healthcare	Billings	Montana	United States	59101
198	Montana Cancer Consortium NCORP	Billings	Montana	United States	59102
199	Saint Vincent Frontier Cancer Center	Billings	Montana	United States	59102
200	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
201	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
202	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
203	Great Falls Clinic	Great Falls	Montana	United States	59405
204	Northern Montana Hospital	Havre	Montana	United States	59501
205	Saint Peter's Community Hospital	Helena	Montana	United States	59601
206	Glacier Oncology PLLC	Kalispell	Montana	United States	59901
207	Kalispell Medical Oncology	Kalispell	Montana	United States	59901
208	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
209	Montana Cancer Specialists	Missoula	Montana	United States	59802
210	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
211	CHI Health Saint Francis	Grand Island	Nebraska	United States	68803
212	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
213	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
214	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
215	Nevada Cancer Research Foundation NCORP	Las Vegas	Nevada	United States	89169
216	New Hampshire Oncology Hematology PA-Concord	Concord	New Hampshire	United States	03301
217	LRGHealthcare-Lakes Region General Hospital	Laconia	New Hampshire	United States	03246
218	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
219	Norris Cotton Cancer Center-Manchester	Manchester	New Hampshire	United States	03102
220	Solinsky Center for Cancer Care	Manchester	New Hampshire	United States	03103
221	Cooper Hospital University Medical Center	Camden	New Jersey	United States	08103
222	Veterans Adminstration New Jersey Health Care System	East Orange	New Jersey	United States	07018-1095
223	Virtua Memorial	Mount Holly	New Jersey	United States	08060
224	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
225	Saint Joseph's Regional Medical Center	Paterson	New Jersey	United States	07503
226	Virtua Voorhees	Voorhees	New Jersey	United States	08043
227	Lovelace Medical Center-Saint Joseph Square	Albuquerque	New Mexico	United States	87102
228	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
229	Memorial Medical Center - Las Cruces	Las Cruces	New Mexico	United States	88011
230	Montefiore Medical Center-Weiler Hospital	Bronx	New York	United States	10461
231	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
232	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
233	Northwell Health NCORP	Lake Success	New York	United States	11042
234	Northwell Health/Center for Advanced Medicine	Lake Success	New York	United States	11042
235	North Shore University Hospital	Manhasset	New York	United States	11030
236	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
237	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
238	Mount Sinai Hospital	New York	New York	United States	10029
239	NYP/Weill Cornell Medical Center	New York	New York	United States	10065
240	University of Rochester	Rochester	New York	United States	14642
241	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
242	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
243	Randolph Hospital	Asheboro	North Carolina	United States	27203
244	Mission Hospital	Asheville	North Carolina	United States	28801
245	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
246	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina	United States	28203
247	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
248	Cone Health Cancer Center	Greensboro	North Carolina	United States	27403
249	East Carolina University	Greenville	North Carolina	United States	27834
250	Margaret R Pardee Memorial Hospital	Hendersonville	North Carolina	United States	28791
251	Vidant Oncology-Kinston	Kinston	North Carolina	United States	28501
252	Annie Penn Memorial Hospital	Reidsville	North Carolina	United States	27320
253	Iredell Memorial Hospital	Statesville	North Carolina	United States	28677
254	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
255	Mary Rutan Hospital	Bellefontaine	Ohio	United States	43311
256	Aultman Health Foundation	Canton	Ohio	United States	44710
257	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
258	Case Western Reserve University	Cleveland	Ohio	United States	44106
259	MetroHealth Medical Center	Cleveland	Ohio	United States	44109
260	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
261	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
262	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
263	Columbus NCI Community Oncology Research Program	Columbus	Ohio	United States	43215
264	Grant Medical Center	Columbus	Ohio	United States	43215
265	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
266	Doctors Hospital	Columbus	Ohio	United States	43228
267	Grandview Hospital	Dayton	Ohio	United States	45405
268	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
269	Miami Valley Hospital	Dayton	Ohio	United States	45409
270	Miami Valley Hospital North	Dayton	Ohio	United States	45415
271	Dayton NCI Community Oncology Research Program	Dayton	Ohio	United States	45459
272	Grady Memorial Hospital	Delaware	Ohio	United States	43015
273	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
274	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
275	Wayne Hospital	Greenville	Ohio	United States	45331
276	Kettering Medical Center	Kettering	Ohio	United States	45429
277	Fairfield Medical Center	Lancaster	Ohio	United States	43130
278	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
279	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
280	Licking Memorial Hospital	Newark	Ohio	United States	43055
281	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
282	Upper Valley Medical Center	Troy	Ohio	United States	45373
283	Saint Ann's Hospital	Westerville	Ohio	United States	43081
284	Clinton Memorial Hospital	Wilmington	Ohio	United States	45177
285	Greene Memorial Hospital	Xenia	Ohio	United States	45385
286	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
287	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
288	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
289	Easton Hospital	Easton	Pennsylvania	United States	18042
290	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
291	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
292	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
293	Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301
294	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
295	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
296	Pottstown Hospital	Pottstown	Pennsylvania	United States	19464
297	Geisinger Medical Group	State College	Pennsylvania	United States	16801
298	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
299	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
300	Geisinger South Wilkes-Barre	Wilkes-Barre	Pennsylvania	United States	18765
301	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
302	Main Line Health NCORP	Wynnewood	Pennsylvania	United States	19096
303	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina	United States	29316
304	Medical University of South Carolina	Charleston	South Carolina	United States	29425
305	Prisma Health Cancer Institute - Easley	Easley	South Carolina	United States	29640
306	McLeod Regional Medical Center	Florence	South Carolina	United States	29506
307	Greenville Health System Cancer Institute-Andrews	Greenville	South Carolina	United States	29601
308	Saint Francis Hospital	Greenville	South Carolina	United States	29601
309	Prisma Health Cancer Institute - Butternut	Greenville	South Carolina	United States	29605
310	Prisma Health Cancer Institute - Faris	Greenville	South Carolina	United States	29605
311	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina	United States	29605
312	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina	United States	29615
313	Self Regional Healthcare	Greenwood	South Carolina	United States	29646
314	Prisma Health Cancer Institute - Greer	Greer	South Carolina	United States	29650
315	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina	United States	29672
316	Thompson Cancer Survival Center	Knoxville	Tennessee	United States	37916
317	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
318	Baylor University Medical Center	Dallas	Texas	United States	75246
319	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont	United States	05602
320	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
321	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont	United States	05819
322	Danville Regional Medical Center	Danville	Virginia	United States	24541
323	Sovah Health Martinsville	Martinsville	Virginia	United States	24115
324	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
325	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
326	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia	United States	26003
327	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
328	HSHS Sacred Heart Hospital	Eau Claire	Wisconsin	United States	54701
329	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin	United States	54701
330	Green Bay Oncology at Saint Vincent Hospital	Green Bay	Wisconsin	United States	54301-3526
331	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301
332	Green Bay Oncology Limited at Saint Mary's Hospital	Green Bay	Wisconsin	United States	54303
333	Saint Vincent Hospital Cancer Center at Saint Mary's	Green Bay	Wisconsin	United States	54303
334	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin	United States	53038
335	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
336	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin	United States	53792
337	Holy Family Memorial Hospital	Manitowoc	Wisconsin	United States	54221
338	Bay Area Medical Center	Marinette	Wisconsin	United States	54143
339	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin	United States	54449
340	Marshfield Medical Center	Marshfield	Wisconsin	United States	54449
341	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin	United States	54548
342	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
343	Saint Vincent Hospital Cancer Center at Oconto Falls	Oconto Falls	Wisconsin	United States	54154
344	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
345	Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
346	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin	United States	54868
347	HSHS Saint Nicholas Hospital	Sheboygan	Wisconsin	United States	53081
348	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
349	Green Bay Oncology - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
350	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
351	Diagnostic and Treatment Center	Weston	Wisconsin	United States	54476
352	Marshfield Medical Center - Weston	Weston	Wisconsin	United States	54476
353	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494
354	Rocky Mountain Oncology	Casper	Wyoming	United States	82609
355	Welch Cancer Center	Sheridan	Wyoming	United States	82801
356	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
357	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
358	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
359	QEII Health Sciences Centre/Nova Scotia Health Authority	Halifax	Nova Scotia	Canada	B3H 2Y9
360	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario	Canada	L8V 5C2
361	University Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
362	CSSS Champlain-Charles Le Moyne	Greenfield Park	Quebec	Canada	J4V 2H1
363	McGill University Health Centre at Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1
364	CHU de Quebec-Hopital du Saint-Sacrement (HSS)	Quebec City	Quebec	Canada	G1S 4L8

Sponsors and Collaborators

• National Cancer Institute (NCI)
• Eastern Cooperative Oncology Group
• NCIC Clinical Trials Group
• Southwest Oncology Group

Investigators

• Principal Investigator: John C Byrd, Alliance for Clinical Trials in Oncology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00602459
• Other Study ID Numbers: NCI-2009-00441; NCI-2009-00441; CDR0000584205; ECOG-10404; SWOG-C10404; 11-00126; SWOG C10404; ECOG 10404; CAN-NCIC-CL3; CALGB 10404; CALGB-10404; U10CA180821; U10CA031946
• First Posted: Jan 28, 2008
• Last Update Posted: Jul 28, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate; Lenalidomide; Antineoplastic Agents, Immunological; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	From January 2008 to August 2012, 418 participants were recruited to this study.

Arm/Group Title	Arm A (Rituximab, Fludarabine Phosphate)	Arm B (Rituximab, Fludarabine Phosphate, Lenalidomide)	Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)	Arm D (Rituximab, Fludarabine, Cyclophosphamide, Lenalidomide)
Arm/Group Description	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 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.	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.	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.
Period Title: Initial Registration/Randomization
STARTED	138	140	140	0
COMPLETED	133	130	137	0
NOT COMPLETED	5	10	3	0
Period Title: Initial Registration/Randomization
STARTED	123	109	137	31
COMPLETED	123	109	137	31
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Arm A (Rituximab, Fludarabine Phosphate)	Arm B (Rituximab, Fludarabine Phosphate, Lenalidomide)	Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)	Arm D (Rituximab, Fludarabine, Cyclophosphamide, Lenalidomide)	Total
Arm/Group Description	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 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.	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.	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.	Total of all reporting groups
Overall Participants	123	109	137	31	400
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	80 65%	67 61.5%	88 64.2%	21 67.7%	256 64%
>=65 years	43 35%	42 38.5%	49 35.8%	10 32.3%	144 36%
Sex: Female, Male (Count of Participants)
Female	40 32.5%	40 36.7%	51 37.2%	8 25.8%	139 34.8%
Male	83 67.5%	69 63.3%	86 62.8%	23 74.2%	261 65.3%
Region of Enrollment (participants) [Number]
Canada	15 12.2%	14 12.8%	16 11.7%	8 25.8%	53 13.3%
United States	108 87.8%	95 87.2%	121 88.3%	23 74.2%	347 86.8%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients re-assigned to Arm C were split into two analysis groups, patients with del(11q22.3), as assessed by interphase cytogenetics and present in at least 20% of cells, and those without del(11q22.3). This endpoint is limited to patients without del(11q22.3).

Arm/Group Title	Arm A, FR in Non-del(11q22.3)	Arm B, FR+L in Non-del(11q22.3)	Arm C1, FCR in Non-del(11q22.3)
Arm/Group Description	Participants, who are non-del(11q22.3), receive induction therapy (every 28 days for up to 6 cycles) of: rituximab (R) 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 (F) 25 mg/m^2/day IV over 30 minutes or PO on days 1-5.	Participants, who are non-del(11q22.3), receive induction therapy (every 28 days for up to 6 cycles) of: rituximab (R) 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 (F) 25 mg/m^2/day IV over 30 minutes or PO on days 1-5. Participants without progression receive consolidation therapy lenalidomide (L) 5mg/day cycle 1, 10 mg/day cycles 2-6 PO QD on days 1-21 of 28 day cycle.	Participants, who are non-del(11q22.3), receive induction therapy (every 28 days for up to 6 cycles) of: rituximab (R) 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 (F) (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 (C) (age < 70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) IV piggyback over 30 minutes on days 1-3.
Measure Participants	123	109	110
Number (90% Confidence Interval) [proportion of participants]	0.64 0.5%	0.71 0.7%	0.74 0.5%

2. Secondary Outcome

Title	Overall Response Rate in Patients Without Del(11q22.3)
Description	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.
Time Frame	Up to 15 years

Outcome Measure Data

Analysis Population Description

Patients without Del(11q22.3) were included in this analysis.

Arm/Group Title	Arm A (Rituximab, Fludarabine Phosphate)	Arm B (Rituximab, Fludarabine Phosphate, Lenalidomide)	Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)
Arm/Group Description	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 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.	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.
Measure Participants	123	109	110
Number (90% Confidence Interval) [percentage of participants]	75 61%	69 63.3%	71 51.8%

3. Secondary Outcome

Title	Overall Response Rates in Patients With Del(11q22.3)
Description	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.
Time Frame	Up to 15 years

Outcome Measure Data

Analysis Population Description

Patients with del(11q22.3) were included in this analysis.

Arm/Group Title	Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)	Arm D (Rituximab, Fludarabine, Cyclophosphamide, Lenalidomide)
Arm/Group Description	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.	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.
Measure Participants	27	31
Number (90% Confidence Interval) [percentage of participants]	59 48%	74 67.9%

4. Secondary Outcome

Title	PFS Rate of Patients With Del(11q22.3)
Description	Proportion of del (11q22.3) participants who were alive and progression free at 2 years.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

This endpoint is limited to patients with del(11q22.3).

Arm/Group Title	Arm C2, FCR in Del(11q22.3)	Arm D, FCR+L in Del(11q22.3)
Arm/Group Description	Participants who have del(11q22.3) 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.	Patients who have del(11q22.3)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.
Measure Participants	27	31
Number (90% Confidence Interval) [proportion of participants]	0.56 0.5%	0.65 0.6%

5. Secondary Outcome

Title	Time-to-progression in Patients Without Del(11q22.3)
Description	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.
Time Frame	Up to 15 years

Outcome Measure Data

Analysis Population Description

This endpoint is limited to patients without del(11q22.3).

Arm/Group Title	Arm A, FR in Non-del(11q22.3)	Arm B, FR+L in Non-del(11q22.3)	Arm C1, FCR in Non-del(11q22.3)
Arm/Group Description	Participants, who are non-del(11q22.3), receive induction therapy (every 28 days for up to 6 cycles) of: rituximab (R) 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 (F) 25 mg/m^2/day IV over 30 minutes or PO on days 1-5.	Participants, who are non-del(11q22.3), receive induction therapy (every 28 days for up to 6 cycles) of: rituximab (R) 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 (F) 25 mg/m^2/day IV over 30 minutes or PO on days 1-5. Participants without progression receive consolidation therapy lenalidomide (L) 5mg/day cycle 1, 10 mg/day cycles 2-6 PO QD on days 1-21 of 28 day cycle.	Participants, who are non-del(11q22.3), receive induction therapy (every 28 days for up to 6 cycles) of: rituximab (R) 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 (F) (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 (C) (age < 70: 250 mg/m^2/day; age >= 70: 150 mg/m^2/day) IV piggyback over 30 minutes on days 1-3.
Measure Participants	123	109	110
Median (95% Confidence Interval) [months]	43.5	66.0	78.0

6. Secondary Outcome

Title	Time-to-progression in Patients With Del(11q22.3)
Description	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.
Time Frame	Up to 15 years

Outcome Measure Data

Analysis Population Description

This endpoint is limited to patients with del(11q22.3).

Arm/Group Title	Arm C2, FCR in Del(11q22.3)	Arm D, FCR+L in Del(11q22.3)
Arm/Group Description	Participants who have del(11q22.3) 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.	Patients who have del(11q22.3)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.
Measure Participants	27	31
Median (95% Confidence Interval) [months]	35.5	44.6

Adverse Events

Arm/Group Title	Arm A (Rituximab, Fludarabine Phosphate)		Arm B (Rituximab, Fludarabine Phosphate, Lenalidomide)		Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)		Arm D (Rituximab, Fludarabine, Cyclophosphamide, Lenalidomide)
Arm/Group Description	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.		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.		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.		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.
All Cause Mortality
	Arm A (Rituximab, Fludarabine Phosphate)		Arm B (Rituximab, Fludarabine Phosphate, Lenalidomide)		Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)		Arm D (Rituximab, Fludarabine, Cyclophosphamide, Lenalidomide)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (Rituximab, Fludarabine Phosphate)		Arm B (Rituximab, Fludarabine Phosphate, Lenalidomide)		Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)		Arm D (Rituximab, Fludarabine, Cyclophosphamide, Lenalidomide)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/123 (10.6%)		21/109 (19.3%)		14/137 (10.2%)		3/31 (9.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/123 (0.8%)	1	6/109 (5.5%)	6	4/137 (2.9%)	4	0/31 (0%)	0
Hemoglobin decreased	8/123 (6.5%)	8	15/109 (13.8%)	17	10/137 (7.3%)	10	1/31 (3.2%)	1
Hemolysis	1/123 (0.8%)	1	2/109 (1.8%)	2	0/137 (0%)	0	1/31 (3.2%)	1
Lymphatic disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Cardiac disorders
Atrial fibrillation	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Cardiac disorder	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Left ventricular dysfunction	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Left ventricular failure	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Premature ventricular contractions	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Sinus tachycardia	1/123 (0.8%)	1	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Ear and labyrinth disorders
Ear disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Ear pain	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Tinnitus	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Abdominal pain	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Anal fistula	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Ascites	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Colitis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Constipation	0/123 (0%)	0	3/109 (2.8%)	3	1/137 (0.7%)	1	0/31 (0%)	0
Diarrhea	0/123 (0%)	0	3/109 (2.8%)	3	1/137 (0.7%)	1	1/31 (3.2%)	1
Dry mouth	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Dyspepsia	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Gastric perforation	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Lower gastrointestinal hemorrhage	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Mucositis oral	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Nausea	2/123 (1.6%)	2	8/109 (7.3%)	8	2/137 (1.5%)	2	0/31 (0%)	0
Oral pain	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Periodontal disease	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Upper gastrointestinal hemorrhage	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Vomiting	2/123 (1.6%)	2	3/109 (2.8%)	3	1/137 (0.7%)	1	0/31 (0%)	0
General disorders
Chest pain	1/123 (0.8%)	1	3/109 (2.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Chills	1/123 (0.8%)	1	7/109 (6.4%)	7	2/137 (1.5%)	2	0/31 (0%)	0
Death NOS	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Disease progression	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Edema limbs	1/123 (0.8%)	1	3/109 (2.8%)	4	1/137 (0.7%)	1	0/31 (0%)	0
Fatigue	8/123 (6.5%)	8	15/109 (13.8%)	17	6/137 (4.4%)	6	1/31 (3.2%)	1
Fever	0/123 (0%)	0	5/109 (4.6%)	5	2/137 (1.5%)	2	0/31 (0%)	0
Localized edema	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Pain	2/123 (1.6%)	2	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Immune system disorders
Hypersensitivity	0/123 (0%)	0	4/109 (3.7%)	4	1/137 (0.7%)	1	0/31 (0%)	0
Infections and infestations
Bladder infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Bronchitis	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Joint infection	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Peripheral nerve infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Pneumonia	0/123 (0%)	0	2/109 (1.8%)	2	3/137 (2.2%)	3	0/31 (0%)	0
Sepsis	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Sinusitis	0/123 (0%)	0	3/109 (2.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Skin infection	0/123 (0%)	0	2/109 (1.8%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Upper respiratory infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Urinary tract infection	0/123 (0%)	0	1/109 (0.9%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Vaginal infection	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Vulvitis	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Alanine aminotransferase increased	0/123 (0%)	0	3/109 (2.8%)	3	2/137 (1.5%)	2	0/31 (0%)	0
Alkaline phosphatase increased	0/123 (0%)	0	1/109 (0.9%)	1	3/137 (2.2%)	3	0/31 (0%)	0
Aspartate aminotransferase increased	0/123 (0%)	0	5/109 (4.6%)	5	1/137 (0.7%)	1	0/31 (0%)	0
Blood bilirubin increased	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	1/31 (3.2%)	1
Carbon monoxide diffusing capacity decreased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Creatine phosphokinase increased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Creatinine increased	0/123 (0%)	0	5/109 (4.6%)	5	2/137 (1.5%)	2	0/31 (0%)	0
Electrocardiogram QTc interval prolonged	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Haptoglobin decreased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
INR increased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Laboratory test abnormal	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Leukocyte count decreased	1/123 (0.8%)	1	7/109 (6.4%)	7	5/137 (3.6%)	5	0/31 (0%)	0
Lymphocyte count decreased	1/123 (0.8%)	1	4/109 (3.7%)	4	4/137 (2.9%)	4	0/31 (0%)	0
Neutrophil count decreased	7/123 (5.7%)	7	12/109 (11%)	14	8/137 (5.8%)	8	0/31 (0%)	0
Platelet count decreased	9/123 (7.3%)	9	10/109 (9.2%)	12	9/137 (6.6%)	9	0/31 (0%)	0
Serum cholesterol increased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Weight loss	2/123 (1.6%)	2	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Metabolism and nutrition disorders
Acidosis	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Alkalosis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Anorexia	1/123 (0.8%)	1	5/109 (4.6%)	5	1/137 (0.7%)	1	0/31 (0%)	0
Blood bicarbonate decreased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Blood glucose increased	2/123 (1.6%)	2	9/109 (8.3%)	9	4/137 (2.9%)	4	0/31 (0%)	0
Blood uric acid increased	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Dehydration	1/123 (0.8%)	1	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Renal tubular disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Serum albumin decreased	0/123 (0%)	0	2/109 (1.8%)	2	2/137 (1.5%)	2	0/31 (0%)	0
Serum calcium decreased	2/123 (1.6%)	2	5/109 (4.6%)	5	3/137 (2.2%)	3	0/31 (0%)	0
Serum calcium increased	0/123 (0%)	0	0/109 (0%)	0	2/137 (1.5%)	2	0/31 (0%)	0
Serum glucose decreased	2/123 (1.6%)	2	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Serum magnesium decreased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Serum magnesium increased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Serum phosphate decreased	0/123 (0%)	0	4/109 (3.7%)	4	0/137 (0%)	0	0/31 (0%)	0
Serum potassium decreased	2/123 (1.6%)	2	5/109 (4.6%)	5	2/137 (1.5%)	2	0/31 (0%)	0
Serum potassium increased	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Serum sodium decreased	1/123 (0.8%)	1	2/109 (1.8%)	2	5/137 (3.6%)	5	0/31 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/123 (0%)	0	2/109 (1.8%)	3	1/137 (0.7%)	1	0/31 (0%)	0
Back pain	1/123 (0.8%)	1	1/109 (0.9%)	2	0/137 (0%)	0	0/31 (0%)	0
Muscle weakness	0/123 (0%)	0	2/109 (1.8%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Muscle weakness left-sided	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Muscle weakness lower limb	0/123 (0%)	0	0/109 (0%)	0	2/137 (1.5%)	2	0/31 (0%)	0
Muscle weakness upper limb	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Myalgia	0/123 (0%)	0	2/109 (1.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Pain in extremity	1/123 (0.8%)	1	2/109 (1.8%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	2/123 (1.6%)	2	0/109 (0%)	0	3/137 (2.2%)	3	0/31 (0%)	0
Tumor pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Nervous system disorders
Ataxia	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Dizziness	1/123 (0.8%)	1	4/109 (3.7%)	4	1/137 (0.7%)	1	0/31 (0%)	0
Dysgeusia	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Encephalopathy	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Headache	1/123 (0.8%)	1	3/109 (2.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Memory impairment	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Peripheral motor neuropathy	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Sinus pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Speech disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Syncope	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Psychiatric disorders
Agitation	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Anxiety	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Confusion	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Depression	0/123 (0%)	0	2/109 (1.8%)	2	2/137 (1.5%)	2	1/31 (3.2%)	1
Insomnia	0/123 (0%)	0	1/109 (0.9%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Personality change	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Renal and urinary disorders
Glomerular filtration rate decreased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Hemoglobin urine positive	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Renal failure	1/123 (0.8%)	1	3/109 (2.8%)	3	1/137 (0.7%)	1	0/31 (0%)	0
Urethral pain	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Urinary frequency	0/123 (0%)	0	2/109 (1.8%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Urinary incontinence	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Urinary retention	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Urogenital disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Reproductive system and breast disorders
Breast pain	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Atelectasis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Bronchospasm	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Cough	2/123 (1.6%)	2	8/109 (7.3%)	9	1/137 (0.7%)	1	0/31 (0%)	0
Dyspnea	5/123 (4.1%)	5	7/109 (6.4%)	7	3/137 (2.2%)	3	0/31 (0%)	0
Hypoxia	0/123 (0%)	0	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Pharyngolaryngeal pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Pleural effusion	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Respiratory disorder	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Voice alteration	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Skin and subcutaneous tissue disorders
Petechiae	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Pruritus	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Rash desquamating	2/123 (1.6%)	2	3/109 (2.8%)	3	2/137 (1.5%)	2	0/31 (0%)	0
Sweating	1/123 (0.8%)	1	2/109 (1.8%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Vascular disorders
Flushing	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Hematoma	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Hot flashes	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Hypertension	0/123 (0%)	0	2/109 (1.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Hypotension	0/123 (0%)	0	3/109 (2.8%)	3	2/137 (1.5%)	2	0/31 (0%)	0
Vascular disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A (Rituximab, Fludarabine Phosphate)		Arm B (Rituximab, Fludarabine Phosphate, Lenalidomide)		Arm C (Rituximab, Fludarabine Phosphate, Cyclophosphamide)		Arm D (Rituximab, Fludarabine, Cyclophosphamide, Lenalidomide)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	117/123 (95.1%)		107/109 (98.2%)		132/137 (96.4%)		30/31 (96.8%)
Blood and lymphatic system disorders
Blood disorder	8/123 (6.5%)	22	5/109 (4.6%)	21	8/137 (5.8%)	26	1/31 (3.2%)	1
Febrile neutropenia	14/123 (11.4%)	17	13/109 (11.9%)	13	18/137 (13.1%)	18	5/31 (16.1%)	6
Hemoglobin decreased	92/123 (74.8%)	398	90/109 (82.6%)	436	116/137 (84.7%)	516	23/31 (74.2%)	91
Hemolysis	1/123 (0.8%)	1	3/109 (2.8%)	3	0/137 (0%)	0	2/31 (6.5%)	2
Lymph node pain	6/123 (4.9%)	16	0/109 (0%)	0	2/137 (1.5%)	4	1/31 (3.2%)	1
Lymphatic disorder	0/123 (0%)	0	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Thrombotic microangiopathy	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Cardiac disorders
Arrhythmia	4/123 (3.3%)	4	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Atrial fibrillation	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	2	0/31 (0%)	0
Atrial flutter	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Cardiac disorder	0/123 (0%)	0	2/109 (1.8%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Conduction disorder	1/123 (0.8%)	4	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Edema	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Left ventricular dysfunction	1/123 (0.8%)	1	1/109 (0.9%)	2	0/137 (0%)	0	0/31 (0%)	0
Left ventricular failure	0/123 (0%)	0	1/109 (0.9%)	1	3/137 (2.2%)	3	0/31 (0%)	0
Myocardial ischemia	2/123 (1.6%)	2	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Palpitations	1/123 (0.8%)	1	4/109 (3.7%)	4	3/137 (2.2%)	3	0/31 (0%)	0
Pericardial effusion	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Premature ventricular contractions	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	1/31 (3.2%)	1
Restrictive cardiomyopathy	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Sinus bradycardia	0/123 (0%)	0	4/109 (3.7%)	8	2/137 (1.5%)	6	1/31 (3.2%)	1
Sinus tachycardia	4/123 (3.3%)	5	9/109 (8.3%)	9	3/137 (2.2%)	4	2/31 (6.5%)	2
Ventricular bigeminy	1/123 (0.8%)	2	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Ear and labyrinth disorders
Ear disorder	2/123 (1.6%)	3	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Ear pain	1/123 (0.8%)	1	4/109 (3.7%)	5	3/137 (2.2%)	8	1/31 (3.2%)	1
External ear pain	0/123 (0%)	0	0/109 (0%)	0	2/137 (1.5%)	2	0/31 (0%)	0
Hearing impaired	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	1/31 (3.2%)	3
Middle ear inflammation	1/123 (0.8%)	2	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Tinnitus	5/123 (4.1%)	16	0/109 (0%)	0	1/137 (0.7%)	6	0/31 (0%)	0
Endocrine disorders
Endocrine disorder	0/123 (0%)	0	2/109 (1.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Hyperthyroidism	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Hypothyroidism	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Eye disorders
Cataract	0/123 (0%)	0	0/109 (0%)	0	3/137 (2.2%)	4	0/31 (0%)	0
Conjunctivitis	1/123 (0.8%)	1	1/109 (0.9%)	1	1/137 (0.7%)	2	0/31 (0%)	0
Diplopia	0/123 (0%)	0	1/109 (0.9%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Dry eye syndrome	1/123 (0.8%)	3	0/109 (0%)	0	2/137 (1.5%)	4	0/31 (0%)	0
Eye disorder	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	4	0/31 (0%)	0
Eye pain	3/123 (2.4%)	6	1/109 (0.9%)	2	1/137 (0.7%)	4	0/31 (0%)	0
Eyelid function disorder	0/123 (0%)	0	0/109 (0%)	0	2/137 (1.5%)	2	0/31 (0%)	0
Flashing vision	1/123 (0.8%)	1	2/109 (1.8%)	6	1/137 (0.7%)	2	0/31 (0%)	0
Keratitis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Photophobia	0/123 (0%)	0	4/109 (3.7%)	5	0/137 (0%)	0	1/31 (3.2%)	4
Retinopathy	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Vision blurred	6/123 (4.9%)	7	8/109 (7.3%)	10	4/137 (2.9%)	4	0/31 (0%)	0
Vitreous hemorrhage	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Watering eyes	0/123 (0%)	0	1/109 (0.9%)	2	1/137 (0.7%)	1	0/31 (0%)	0
Gastrointestinal disorders
Abdominal distension	1/123 (0.8%)	1	4/109 (3.7%)	7	2/137 (1.5%)	2	0/31 (0%)	0
Abdominal pain	17/123 (13.8%)	22	18/109 (16.5%)	26	23/137 (16.8%)	24	4/31 (12.9%)	5
Anal exam abnormal	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Anal mucositis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Anal pain	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Ascites	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Cheilitis	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Colitis	1/123 (0.8%)	1	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Colonic fistula	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Constipation	35/123 (28.5%)	90	47/109 (43.1%)	123	46/137 (33.6%)	89	10/31 (32.3%)	23
Diarrhea	30/123 (24.4%)	47	35/109 (32.1%)	88	39/137 (28.5%)	60	6/31 (19.4%)	15
Dry mouth	4/123 (3.3%)	6	4/109 (3.7%)	10	1/137 (0.7%)	1	1/31 (3.2%)	1
Duodenal hemorrhage	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Duodenal ulcer	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Dyspepsia	6/123 (4.9%)	17	15/109 (13.8%)	24	10/137 (7.3%)	24	2/31 (6.5%)	3
Dysphagia	2/123 (1.6%)	9	1/109 (0.9%)	1	5/137 (3.6%)	6	0/31 (0%)	0
Ear, nose and throat examination abnormal	1/123 (0.8%)	2	6/109 (5.5%)	17	4/137 (2.9%)	5	1/31 (3.2%)	1
Esophagitis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Flatulence	1/123 (0.8%)	2	3/109 (2.8%)	3	1/137 (0.7%)	1	0/31 (0%)	0
Gastric hemorrhage	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Gastritis	2/123 (1.6%)	3	2/109 (1.8%)	2	3/137 (2.2%)	3	0/31 (0%)	0
Gastrointestinal disorder	6/123 (4.9%)	6	3/109 (2.8%)	3	3/137 (2.2%)	3	0/31 (0%)	0
Gastrointestinal pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Gingival pain	0/123 (0%)	0	2/109 (1.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Hemorrhoids	4/123 (3.3%)	15	3/109 (2.8%)	4	4/137 (2.9%)	8	0/31 (0%)	0
Lower gastrointestinal hemorrhage	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Mucositis oral	8/123 (6.5%)	11	6/109 (5.5%)	10	2/137 (1.5%)	2	0/31 (0%)	0
Nausea	64/123 (52%)	158	57/109 (52.3%)	155	79/137 (57.7%)	197	22/31 (71%)	50
Oral hemorrhage	0/123 (0%)	0	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Oral pain	0/123 (0%)	0	2/109 (1.8%)	3	1/137 (0.7%)	3	0/31 (0%)	0
Pancreatitis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Peritoneal pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Proctitis	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Rectal hemorrhage	1/123 (0.8%)	2	0/109 (0%)	0	3/137 (2.2%)	3	0/31 (0%)	0
Rectal pain	0/123 (0%)	0	1/109 (0.9%)	1	2/137 (1.5%)	9	0/31 (0%)	0
Salivary gland disorder	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Stomach pain	2/123 (1.6%)	2	3/109 (2.8%)	10	1/137 (0.7%)	1	1/31 (3.2%)	1
Tooth disorder	1/123 (0.8%)	1	2/109 (1.8%)	2	3/137 (2.2%)	3	0/31 (0%)	0
Toothache	3/123 (2.4%)	5	3/109 (2.8%)	6	3/137 (2.2%)	4	0/31 (0%)	0
Vomiting	23/123 (18.7%)	41	17/109 (15.6%)	31	47/137 (34.3%)	74	5/31 (16.1%)	9
General disorders
Chest pain	13/123 (10.6%)	14	13/109 (11.9%)	19	21/137 (15.3%)	30	1/31 (3.2%)	1
Chills	39/123 (31.7%)	50	39/109 (35.8%)	57	44/137 (32.1%)	61	5/31 (16.1%)	6
Edema limbs	15/123 (12.2%)	31	20/109 (18.3%)	41	20/137 (14.6%)	49	3/31 (9.7%)	10
Facial pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Fatigue	89/123 (72.4%)	401	90/109 (82.6%)	481	106/137 (77.4%)	408	24/31 (77.4%)	119
Fever	19/123 (15.4%)	20	23/109 (21.1%)	27	23/137 (16.8%)	29	7/31 (22.6%)	8
Flu-like symptoms	0/123 (0%)	0	6/109 (5.5%)	10	4/137 (2.9%)	5	2/31 (6.5%)	2
Gait abnormal	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
General symptom	3/123 (2.4%)	3	1/109 (0.9%)	1	3/137 (2.2%)	6	0/31 (0%)	0
Injection site reaction	1/123 (0.8%)	1	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Irritability	0/123 (0%)	0	1/109 (0.9%)	3	1/137 (0.7%)	1	1/31 (3.2%)	4
Localized edema	3/123 (2.4%)	3	4/109 (3.7%)	4	10/137 (7.3%)	14	1/31 (3.2%)	2
Pain	12/123 (9.8%)	16	18/109 (16.5%)	38	19/137 (13.9%)	26	1/31 (3.2%)	1
Pericardial pain	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Hepatobiliary disorders
Cholecystitis	2/123 (1.6%)	2	1/109 (0.9%)	1	2/137 (1.5%)	3	0/31 (0%)	0
Gallbladder pain	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Hepatic failure	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Immune system disorders
Autoimmune disorder	2/123 (1.6%)	4	0/109 (0%)	0	2/137 (1.5%)	4	0/31 (0%)	0
Cytokine release syndrome	6/123 (4.9%)	6	5/109 (4.6%)	5	3/137 (2.2%)	3	1/31 (3.2%)	1
Hypersensitivity	7/123 (5.7%)	7	11/109 (10.1%)	16	11/137 (8%)	13	2/31 (6.5%)	2
Immune system disorder	1/123 (0.8%)	1	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Infections and infestations
Abdominal infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Anorectal infection	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Appendicitis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Bladder infection	3/123 (2.4%)	3	2/109 (1.8%)	2	2/137 (1.5%)	3	1/31 (3.2%)	1
Bone infection	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	2	0/31 (0%)	0
Bronchitis	9/123 (7.3%)	11	11/109 (10.1%)	13	5/137 (3.6%)	7	1/31 (3.2%)	1
Catheter related infection	3/123 (2.4%)	5	0/109 (0%)	0	4/137 (2.9%)	4	1/31 (3.2%)	1
Colitis, infectious (e.g., Clostridium difficile)	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Conjunctivitis infective	1/123 (0.8%)	1	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Corneal infection	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Esophageal infection	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Eye infection	0/123 (0%)	0	3/109 (2.8%)	4	1/137 (0.7%)	5	1/31 (3.2%)	1
Eye infection intraocular	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Gallbladder infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Gastric infection	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Gingival infection	0/123 (0%)	0	2/109 (1.8%)	3	2/137 (1.5%)	2	0/31 (0%)	0
Hepatic infection	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Infection	7/123 (5.7%)	16	9/109 (8.3%)	12	4/137 (2.9%)	5	1/31 (3.2%)	1
Infection with unknown ANC	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Infectious meningitis	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Joint infection	0/123 (0%)	0	0/109 (0%)	0	0/137 (0%)	0	1/31 (3.2%)	1
Laryngitis	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Lip infection	2/123 (1.6%)	3	4/109 (3.7%)	5	3/137 (2.2%)	3	0/31 (0%)	0
Mucosal infection	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Nail infection	0/123 (0%)	0	1/109 (0.9%)	5	2/137 (1.5%)	4	0/31 (0%)	0
Opportunistic infection	1/123 (0.8%)	1	1/109 (0.9%)	2	3/137 (2.2%)	10	0/31 (0%)	0
Otitis externa	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Otitis media	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Penile infection	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	2	0/31 (0%)	0
Peripheral nerve infection	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Pharyngitis	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Pneumonia	8/123 (6.5%)	10	8/109 (7.3%)	9	5/137 (3.6%)	5	2/31 (6.5%)	2
Rhinitis infective	1/123 (0.8%)	1	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Salivary gland infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Sepsis	2/123 (1.6%)	2	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Sinusitis	13/123 (10.6%)	18	12/109 (11%)	24	8/137 (5.8%)	11	0/31 (0%)	0
Skin infection	8/123 (6.5%)	9	7/109 (6.4%)	10	8/137 (5.8%)	10	1/31 (3.2%)	1
Small intestine infection	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Soft tissue infection	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Tooth infection	3/123 (2.4%)	3	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Tracheitis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Upper aerodigestive tract infection	2/123 (1.6%)	2	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Upper respiratory infection	15/123 (12.2%)	20	13/109 (11.9%)	21	12/137 (8.8%)	14	2/31 (6.5%)	3
Ureteritis	10/123 (8.1%)	13	8/109 (7.3%)	9	9/137 (6.6%)	13	1/31 (3.2%)	2
Urinary tract infection	3/123 (2.4%)	5	6/109 (5.5%)	8	9/137 (6.6%)	12	1/31 (3.2%)	1
Vaginal infection	1/123 (0.8%)	1	4/109 (3.7%)	4	1/137 (0.7%)	1	0/31 (0%)	0
Viral hepatitis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Vulvitis	1/123 (0.8%)	3	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Wound infection	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Injury, poisoning and procedural complications
Bruising	1/123 (0.8%)	1	6/109 (5.5%)	20	6/137 (4.4%)	6	1/31 (3.2%)	1
Fracture	3/123 (2.4%)	3	3/109 (2.8%)	7	1/137 (0.7%)	1	0/31 (0%)	0
Intraoperative neurological injury - NERVES: Sciatic	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Seroma	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	3	0/31 (0%)	0
Thermal burn	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Vascular access complication	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Venous injury - Extremity-upper	1/123 (0.8%)	1	1/109 (0.9%)	4	0/137 (0%)	0	0/31 (0%)	0
Wound dehiscence	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Investigations
Activated partial thromboplastin time prolonged	1/123 (0.8%)	1	3/109 (2.8%)	4	1/137 (0.7%)	4	0/31 (0%)	0
Alanine aminotransferase increased	28/123 (22.8%)	74	29/109 (26.6%)	89	33/137 (24.1%)	89	7/31 (22.6%)	19
Alkaline phosphatase increased	19/123 (15.4%)	39	15/109 (13.8%)	42	23/137 (16.8%)	50	4/31 (12.9%)	4
Amylase increased	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Aspartate aminotransferase increased	31/123 (25.2%)	67	33/109 (30.3%)	76	33/137 (24.1%)	72	7/31 (22.6%)	13
Blood bilirubin increased	24/123 (19.5%)	59	17/109 (15.6%)	49	9/137 (6.6%)	9	4/31 (12.9%)	19
CD4 lymphocytes decreased	1/123 (0.8%)	1	3/109 (2.8%)	3	4/137 (2.9%)	7	1/31 (3.2%)	6
Cardiac troponin I increased	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Creatine phosphokinase increased	1/123 (0.8%)	2	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Creatinine increased	22/123 (17.9%)	34	18/109 (16.5%)	34	19/137 (13.9%)	39	2/31 (6.5%)	3
Electrocardiogram QTc interval prolonged	0/123 (0%)	0	1/109 (0.9%)	1	2/137 (1.5%)	3	0/31 (0%)	0
Gamma-glutamyltransferase increased	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Haptoglobin decreased	1/123 (0.8%)	1	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
INR increased	2/123 (1.6%)	4	2/109 (1.8%)	3	6/137 (4.4%)	18	0/31 (0%)	0
Laboratory test abnormal	8/123 (6.5%)	22	8/109 (7.3%)	20	11/137 (8%)	30	3/31 (9.7%)	3
Leukocyte count decreased	64/123 (52%)	258	61/109 (56%)	271	64/137 (46.7%)	273	14/31 (45.2%)	67
Lipase increased	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Lymphocyte count decreased	49/123 (39.8%)	225	48/109 (44%)	216	55/137 (40.1%)	281	10/31 (32.3%)	58
Neutrophil count decreased	100/123 (81.3%)	356	97/109 (89%)	420	109/137 (79.6%)	370	28/31 (90.3%)	106
Platelet count decreased	95/123 (77.2%)	528	85/109 (78%)	470	114/137 (83.2%)	546	22/31 (71%)	116
Serum cholesterol increased	2/123 (1.6%)	2	2/109 (1.8%)	5	2/137 (1.5%)	7	0/31 (0%)	0
Weight gain	13/123 (10.6%)	31	13/109 (11.9%)	21	12/137 (8.8%)	29	1/31 (3.2%)	1
Weight loss	5/123 (4.1%)	5	12/109 (11%)	15	10/137 (7.3%)	16	3/31 (9.7%)	3
Metabolism and nutrition disorders
Acidosis	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Alkalosis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Anorexia	23/123 (18.7%)	41	28/109 (25.7%)	49	20/137 (14.6%)	26	7/31 (22.6%)	16
Blood bicarbonate decreased	1/123 (0.8%)	1	2/109 (1.8%)	2	5/137 (3.6%)	6	0/31 (0%)	0
Blood glucose increased	54/123 (43.9%)	185	54/109 (49.5%)	217	62/137 (45.3%)	212	10/31 (32.3%)	39
Blood uric acid increased	7/123 (5.7%)	12	9/109 (8.3%)	22	10/137 (7.3%)	16	0/31 (0%)	0
Dehydration	2/123 (1.6%)	4	2/109 (1.8%)	6	2/137 (1.5%)	2	1/31 (3.2%)	1
Glucose intolerance	1/123 (0.8%)	3	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Iron overload	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Obesity	0/123 (0%)	0	0/109 (0%)	0	3/137 (2.2%)	11	0/31 (0%)	0
Serum albumin decreased	15/123 (12.2%)	23	23/109 (21.1%)	43	20/137 (14.6%)	29	4/31 (12.9%)	12
Serum calcium decreased	31/123 (25.2%)	59	42/109 (38.5%)	78	38/137 (27.7%)	68	7/31 (22.6%)	20
Serum calcium increased	4/123 (3.3%)	7	5/109 (4.6%)	10	2/137 (1.5%)	8	0/31 (0%)	0
Serum glucose decreased	6/123 (4.9%)	14	5/109 (4.6%)	12	8/137 (5.8%)	10	1/31 (3.2%)	2
Serum magnesium decreased	3/123 (2.4%)	5	6/109 (5.5%)	14	6/137 (4.4%)	7	1/31 (3.2%)	1
Serum magnesium increased	1/123 (0.8%)	1	0/109 (0%)	0	1/137 (0.7%)	2	0/31 (0%)	0
Serum phosphate decreased	12/123 (9.8%)	23	15/109 (13.8%)	36	8/137 (5.8%)	13	3/31 (9.7%)	5
Serum potassium decreased	16/123 (13%)	33	19/109 (17.4%)	35	22/137 (16.1%)	36	3/31 (9.7%)	4
Serum potassium increased	11/123 (8.9%)	13	10/109 (9.2%)	14	12/137 (8.8%)	15	1/31 (3.2%)	2
Serum sodium decreased	21/123 (17.1%)	40	28/109 (25.7%)	46	23/137 (16.8%)	44	3/31 (9.7%)	3
Serum sodium increased	7/123 (5.7%)	8	1/109 (0.9%)	1	2/137 (1.5%)	5	0/31 (0%)	0
Serum triglycerides increased	3/123 (2.4%)	3	0/109 (0%)	0	2/137 (1.5%)	2	0/31 (0%)	0
Tumor lysis syndrome	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	24/123 (19.5%)	65	24/109 (22%)	57	24/137 (17.5%)	53	3/31 (9.7%)	5
Arthritis	2/123 (1.6%)	5	3/109 (2.8%)	4	6/137 (4.4%)	13	1/31 (3.2%)	1
Back pain	22/123 (17.9%)	28	21/109 (19.3%)	57	23/137 (16.8%)	44	3/31 (9.7%)	4
Bone pain	7/123 (5.7%)	11	7/109 (6.4%)	8	7/137 (5.1%)	11	1/31 (3.2%)	1
Buttock pain	0/123 (0%)	0	1/109 (0.9%)	1	4/137 (2.9%)	6	0/31 (0%)	0
Chest wall pain	2/123 (1.6%)	3	0/109 (0%)	0	4/137 (2.9%)	6	1/31 (3.2%)	1
Fibrosis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Fibrosis deep connective tissue	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Joint disorder	3/123 (2.4%)	11	2/109 (1.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Joint effusion	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	2	0/31 (0%)	0
Muscle weakness	6/123 (4.9%)	11	10/109 (9.2%)	12	3/137 (2.2%)	10	2/31 (6.5%)	3
Muscle weakness lower limb	1/123 (0.8%)	2	5/109 (4.6%)	11	1/137 (0.7%)	2	0/31 (0%)	0
Muscle weakness right-sided	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Muscle weakness upper limb	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	2	0/31 (0%)	0
Musculoskeletal disorder	0/123 (0%)	0	5/109 (4.6%)	6	5/137 (3.6%)	7	2/31 (6.5%)	2
Myalgia	17/123 (13.8%)	31	15/109 (13.8%)	43	16/137 (11.7%)	25	4/31 (12.9%)	5
Myositis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Neck pain	7/123 (5.7%)	9	5/109 (4.6%)	8	11/137 (8%)	20	2/31 (6.5%)	2
Neck soft tissue necrosis	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Osteoporosis	0/123 (0%)	0	0/109 (0%)	0	2/137 (1.5%)	3	0/31 (0%)	0
Pain in extremity	17/123 (13.8%)	34	18/109 (16.5%)	39	16/137 (11.7%)	33	0/31 (0%)	0
Trismus	0/123 (0%)	0	0/109 (0%)	0	2/137 (1.5%)	2	0/31 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	3/123 (2.4%)	3	2/109 (1.8%)	2	1/137 (0.7%)	1	3/31 (9.7%)	3
Tumor flare	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	1/31 (3.2%)	2
Tumor pain	4/123 (3.3%)	4	8/109 (7.3%)	16	5/137 (3.6%)	8	0/31 (0%)	0
Nervous system disorders
Acoustic nerve disorder NOS	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Ataxia	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Cerebrospinal fluid leakage	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Cognitive disturbance	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	1/31 (3.2%)	5
Depressed level of consciousness	1/123 (0.8%)	1	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Dizziness	17/123 (13.8%)	33	25/109 (22.9%)	49	19/137 (13.9%)	32	2/31 (6.5%)	5
Dysgeusia	9/123 (7.3%)	14	12/109 (11%)	19	5/137 (3.6%)	6	1/31 (3.2%)	4
Encephalopathy	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Extrapyramidal disorder	1/123 (0.8%)	1	2/109 (1.8%)	3	3/137 (2.2%)	3	1/31 (3.2%)	2
Headache	33/123 (26.8%)	62	35/109 (32.1%)	72	27/137 (19.7%)	60	8/31 (25.8%)	22
Memory impairment	3/123 (2.4%)	3	3/109 (2.8%)	22	5/137 (3.6%)	9	1/31 (3.2%)	1
Neuralgia	0/123 (0%)	0	2/109 (1.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Neurological disorder NOS	4/123 (3.3%)	6	5/109 (4.6%)	10	7/137 (5.1%)	12	1/31 (3.2%)	1
Nystagmus	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Peripheral motor neuropathy	0/123 (0%)	0	2/109 (1.8%)	3	2/137 (1.5%)	2	0/31 (0%)	0
Peripheral sensory neuropathy	18/123 (14.6%)	39	20/109 (18.3%)	69	17/137 (12.4%)	56	2/31 (6.5%)	3
Phrenic nerve paralysis	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Seizure	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Sinus pain	4/123 (3.3%)	4	3/109 (2.8%)	6	2/137 (1.5%)	2	0/31 (0%)	0
Speech disorder	2/123 (1.6%)	2	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Syncope	0/123 (0%)	0	3/109 (2.8%)	3	0/137 (0%)	0	0/31 (0%)	0
Tremor	3/123 (2.4%)	4	3/109 (2.8%)	4	0/137 (0%)	0	1/31 (3.2%)	1
Psychiatric disorders
Agitation	0/123 (0%)	0	3/109 (2.8%)	10	3/137 (2.2%)	4	0/31 (0%)	0
Anxiety	14/123 (11.4%)	38	17/109 (15.6%)	27	13/137 (9.5%)	22	2/31 (6.5%)	4
Confusion	1/123 (0.8%)	2	2/109 (1.8%)	3	1/137 (0.7%)	1	0/31 (0%)	0
Depression	8/123 (6.5%)	35	11/109 (10.1%)	23	9/137 (6.6%)	16	2/31 (6.5%)	18
Euphoria	0/123 (0%)	0	2/109 (1.8%)	8	0/137 (0%)	0	0/31 (0%)	0
Insomnia	19/123 (15.4%)	45	23/109 (21.1%)	52	25/137 (18.2%)	55	5/31 (16.1%)	12
Libido decreased	0/123 (0%)	0	1/109 (0.9%)	6	1/137 (0.7%)	1	0/31 (0%)	0
Renal and urinary disorders
Cystitis	0/123 (0%)	0	2/109 (1.8%)	5	3/137 (2.2%)	3	0/31 (0%)	0
Glomerular filtration rate decreased	0/123 (0%)	0	1/109 (0.9%)	1	4/137 (2.9%)	7	0/31 (0%)	0
Hemorrhage urinary tract	1/123 (0.8%)	1	5/109 (4.6%)	10	2/137 (1.5%)	2	0/31 (0%)	0
Kidney pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Proteinuria	1/123 (0.8%)	1	6/109 (5.5%)	7	1/137 (0.7%)	1	0/31 (0%)	0
Renal failure	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Urethral pain	0/123 (0%)	0	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Urinary frequency	6/123 (4.9%)	15	9/109 (8.3%)	17	12/137 (8.8%)	21	2/31 (6.5%)	2
Urinary incontinence	0/123 (0%)	0	3/109 (2.8%)	3	4/137 (2.9%)	16	0/31 (0%)	0
Urinary retention	3/123 (2.4%)	4	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Urine discoloration	0/123 (0%)	0	0/109 (0%)	0	2/137 (1.5%)	2	1/31 (3.2%)	1
Urogenital disorder	5/123 (4.1%)	9	4/109 (3.7%)	10	5/137 (3.6%)	15	2/31 (6.5%)	3
Reproductive system and breast disorders
Breast pain	2/123 (1.6%)	2	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Erectile dysfunction	0/123 (0%)	0	2/109 (1.8%)	7	0/137 (0%)	0	0/31 (0%)	0
Pelvic pain	1/123 (0.8%)	2	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Perineal pain	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Prostatic obstruction	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Reproductive tract disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Scrotal pain	1/123 (0.8%)	1	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Testicular pain	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Vaginal dryness	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Vaginal hemorrhage	0/123 (0%)	0	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Vaginal pain	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Allergic rhinitis	18/123 (14.6%)	48	18/109 (16.5%)	42	13/137 (9.5%)	24	1/31 (3.2%)	3
Aspiration	1/123 (0.8%)	1	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Atelectasis	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Bronchospasm	2/123 (1.6%)	2	0/109 (0%)	0	3/137 (2.2%)	7	0/31 (0%)	0
Cough	30/123 (24.4%)	69	48/109 (44%)	122	44/137 (32.1%)	91	8/31 (25.8%)	11
Dyspnea	32/123 (26%)	102	43/109 (39.4%)	104	43/137 (31.4%)	90	9/31 (29%)	22
Epistaxis	2/123 (1.6%)	2	3/109 (2.8%)	8	4/137 (2.9%)	7	0/31 (0%)	0
Hiccups	1/123 (0.8%)	1	2/109 (1.8%)	2	4/137 (2.9%)	6	0/31 (0%)	0
Hypoxia	0/123 (0%)	0	2/109 (1.8%)	2	1/137 (0.7%)	1	2/31 (6.5%)	2
Nasal congestion	7/123 (5.7%)	9	2/109 (1.8%)	2	2/137 (1.5%)	2	0/31 (0%)	0
Pharyngeal hemorrhage	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0
Pharyngeal mucositis	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Pharyngolaryngeal pain	7/123 (5.7%)	14	8/109 (7.3%)	19	13/137 (9.5%)	16	0/31 (0%)	0
Pleural effusion	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Pleuritic pain	0/123 (0%)	0	1/109 (0.9%)	1	2/137 (1.5%)	2	0/31 (0%)	0
Pneumonitis	1/123 (0.8%)	1	1/109 (0.9%)	1	4/137 (2.9%)	4	0/31 (0%)	0
Respiratory disorder	5/123 (4.1%)	6	6/109 (5.5%)	10	1/137 (0.7%)	4	2/31 (6.5%)	4
Respiratory tract hemorrhage	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Voice alteration	1/123 (0.8%)	1	3/109 (2.8%)	5	2/137 (1.5%)	2	0/31 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	4/123 (3.3%)	9	4/109 (3.7%)	16	3/137 (2.2%)	5	0/31 (0%)	0
Decubitus ulcer	0/123 (0%)	0	0/109 (0%)	0	0/137 (0%)	0	1/31 (3.2%)	1
Dry skin	4/123 (3.3%)	5	10/109 (9.2%)	21	6/137 (4.4%)	21	2/31 (6.5%)	5
Erythema multiforme	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Hand-and-foot syndrome	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Nail disorder	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Pain of skin	1/123 (0.8%)	5	2/109 (1.8%)	3	2/137 (1.5%)	2	0/31 (0%)	0
Petechiae	3/123 (2.4%)	3	0/109 (0%)	0	2/137 (1.5%)	3	0/31 (0%)	0
Pruritus	14/123 (11.4%)	24	20/109 (18.3%)	35	18/137 (13.1%)	25	7/31 (22.6%)	14
Rash acneiform	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Rash desquamating	32/123 (26%)	48	49/109 (45%)	122	50/137 (36.5%)	99	15/31 (48.4%)	28
Scalp pain	0/123 (0%)	0	2/109 (1.8%)	2	0/137 (0%)	0	0/31 (0%)	0
Skin disorder	3/123 (2.4%)	3	10/109 (9.2%)	11	9/137 (6.6%)	14	4/31 (12.9%)	4
Skin hyperpigmentation	0/123 (0%)	0	0/109 (0%)	0	0/137 (0%)	0	1/31 (3.2%)	1
Skin hypopigmentation	0/123 (0%)	0	1/109 (0.9%)	4	0/137 (0%)	0	0/31 (0%)	0
Skin ulceration	3/123 (2.4%)	4	1/109 (0.9%)	1	0/137 (0%)	0	1/31 (3.2%)	1
Sweating	21/123 (17.1%)	52	27/109 (24.8%)	50	31/137 (22.6%)	81	6/31 (19.4%)	12
Telangiectasia	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	1	0/31 (0%)	0
Urticaria	4/123 (3.3%)	9	4/109 (3.7%)	7	6/137 (4.4%)	8	1/31 (3.2%)	1
Vascular disorders
Flushing	4/123 (3.3%)	9	7/109 (6.4%)	17	2/137 (1.5%)	2	0/31 (0%)	0
Hematoma	1/123 (0.8%)	1	1/109 (0.9%)	1	1/137 (0.7%)	1	0/31 (0%)	0
Hemorrhage	0/123 (0%)	0	4/109 (3.7%)	9	1/137 (0.7%)	1	0/31 (0%)	0
Hot flashes	5/123 (4.1%)	9	3/109 (2.8%)	10	6/137 (4.4%)	14	2/31 (6.5%)	6
Hypertension	16/123 (13%)	27	18/109 (16.5%)	76	20/137 (14.6%)	55	1/31 (3.2%)	1
Hypotension	15/123 (12.2%)	24	12/109 (11%)	13	20/137 (14.6%)	30	2/31 (6.5%)	2
Lymphedema	0/123 (0%)	0	1/109 (0.9%)	1	0/137 (0%)	0	0/31 (0%)	0
Lymphocele	0/123 (0%)	0	0/109 (0%)	0	1/137 (0.7%)	2	0/31 (0%)	0
Phlebitis	5/123 (4.1%)	6	1/109 (0.9%)	3	1/137 (0.7%)	1	0/31 (0%)	0
Thrombosis	1/123 (0.8%)	1	0/109 (0%)	0	2/137 (1.5%)	2	0/31 (0%)	0
Vascular disorder	1/123 (0.8%)	1	0/109 (0%)	0	0/137 (0%)	0	0/31 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.