Early or Delayed Fludarabine and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00513747
• Collaborator: National Cancer Institute (NCI) (NIH)

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving fludarabine together with rituximab may kill more cancer cells. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving fludarabine together with rituximab early is more effective than giving fludarabine and rituximab after observation in treating chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying fludarabine and rituximab to compare how well they work when given early or after observation in treating patients with previously untreated chronic lymphocytic leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: rituximab; Drug: fludarabine phosphate	Phase 3

Detailed Description

OBJECTIVES:

Primary

• To determine if early treatment with chemoimmunotherapy comprising fludarabine phosphate and rituximab extends the time to second treatment in patients with genetically high-risk (unmutated IgV_H), asymptomatic, previously untreated chronic lymphocytic leukemia (CLL).

• To determine the time to disease progression that would warrant second treatment.

• To determine overall survival.

Secondary

• To measure the proportion of patients with asymptomatic, previously untreated CLL who have mutated and unmutated IgV_H genes.

• To determine the differences in acute and chronic toxicity of administering chemoimmunotherapy early to patients with genetically high-risk CLL compared to waiting until symptoms develop.

• To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction [primary and secondary]) on response, time to second treatment, and overall survival of patients with genetically high-risk CLL randomized to early treatment.

• To determine the effect of select pretreatment clinical and biological characteristics (such as interphase cytogenetic abnormalities, ZAP-70 expression, and p53 dysfunction) on response, time to first and second treatments, and overall survival of patients with genetically high-risk CLL randomized to standard treatment (observation until symptoms occur).

• To describe the natural history of patients with genetically low-risk (mutated IgV_H genes), asymptomatic, previously untreated CLL, in terms of time to initial treatment, response, progression, and survival.

• To determine the effect of select pretreatment characteristics on time to first treatment, response, progression, and survival of patients with genetically low-risk CLL.

• To correlate patterns of resistance that emerge in patients with unmutated IgV_H genes who have relapsing or refractory CLL following receipt of chemoimmunotherapy with clonal evolution, including acquisition of high-risk karyotype abnormalities, p53 mutations, p53 dysfunction (primary and secondary), altered mRNA and protein expression related to treatment resistance, DNA mutations, microRNA gene expression, and methylation changes.

• To determine whether highly sensitive flow cytometry negativity at completion of therapy in patients randomized to early treatment is an effective surrogate marker for prolonged time to second treatment, overall survival, and other clinical benefits.

• To collect demographic data on familial CLL in newly diagnosed patients participating on this study.

OUTLINE: This is a multicenter study.

• Genetically high-risk disease: Patients are stratified according to age (< 50 years vs 50 to 70 years vs > 70 years) and presence of the high-risk genetic feature [del(11)(q22.3) or del(17)(p13.1)] by FISH (yes vs no). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.

• Arm II: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.

• Genetically low-risk disease: Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.

Patients undergo blood sample collection periodically for correlative studies.

After finishing treatment, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III Intergroup CLL Study of Asymptomatic Patients With Untreated Chronic Lymphocytic Leukemia Randomized to Early Intervention Versus Observation With Later Treatment in the High Risk Genetic Subset With IGVH Unmutated Disease
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Jun 1, 2016
• Actual Study Completion Date: Jun 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive rituximab IV over 4 hours on days 1, 3, and 5 of week 1 and then on day 1 of weeks 5, 9, 13, 17, and 21. Patients also receive fludarabine phosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Biological: rituximab; Given IV over 4 hours; Drug: fludarabine phosphate; Given IV over 30 minutes
Active Comparator: Arm II Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in arm I. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Biological: rituximab; Given IV over 4 hours; Drug: fludarabine phosphate; Given IV over 30 minutes

Outcome Measures

Primary Outcome Measures

1. Time to Second Treatment in High Risk Patients [Up to 72 months]

   Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to second treatment or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.

2. Disease-Free Survival in High Risk Patients [Up to 72 months]

   Kaplan-Meier analysis was conducted to estimate disease free survival defined as:> Arm A: Time from randomization until Second Treatment (first relapse) or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.> Arm B: Time from randomization until First Treatment (first relapse) or death whichever comes first. Events were defined as the start of first treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.

3. Overall Survival (OS) for High Risk Patients [Up to 72 months]

   Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to death from any cause. Estimates were not stratified. Patients who did not experience this primary outcome had their survival times censored at their last follow-up.

Secondary Outcome Measures

1. Number of Patients With Mutated and Unmutated IgVH Genes [Once at baseline]

   Number of patients with mutated and unmutated IgVH genes are reported below.

2. Overall Survival in Low Risk Patients [Up to 72 months]

   Overall survival in low risk patients (registration to first treatment or death)> • Events were defined as death from any cause. Low risk Patients who were alive were censored at their last known follow-up.

3. Time to First Treatment Survival in Low Risk Patients [Up to 72 months]

   Time to First Treatment Survival in low risk patients (registration to first treatment or death)> • Events were defined as the start of first treatment or death from any cause. Patients who didn't receive their first treatment were censored at their last known follow-up.

Eligibility Criteria

Criteria

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

Eligibility Criteria for Pre-Registration:

1. Patients must be within 6 months of the initial flow cytometric confirmation of B-cell chronic lymphocytic leukemia (CLL). This interval begins with the initial flow cytometric confirmation of disease.

2. Clinical and immunophenotypic evidence of CLL including:

2.1 An absolute lymphocytosis of > 5,000/μL

• Morphologically, the lymphocytes must appear mature with < 55% prolymphocytes.

• Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, 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 κ or λ and have surface immunoglobulin expression of low density.

• Patients with bright surface immunoglobulin levels must have CD23 coexpression and absence of t(11;14) on interphase cytogenetics or have negative tumor protein staining for cyclin D1.

2.2 Staging - Patients must be in the low category (i.e., only stages 0 or I) of the modified three-stage Rai staging system as described in the protocol.

1. Patients should not have evidence of active disease as demonstrated by any of the following criteria:

• Splenomegaly and/or massive/progressive lymphadenopathy that would require therapy

• Presence of weight loss > 10% over the preceding 6 month period

• Grade 2 or 3 fatigue

• Fevers > 100.5°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.

1. Prior Treatment: No prior therapy for CLL including corticosteroids for autoimmune complications that have developed since the initial diagnosis of CLL.

2. Age ≥ 18 years

3. Performance Status 0 - 1.

4. No HIV disease. Due to alterations in host immunity, patients known to have HIV infection may not be enrolled.

5. Non-pregnant and non-nursing. Due to the unknown teratogenic potential of chemotherapy, pregnant or nursing women may not be enrolled. Women and men of reproductive potential should agree to use an effective means of birth control.

6. Required Initial Laboratory Values:

• Creatinine ≤ 1.5 x upper limit of normal

Eligibility Criteria for Registration (to Low-Risk Cohort or High-Risk Cohort Randomization between Early Intervention Versus Observation with Later Treatment)

1. Successful determination of IgVH mutational status by reference laboratory.

2. Absence of progression of CLL, i.e., absence of the following:

• Progressive splenomegaly and/or lymphadenopathy on two independent measures spaced two weeks apart. If one assessment notes progression, this should be repeated prior to re-registration.

• Development of anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100,000/μL).

• Progressive lymphocytosis with an increase of > 50% over a 2 month period or an anticipated doubling time of less than 6 months.

• Symptoms referable to CLL, including weight loss > 10% over the preceding 6 month period; grade 2 or 3 fatigue; or fevers > 100.5°F and/or night sweats for greater than 2 weeks without evidence of infection.

1. Required Laboratory Value:

• Creatinine ≤ 1.5 x upper limit of normal

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Regional Medical Center	Anniston	Alabama	United States	36202
2	Clearview Cancer Institute	Huntsville	Alabama	United States	35805
3	Sparks Regional Medical Center	Fort Smith	Arkansas	United States	72901
4	Providence Saint Joseph Medical Center - Burbank	Burbank	California	United States	91505
5	Virginia K. Crosson Cancer Center at St. Jude Medical Center	Fullerton	California	United States	92835
6	Memorial Medical Center	Modesto	California	United States	95355
7	Camino Medical Group - Treatment Center	Mountain View	California	United States	94040
8	Palo Alto Medical Foundation	Palo Alto	California	United States	94301
9	University of California Davis Cancer Center	Sacramento	California	United States	95817
10	Kaiser Permanente Medical Office -Vandever Medical Office	San Diego	California	United States	92120
11	Aurora Presbyterian Hospital	Aurora	Colorado	United States	80012
12	Boulder Community Hospital	Boulder	Colorado	United States	80301-9019
13	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
14	St. Anthony Central Hospital	Denver	Colorado	United States	80204
15	Porter Adventist Hospital	Denver	Colorado	United States	80210
16	Presbyterian - St. Luke's Medical Center	Denver	Colorado	United States	80218
17	St. Joseph Hospital	Denver	Colorado	United States	80218
18	Rose Medical Center	Denver	Colorado	United States	80220
19	CCOP - Colorado Cancer Research Program	Denver	Colorado	United States	80224-2522
20	Swedish Medical Center	Englewood	Colorado	United States	80110
21	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center	Grand Junction	Colorado	United States	81502
22	North Colorado Medical Center	Greeley	Colorado	United States	80631
23	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
24	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado	United States	80501
25	McKee Medical Center	Loveland	Colorado	United States	80539
26	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado	United States	81004
27	North Suburban Medical Center	Thornton	Colorado	United States	80229
28	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
29	Manchester Memorial Hospital	Manchester	Connecticut	United States	06040
30	Tunnell Cancer Center at Beebe Medical Center	Lewes	Delaware	United States	19958
31	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
32	Lombardi Comprehensive Cancer Center at Georgetown University Medical Center	Washington	District of Columbia	United States	20007
33	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307-5001
34	Michael and Dianne Bienes Comprehensive Cancer Center at Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
35	Memorial Cancer Institute at Memorial Regional Hospital	Hollywood	Florida	United States	33021
36	Ella Milbank Foshay Cancer Center at Jupiter Medical Center	Jupiter	Florida	United States	33458
37	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
38	Florida Hospital Cancer Institute at Florida Hospital Orlando	Orlando	Florida	United States	32803-1273
39	M.D. Anderson Cancer Center at Orlando	Orlando	Florida	United States	32806
40	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida	United States	32504
41	West Florida Cancer Institute at West Florida Hospital - Pensacola	Pensacola	Florida	United States	32514
42	Phoebe Cancer Center at Phoebe Putney Memorial Hospital	Albany	Georgia	United States	31701
43	John B. Amos Cancer Center	Columbus	Georgia	United States	31904
44	Mountain States Tumor Institute at St. Luke's Regional Medical Center	Boise	Idaho	United States	83712
45	Saint Anthony's Hospital at Saint Anthony's Health Center	Alton	Illinois	United States	62002
46	Hematology Oncology Associates of Illinois - Berwyn	Berwyn	Illinois	United States	60402
47	Illinois CancerCare - Bloomington	Bloomington	Illinois	United States	61701
48	St. Joseph Medical Center	Bloomington	Illinois	United States	61701
49	Illinois CancerCare - Canton	Canton	Illinois	United States	61520
50	Illinois CancerCare - Carthage	Carthage	Illinois	United States	62321
51	Memorial Hospital	Carthage	Illinois	United States	62321
52	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
53	Hematology and Oncology Associates	Chicago	Illinois	United States	60611
54	Rush University Medical Center	Chicago	Illinois	United States	60612
55	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
56	Elmhurst Memorial Hospital	Elmhurst	Illinois	United States	60126
57	Eureka Community Hospital	Eureka	Illinois	United States	61530
58	Illinois CancerCare - Eureka	Eureka	Illinois	United States	61530
59	Galesburg Clinic, PC	Galesburg	Illinois	United States	61401
60	Galesburg Cottage Hospital	Galesburg	Illinois	United States	61401
61	Illinois CancerCare - Galesburg	Galesburg	Illinois	United States	61401
62	Illinois CancerCare - Havana	Havana	Illinois	United States	62644
63	Mason District Hospital	Havana	Illinois	United States	62644
64	Kellogg Cancer Care Center	Highland Park	Illinois	United States	60035
65	Midwest Center for Hematology/Oncology	Joliet	Illinois	United States	60432
66	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois	United States	61443
67	North Shore Oncology and Hematology Associates, Limited - Libertyville	Libertyville	Illinois	United States	60048
68	Illinois CancerCare - Macomb	Macomb	Illinois	United States	61455
69	McDonough District Hospital	Macomb	Illinois	United States	61455
70	Cardinal Bernardin Cancer Center at Loyola University Medical Center	Maywood	Illinois	United States	60153
71	Trinity Cancer Center at Trinity Medical Center - 7th Street Campus	Moline	Illinois	United States	61265
72		Moline	Illinois	United States	61265
73	Illinois CancerCare - Monmouth	Monmouth	Illinois	United States	61462
74	OSF Holy Family Medical Center	Monmouth	Illinois	United States	61462
75	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
76	Edward Hospital Cancer Center	Naperville	Illinois	United States	60540
77	La Grange Oncology Associates - Geneva	Naperville	Illinois	United States	60563
78	Cancer Care and Hematology Specialists of Chicagoland - Niles	Niles	Illinois	United States	60714
79	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
80	Community Cancer Center	Normal	Illinois	United States	61761
81	Illinois CancerCare - Community Cancer Center	Normal	Illinois	United States	61761
82	Community Hospital of Ottawa	Ottawa	Illinois	United States	61350
83	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois	United States	61350
84	Cancer Treatment Center at Pekin Hospital	Pekin	Illinois	United States	61554
85	Illinois CancerCare - Pekin	Pekin	Illinois	United States	61603
86	Proctor Hospital	Peoria	Illinois	United States	61614
87	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615
88	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
89	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
90	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
91	Illinois CancerCare - Peru	Peru	Illinois	United States	61354
92	Illinois Valley Community Hospital	Peru	Illinois	United States	61354
93	Illinois CancerCare - Princeton	Princeton	Illinois	United States	61356
94	Perry Memorial Hospital	Princeton	Illinois	United States	61356
95	Swedish-American Regional Cancer Center	Rockford	Illinois	United States	61104-2315
96	Hematology Oncology Associates - Skokie	Skokie	Illinois	United States	60076
97	Illinois CancerCare - Spring Valley	Spring Valley	Illinois	United States	61362
98	St. Margaret's Hospital	Spring Valley	Illinois	United States	61362
99	Central Dupage Cancer Center	Winfield	Illinois	United States	60190
100	St. Francis Hospital and Health Centers - Beech Grove Campus	Beech Grove	Indiana	United States	46107
101	Community Hospital	Munster	Indiana	United States	46321
102	Reid Hospital & Health Care Services	Richmond	Indiana	United States	47374
103	McFarland Clinic, PC	Ames	Iowa	United States	50010
104	Hematology Oncology Associates of the Quad Cities	Bettendorf	Iowa	United States	52722
105		Bettendorf	Iowa	United States	52722
106	Medical Oncology and Hematology Associates - West Des Moines	Clive	Iowa	United States	50325
107	Genesis Regional Cancer Center at Genesis Medical Center	Davenport	Iowa	United States	52803
108	Genesis Medical Center - West Campus	Davenport	Iowa	United States	52804
109	Mercy Capitol Hospital	Des Moines	Iowa	United States	50307
110	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309
111	John Stoddard Cancer Center at Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
112	Medical Oncology and Hematology Associates at John Stoddard Cancer Center	Des Moines	Iowa	United States	50309
113	Medical Oncology and Hematology Associates at Mercy Cancer Center	Des Moines	Iowa	United States	50314
114	Mercy Cancer Center at Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
115	John Stoddard Cancer Center at Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
116	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa	United States	52242-1002
117	Veterans Affairs Medical Center - Iowa City	Iowa City	Iowa	United States	52246
118	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
119	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51104
120	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
121	Cedar Valley Medical Specialists, PC - West Ridgeway Avenue	Waterloo	Iowa	United States	50701
122	Covenant Cancer Treatment Center	Waterloo	Iowa	United States	50702
123	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
124	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
125	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
126	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
127	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
128	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
129	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
130	Southwest Medical Center	Liberal	Kansas	United States	67901
131	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
132	Menorah Medical Center	Overland Park	Kansas	United States	66209
133	Saint Luke's Hospital - South	Overland Park	Kansas	United States	66213
134	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
135	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
136	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67042
137	Shawnee Mission Medical Center	Shawnee Mission	Kansas	United States	66204
138	Cotton-O'Neil Cancer Center	Topeka	Kansas	United States	66606
139	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
140	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
141	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
142	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
143	CCOP - Wichita	Wichita	Kansas	United States	67214
144	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
145	Wesley Medical Center	Wichita	Kansas	United States	67214
146	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
147	CancerCare of Maine at Eastern Maine Medical Center	Bangor	Maine	United States	04401
148	MaineGeneral Medical Center - Waterville	Waterville	Maine	United States	04901
149	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
150	Union Hospital Cancer Program at Union Hospital	Elkton	Maryland	United States	21921
151	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
152	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts	United States	02115
153	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
154	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
155	Lahey Clinic Medical Center - Burlington	Burlington	Massachusetts	United States	01805
156	Hickman Cancer Center at Bixby Medical Center	Adrian	Michigan	United States	49221
157	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
158	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan	United States	48106
159	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123-2500
160	Green Bay Oncology, Limited - Escanaba	Escanaba	Michigan	United States	49431
161	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
162	Hurley Medical Center	Flint	Michigan	United States	48503
163	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
164	Dickinson County Healthcare System	Iron Mountain	Michigan	United States	49801
165	Foote Memorial Hospital	Jackson	Michigan	United States	49201
166	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
167	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
168	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
169	Haematology-Oncology Associates of Ohio and Michigan, PC	Lambertville	Michigan	United States	48144
170	Sparrow Regional Cancer Center	Lansing	Michigan	United States	48912-1811
171	St. Mary Mercy Hospital	Livonia	Michigan	United States	48154
172	Community Cancer Center of Monroe	Monroe	Michigan	United States	48162
173	Mercy Memorial Hospital - Monroe	Monroe	Michigan	United States	48162
174	St. Joseph Mercy Oakland	Pontiac	Michigan	United States	48341-2985
175	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan	United States	48060
176	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan	United States	48601
177	Oncology Care Associates, PLLC	Saint Joseph	Michigan	United States	49085
178	Providence Cancer Institute at Providence Hospital - Southfield Campus	Southfield	Michigan	United States	48075
179	St. John Macomb Hospital	Warren	Michigan	United States	48093
180		Alexandria	Minnesota	United States	56308
181	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
182	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
183	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
184	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
185	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
186	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
187	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
188	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
189	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
190	Veterans Affairs Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55417
191	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
192	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
193	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
194	Coborn Cancer Center	Saint Cloud	Minnesota	United States	56303
195	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
196	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
197	Regions Hospital Cancer Care Center	Saint Paul	Minnesota	United States	55101
198	United Hospital	Saint Paul	Minnesota	United States	55102
199	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
200	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
201	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
202	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
203	Truman Medical Center - Hospital Hill	Kansas City	Missouri	United States	64108
204	Saint Luke's Cancer Institute at Saint Luke's Hospital	Kansas City	Missouri	United States	64111
205	St. Joseph Medical Center	Kansas City	Missouri	United States	64114
206	North Kansas City Hospital	Kansas City	Missouri	United States	64116
207	Parvin Radiation Oncology	Kansas City	Missouri	United States	64116
208	CCOP - Kansas City	Kansas City	Missouri	United States	64131
209	Research Medical Center	Kansas City	Missouri	United States	64132
210	Saint Luke's East - Lee's Summit	Lee's Summit	Missouri	United States	64086
211	Liberty Hospital	Liberty	Missouri	United States	64068
212	Heartland Regional Medical Center	Saint Joseph	Missouri	United States	64506
213	Midwest Hematology Oncology Group, Incorporated	Saint Louis	Missouri	United States	63109
214	Saint Louis University Cancer Center	Saint Louis	Missouri	United States	63110
215	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
216	CCOP - St. Louis-Cape Girardeau	Saint Louis	Missouri	United States	63141
217	David C. Pratt Cancer Center at St. John's Mercy	Saint Louis	Missouri	United States	63141
218	CCOP - Cancer Research for the Ozarks	Springfield	Missouri	United States	65802
219	St. John's Regional Health Center	Springfield	Missouri	United States	65804
220	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri	United States	65807
221	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
222	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana	United States	59101
223	Northern Rockies Radiation Oncology Center	Billings	Montana	United States	59101
224	St. Vincent Healthcare Cancer Care Services	Billings	Montana	United States	59101
225	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
226	Bozeman Deaconess Cancer Center	Bozeman	Montana	United States	59715
227	St. James Healthcare Cancer Care	Butte	Montana	United States	59701
228	Big Sky Oncology	Great Falls	Montana	United States	59405-5309
229	Great Falls Clinic - Main Facility	Great Falls	Montana	United States	59405
230	Sletten Cancer Institute at Benefis Healthcare	Great Falls	Montana	United States	59405
231		Great Falls	Montana	United States	59405
232	Northern Montana Hospital	Havre	Montana	United States	59501
233	St. Peter's Hospital	Helena	Montana	United States	59601
234	Glacier Oncology, PLLC	Kalispell	Montana	United States	59901
235	Kalispell Medical Oncology at KRMC	Kalispell	Montana	United States	59901
236	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
237	Community Medical Center	Missoula	Montana	United States	59801
238	Guardian Oncology and Center for Wellness	Missoula	Montana	United States	59804
239	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana	United States	59807-7877
240	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana	United States	59807
241	CCOP - Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
242	Methodist Estabrook Cancer Center	Omaha	Nebraska	United States	68114
243	Immanuel Medical Center	Omaha	Nebraska	United States	68122
244	Alegant Health Cancer Center at Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
245	Creighton University Medical Center	Omaha	Nebraska	United States	68131-2197
246	Veterans Affairs Medical Center - East Orange	East Orange	New Jersey	United States	07018-1095
247	Hunterdon Regional Cancer Center at Hunterdon Medical Center	Flemington	New Jersey	United States	08822
248	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey	United States	08053
249	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
250	Fox Chase Virtua Health Cancer Program at Virtua West Jersey	Voorhees	New Jersey	United States	08043
251	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87131-5636
252	New Mexico Cancer Care Associates	Santa Fe	New Mexico	United States	87505
253	CCOP - Hematology-Oncology Associates of Central New York	East Syracuse	New York	United States	13057
254	Adirondack Cancer Care - Glens Falls	Glens Falls	New York	United States	12801
255	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York	United States	11042
256	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
257	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York	United States	11030
258	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
259	New York Weill Cornell Cancer Center at Cornell University	New York	New York	United States	10021
260	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
261	Stony Brook University Cancer Center	Stony Brook	New York	United States	11794-9446
262	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
263	Veterans Affairs Medical Center - Syracuse	Syracuse	New York	United States	13210
264	Mission Hospitals - Memorial Campus	Asheville	North Carolina	United States	28801
265	Batte Cancer Center at Northeast Medical Center	Concord	North Carolina	United States	28025
266	Wayne Memorial Hospital, Incorporated	Goldsboro	North Carolina	United States	27534
267	Pardee Memorial Hospital	Hendersonville	North Carolina	United States	28791
268	Kinston Medical Specialists	Kinston	North Carolina	United States	28501
269	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
270	Bismarck Cancer Center	Bismarck	North Dakota	United States	58501
271	Medcenter One Hospital Cancer Care Center	Bismarck	North Dakota	United States	58501
272	Mid Dakota Clinic, PC	Bismarck	North Dakota	United States	58501
273	St. Alexius Medical Center Cancer Center	Bismarck	North Dakota	United States	58502
274	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
275	Mary Rutan Hospital	Bellefontaine	Ohio	United States	43311
276	Wood County Oncology Center	Bowling Green	Ohio	United States	43402
277	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
278	MetroHealth Cancer Care Center at MetroHealth Medical Center	Cleveland	Ohio	United States	44109
279	North Coast Cancer Care - Clyde	Clyde	Ohio	United States	43410
280	Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center	Columbus	Ohio	United States	43210-1240
281	Riverside Methodist Hospital Cancer Care	Columbus	Ohio	United States	43214-3998
282	CCOP - Columbus	Columbus	Ohio	United States	43215
283	Grant Medical Center Cancer Care	Columbus	Ohio	United States	43215
284	Mount Carmel Health - West Hospital	Columbus	Ohio	United States	43222
285	Doctors Hospital at Ohio Health	Columbus	Ohio	United States	43228
286	Grandview Hospital	Dayton	Ohio	United States	45405
287	Good Samaritan Hospital	Dayton	Ohio	United States	45406
288	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio	United States	45409
289	Samaritan North Cancer Care Center	Dayton	Ohio	United States	45415
290	CCOP - Dayton	Dayton	Ohio	United States	45420
291	Grady Memorial Hospital	Delaware	Ohio	United States	43015
292	Hematology Oncology Center	Elyria	Ohio	United States	44035
293	Blanchard Valley Medical Associates	Findlay	Ohio	United States	45840
294	Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
295	Wayne Hospital	Greenville	Ohio	United States	45331
296	Charles F. Kettering Memorial Hospital	Kettering	Ohio	United States	45429
297	Fairfield Medical Center	Lancaster	Ohio	United States	43130
298	St. Rita's Medical Center	Lima	Ohio	United States	45801
299	Lima Memorial Hospital	Lima	Ohio	United States	45804
300	Strecker Cancer Center at Marietta Memorial Hospital	Marietta	Ohio	United States	45750
301	Northwest Ohio Oncology Center	Maumee	Ohio	United States	43537-1839
302	St. Luke's Hospital	Maumee	Ohio	United States	43537
303	Licking Memorial Cancer Care Program at Licking Memorial Hospital	Newark	Ohio	United States	43055
304	St. Charles Mercy Hospital	Oregon	Ohio	United States	43616
305	Toledo Clinic - Oregon	Oregon	Ohio	United States	43616
306	North Coast Cancer Care, Incorporated	Sandusky	Ohio	United States	44870
307	Mercy Medical Center	Springfield	Ohio	United States	45504
308	Community Hospital of Springfield and Clark County	Springfield	Ohio	United States	45505
309	Flower Hospital Cancer Center	Sylvania	Ohio	United States	43560
310	Mercy Hospital of Tiffin	Tiffin	Ohio	United States	44883
311	Toledo Hospital	Toledo	Ohio	United States	43606
312	St. Vincent Mercy Medical Center	Toledo	Ohio	United States	43608
313	Medical University of Ohio Cancer Center	Toledo	Ohio	United States	43614
314	CCOP - Toledo Community Hospital	Toledo	Ohio	United States	43617
315	St. Anne Mercy Hospital	Toledo	Ohio	United States	43623
316	Toledo Clinic, Incorporated - Main Clinic	Toledo	Ohio	United States	43623
317	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio	United States	45373-1300
318	Fulton County Health Center	Wauseon	Ohio	United States	43567
319	Mount Carmel St. Ann's Cancer Center	Westerville	Ohio	United States	43081
320	Clinton Memorial Hospital	Wilmington	Ohio	United States	45177
321	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio	United States	45385
322	Genesis - Good Samaritan Hospital	Zanesville	Ohio	United States	43701
323	Providence Milwaukie Hospital	Milwaukie	Oregon	United States	97222
324	Providence Cancer Center at Providence Portland Medical Center	Portland	Oregon	United States	97213-2967
325	CCOP - Columbia River Oncology Program	Portland	Oregon	United States	97225
326	Providence St. Vincent Medical Center	Portland	Oregon	United States	97225
327	Kaiser Permanente Health Care - Portland	Portland	Oregon	United States	97232
328	Legacy Meridian Park Hospital	Tualatin	Oregon	United States	97062
329	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
330	Geisinger Hazleton Cancer Center	Hazleton	Pennsylvania	United States	18201
331	Riddle Memorial Hospital Cancer Center	Media	Pennsylvania	United States	19063
332	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
333	Joan Karnell Cancer Center at Pennsylvania Hospital	Philadelphia	Pennsylvania	United States	19107
334	Cancer Center at Phoenixville Hospital	Phoenixville	Pennsylvania	United States	19460
335	Geisinger Medical Group - Scenery Park	State College	Pennsylvania	United States	16801
336	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
337	Memorial Hospital of Rhode Island	Pawtucket	Rhode Island	United States	02860
338	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina	United States	29425
339	McLeod Regional Medical Center	Florence	South Carolina	United States	29501
340	CCOP - Greenville	Greenville	South Carolina	United States	29615
341	Mountainview Medical	Berlin	Vermont	United States	05602
342	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont	United States	05401
343	Fredericksburg Oncology, Incorporated	Fredericksburg	Virginia	United States	22401
344	St. Joseph Cancer Center	Bellingham	Washington	United States	98225
345	Olympic Hematology and Oncology	Bremerton	Washington	United States	98310
346	Columbia Basin Hematology	Kennewick	Washington	United States	99336
347	Harrison Poulsbo Hematology and Onocology	Poulsbo	Washington	United States	98370
348	Minor and James Medical, PLLC	Seattle	Washington	United States	98104
349	Group Health Central Hospital	Seattle	Washington	United States	98112
350	Swedish Cancer Institute at Swedish Medical Center - First Hill Campus	Seattle	Washington	United States	98122-4307
351	Polyclinic First Hill	Seattle	Washington	United States	98122
352	University Cancer Center at University of Washington Medical Center	Seattle	Washington	United States	98195-6043
353	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
354	Evergreen Hematology and Oncology, PS	Spokane	Washington	United States	99218
355	Southwest Washington Medical Center Cancer Center	Vancouver	Washington	United States	98668
356	Marshfield Clinic - Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
357	Marshfield Clinic Cancer Care at Regional Cancer Center	Eau Claire	Wisconsin	United States	54701
358	Central Wisconsin Cancer Program at Agnesian HealthCare	Fond Du Lac	Wisconsin	United States	54935
359	Oncology Alliance, SC - Milwaukee - East	Glendale	Wisconsin	United States	53212-1038
360	Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54301-3526
361	Green Bay Oncology, Limited at St. Mary's Hospital	Green Bay	Wisconsin	United States	54303
362	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin	United States	54303
363	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
364	Holy Family Memorial Medical Center Cancer Care Center	Manitowoc	Wisconsin	United States	54221-1450
365	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
366	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
367	Saint Joseph's Hospital	Marshfield	Wisconsin	United States	54449
368	Marshfield Clinic - Lakeland Center	Minocqua	Wisconsin	United States	54548
369	Regional Cancer Center at Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
370	Green Bay Oncology, Limited - Oconto Falls	Oconto Falls	Wisconsin	United States	54154
371	Ministry Medical Group at Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
372	Marshfield Clinic - Indianhead Center	Rice Lake	Wisconsin	United States	54868
373	Vince Lombardi Cancer Clinic - Sheboygan	Sheboygan	Wisconsin	United States	53081
374	Saint Michael's Hospital Cancer Center	Stevens Point	Wisconsin	United States	54481
375	Green Bay Oncology, Limited - Sturgeon Bay	Sturgeon Bay	Wisconsin	United States	54235
376	Waukesha Memorial Hospital Regional Cancer Center	Waukesha	Wisconsin	United States	53188
377	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
378	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494
379	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming	United States	82801
380	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
381	Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
382	Nova Scotia Cancer Centre	Halifax	Nova Scotia	Canada	B3H 1V8
383	Margaret and Charles Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
384	Northeastern Ontario Regional Cancer Centre	Sudbury	Ontario	Canada	P3E 5J1
385	Edmond Odette Cancer Centre at Sunnybrook	Toronto	Ontario	Canada	M4N 3M5
386	Maisonneuve-Rosemont Hospital	Montreal	Quebec	Canada	H1T 2M4
387	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan	Canada	S4T 7T1

Sponsors and Collaborators

• Alliance for Clinical Trials in Oncology
• National Cancer Institute (NCI)

Investigators

• Study Chair: John C. Byrd, MD, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00513747
• Other Study ID Numbers: CALGB-10501; U10CA031946; CDR0000537685
• First Posted: Aug 9, 2007
• Last Update Posted: Apr 22, 2020
• Last Verified: Apr 1, 2020

• Keywords provided by Alliance for Clinical Trials in Oncology: B-cell chronic lymphocytic leukemia; stage 0 chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Fludarabine; Fludarabine phosphate

Study Results

Participant Flow

Pre-assignment Detail	The Enrollment number in the Protocol Section does not match the number of participants who started in the Participant Flow due to limited data on one participant (i.e. the participant was registered but was not randomized or classified (high vs. low risk) because the participant withdrew consent for all follow-up the same day of registration).

Arm/Group Title	Arm A: High Risk Early Intervention	Arm B: High Risk Observation + Later Treatment	Arm C: Low Risk Observation + Later Treatment
Arm/Group Description	Randomized Patients receive 50, 325, and 375 mg/m^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m^2 rituximab IV on day 1 of weeks 5, 9, 13, > 17, and 21. Patients also receive 25 mg/m^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Patients who were registered to the low-risk arm may elect to provide continued follow-up information on their treatment, disease course, and outcome regardless of the medical therapy they and their physician select. Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
Period Title: Overall Study
STARTED	17	11	55
Received at Least One Dose of Treatment	9	11	40
COMPLETED	17	11	55
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Arm A: High Risk Early Intervention	Arm B: High Risk Observation + Later Treatment	Arm C: Low Risk Observation + Later Treatment	Total
Arm/Group Description	Randomized Patients receive 50, 325, and 375 mg/m^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m^2 rituximab IV on day 1 of weeks 5, 9, 13,> 17, and 21. Patients also receive 25 mg/m^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Patients who were registered to the low-risk arm may elect to provide continued follow-up information on their treatment, disease course, and outcome regardless of the medical therapy they and their physician select. Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Total of all reporting groups
Overall Participants	17	11	55	83
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60	60	59	60
Sex: Female, Male (Count of Participants)
Female	1 5.9%	3 27.3%	23 41.8%	27 32.5%
Male	16 94.1%	8 72.7%	32 58.2%	56 67.5%

Outcome Measures

1. Primary Outcome

Title	Time to Second Treatment in High Risk Patients
Description	Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to second treatment or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.
Time Frame	Up to 72 months

Outcome Measure Data

Analysis Population Description

Randomized High Risk patients are included in this analysis.

Arm/Group Title	Arm A: High Risk Early Intervention	Arm B: High Risk Observation + Later Treatment
Arm/Group Description	Randomized Patients receive 50, 325, and 375 mg/m^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m^2 rituximab IV on day 1 of weeks 5, 9, 13,> 17, and 21. Patients also receive 25 mg/m^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
Measure Participants	17	11
Median (95% Confidence Interval) [months]	62.7	56.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: High Risk Early Intervention, Arm B: High Risk Observation + Later Treatment
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1521
	Comments
	Method	Log Rank
	Comments

2. Primary Outcome

Title	Disease-Free Survival in High Risk Patients
Description	Kaplan-Meier analysis was conducted to estimate disease free survival defined as:> Arm A: Time from randomization until Second Treatment (first relapse) or death whichever comes first. Events were defined as the start of second treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.> Arm B: Time from randomization until First Treatment (first relapse) or death whichever comes first. Events were defined as the start of first treatment or death. Patients who had not experienced one of these defined events of interest were censored at their last known follow-up.
Time Frame	Up to 72 months

Outcome Measure Data

Analysis Population Description

Randomized High Risk patients are included in this analysis.

Arm/Group Title	Arm A: High Risk Early Intervention	Arm B: High Risk Observation + Later Treatment
Arm/Group Description	Randomized Patients receive 50, 325, and 375 mg/m^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m^2 rituximab IV on day 1 of weeks 5, 9, 13,> 17, and 21. Patients also receive 25 mg/m^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
Measure Participants	17	11
Median (95% Confidence Interval) [months]	62.7	39.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: High Risk Early Intervention, Arm B: High Risk Observation + Later Treatment
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0097
	Comments
	Method	Log Rank
	Comments

3. Primary Outcome

Title	Overall Survival (OS) for High Risk Patients
Description	Kaplan-Meier analysis was conducted to estimate the distribution of time from randomization to death from any cause. Estimates were not stratified. Patients who did not experience this primary outcome had their survival times censored at their last follow-up.
Time Frame	Up to 72 months

Outcome Measure Data

Analysis Population Description

Randomized High Risk patients are included in this analysis.

Arm/Group Title	Arm A: High Risk Early Intervention	Arm B: High Risk Observation + Later Treatment
Arm/Group Description	Randomized Patients receive 50, 325, and 375 mg/m^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m^2 rituximab IV on day 1 of weeks 5, 9, 13,> 17, and 21. Patients also receive 25 mg/m^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
Measure Participants	17	11
Median (95% Confidence Interval) [months]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A: High Risk Early Intervention, Arm B: High Risk Observation + Later Treatment
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4645
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Number of Patients With Mutated and Unmutated IgVH Genes
Description	Number of patients with mutated and unmutated IgVH genes are reported below.
Time Frame	Once at baseline

Outcome Measure Data

Analysis Population Description

All patients are included in this analysis.

Arm/Group Title	Arm A: High Risk Early Intervention	Arm B: High Risk Observation + Later Treatment	Arm C: Low Risk Observation + Later Treatment	Total
Arm/Group Description	Randomized Patients receive 50, 325, and 375 mg/m^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m^2 rituximab IV on day 1 of weeks 5, 9, 13,> 17, and 21. Patients also receive 25 mg/m^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Patients who were registered to the low-risk arm may elect to provide continued follow-up information on their treatment, disease course, and outcome regardless of the medical therapy they and their physician select. Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.	Arm A + Arm B + Arm C patients
Measure Participants	17	11	55	83
Unmutated	17 100%	11 100%	0 0%	28 33.7%
Mutated	0 0%	0 0%	55 100%	55 66.3%

5. Secondary Outcome

Title	Overall Survival in Low Risk Patients
Description	Overall survival in low risk patients (registration to first treatment or death)> • Events were defined as death from any cause. Low risk Patients who were alive were censored at their last known follow-up.
Time Frame	Up to 72 months

Outcome Measure Data

Analysis Population Description

Low Risk patients are included in this analysis.

Arm/Group Title	Arm C: Low Risk Observation + Later Treatment
Arm/Group Description	Patients who were registered to the low-risk arm may elect to provide continued follow-up information on their treatment, disease course, and outcome regardless of the medical therapy they and their physician select. Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
Measure Participants	55
Median (95% Confidence Interval) [months]	58.1

6. Secondary Outcome

Title	Time to First Treatment Survival in Low Risk Patients
Description	Time to First Treatment Survival in low risk patients (registration to first treatment or death)> • Events were defined as the start of first treatment or death from any cause. Patients who didn't receive their first treatment were censored at their last known follow-up.
Time Frame	Up to 72 months

Outcome Measure Data

Analysis Population Description

Low Risk patients are included in this analysis.

Arm/Group Title	Arm C: Low Risk Observation + Later Treatment
Arm/Group Description	Patients who were registered to the low-risk arm may elect to provide continued follow-up information on their treatment, disease course, and outcome regardless of the medical therapy they and their physician select. Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
Measure Participants	55
Median (95% Confidence Interval) [months]	58.1

Adverse Events

Time Frame	Up to 72 months
Adverse Event Reporting Description	Participants who received at least one dose of treatment are evaluable for adverse events (AEs) (i.e. summarized in the Serious and Other(Not Including Serious) AEs tables). All participants are followed for their survival status (i.e. summarized in the All-Cause Mortality table).
Arm/Group Title	Arm A: High Risk Early Intervention		Arm B: High Risk Observation + Later Treatment		Arm C: Low Risk Observation + Later Treatment
Arm/Group Description	Randomized Patients receive 50, 325, and 375 mg/m^2 rituximab IV over 4 hours on days 1, 3, and 5 of week 1, respectively; then patients receive 375 mg/m^2 rituximab IV on day 1 of weeks 5, 9, 13, > 17, and 21. Patients also receive 25 mg/m^2/day fludarabine monophosphate IV over 30 minutes on days 1-5 of weeks 1, 5, 9, 13, 17, and 21. After completion of chemoimmunotherapy, patients are followed every 3 months until disease progression. At the time of disease progression, patients receive retreatment with chemoimmunotherapy as above or another treatment regimen.		Randomized Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.		Patients who were registered to the low-risk arm may elect to provide continued follow-up information on their treatment, disease course, and outcome regardless of the medical therapy they and their physician select. Patients are followed every 3 months until disease progression. At the time of disease progression, patients receive rituximab and fludarabine phosphate as in Arm A. Patients are then followed every 3 months until second disease progression. Patients with a second disease progression receive retreatment with chemoimmunotherapy as above or another treatment regimen.
All Cause Mortality
	Arm A: High Risk Early Intervention		Arm B: High Risk Observation + Later Treatment		Arm C: Low Risk Observation + Later Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		2/11 (18.2%)		2/55 (3.6%)
Serious Adverse Events
	Arm A: High Risk Early Intervention		Arm B: High Risk Observation + Later Treatment		Arm C: Low Risk Observation + Later Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/11 (0%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	Arm A: High Risk Early Intervention		Arm B: High Risk Observation + Later Treatment		Arm C: Low Risk Observation + Later Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		11/11 (100%)		40/40 (100%)
Blood and lymphatic system disorders
Blood disorder	0/9 (0%)	0	1/11 (9.1%)	1	5/40 (12.5%)	17
Febrile neutropenia	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Hemoglobin decreased	7/9 (77.8%)	25	5/11 (45.5%)	16	16/40 (40%)	43
Cardiac disorders
Atrial fibrillation	1/9 (11.1%)	2	0/11 (0%)	0	0/40 (0%)	0
Atrioventricular block first degree	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Myocardial ischemia	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Palpitations	0/9 (0%)	0	1/11 (9.1%)	1	0/40 (0%)	0
Ear and labyrinth disorders
External ear pain	0/9 (0%)	0	1/11 (9.1%)	1	0/40 (0%)	0
Hearing impaired	0/9 (0%)	0	1/11 (9.1%)	1	0/40 (0%)	0
Tinnitus	0/9 (0%)	0	1/11 (9.1%)	3	0/40 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	2
Constipation	0/9 (0%)	0	1/11 (9.1%)	2	0/40 (0%)	0
Diarrhea	1/9 (11.1%)	2	1/11 (9.1%)	1	2/40 (5%)	2
Dyspepsia	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	2
Dysphagia	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	3
Gastrointestinal disorder	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	2
Hemorrhoids	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Nausea	4/9 (44.4%)	8	1/11 (9.1%)	1	2/40 (5%)	3
Tooth disorder	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Vomiting	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	2
General disorders
Chest pain	1/9 (11.1%)	1	0/11 (0%)	0	2/40 (5%)	2
Chills	0/9 (0%)	0	1/11 (9.1%)	1	0/40 (0%)	0
Fatigue	9/9 (100%)	32	9/11 (81.8%)	30	19/40 (47.5%)	70
General symptom	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Pain	0/9 (0%)	0	0/11 (0%)	0	3/40 (7.5%)	3
Hepatobiliary disorders
Cholecystitis	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Immune system disorders
Hypersensitivity	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Infections and infestations
Bladder infection(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Bronchitis(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Bronchitis(gr 3/4 ANC)	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	2
Gastric infection(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Gingival infection(gr 0/1/2 ANC)	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Infection(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Infectious colitis(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Infectious meningitis(gr 0/1/2 ANC)	0/9 (0%)	0	1/11 (9.1%)	1	0/40 (0%)	0
Laryngitis(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Lip infection(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Otitis externa(unknown ANC)	0/9 (0%)	0	1/11 (9.1%)	2	1/40 (2.5%)	1
Pharyngitis(gr 3/4 ANC)	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Pneumonia(gr 0/1/2 ANC)	1/9 (11.1%)	1	1/11 (9.1%)	1	1/40 (2.5%)	1
Rhinitis infective(unknown ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Sinusitis(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	6/40 (15%)	7
Sinusitis(unknown ANC)	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	3
Skin infection	2/9 (22.2%)	2	0/11 (0%)	0	1/40 (2.5%)	1
Skin infection(gr 3/4 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Skin infection(unknown ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Soft tissue infection(gr 3/4 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Tooth infection(unknown ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Upper respiratory infection(gr 3/4 ANC)	0/9 (0%)	0	1/11 (9.1%)	1	1/40 (2.5%)	1
Upper respiratory infection(unknown ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Upper respiratory infectn(gr 0/1/2 ANC)	0/9 (0%)	0	0/11 (0%)	0	7/40 (17.5%)	7
Ureteritis(unknown ANC)	0/9 (0%)	0	1/11 (9.1%)	3	1/40 (2.5%)	6
Urinary tract infection(gr 0/1/2 ANC)	1/9 (11.1%)	1	0/11 (0%)	0	4/40 (10%)	5
Urinary tract infection(gr 3/4 ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Urinary tract infection(unknown ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Vaginal infection(unknown ANC)	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Injury, poisoning and procedural complications
Fracture	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Investigations
Alanine aminotransferase increased	1/9 (11.1%)	1	0/11 (0%)	0	2/40 (5%)	2
Aspartate aminotransferase increased	0/9 (0%)	0	1/11 (9.1%)	1	2/40 (5%)	2
Creatinine increased	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Laboratory test abnormal	1/9 (11.1%)	1	0/11 (0%)	0	1/40 (2.5%)	1
Leukocyte count decreased	4/9 (44.4%)	6	0/11 (0%)	0	1/40 (2.5%)	1
Lymphocyte count decreased	4/9 (44.4%)	16	1/11 (9.1%)	1	1/40 (2.5%)	1
Neutrophil count decreased	7/9 (77.8%)	21	2/11 (18.2%)	5	8/40 (20%)	22
Platelet count decreased	5/9 (55.6%)	21	4/11 (36.4%)	17	14/40 (35%)	55
Serum cholesterol increased	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	3
Weight gain	1/9 (11.1%)	3	0/11 (0%)	0	0/40 (0%)	0
Weight loss	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Metabolism and nutrition disorders
Anorexia	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Blood glucose increased	0/9 (0%)	0	3/11 (27.3%)	3	3/40 (7.5%)	11
Glucose intolerance	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	14
Serum albumin decreased	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	2
Serum calcium decreased	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Serum magnesium decreased	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Serum potassium decreased	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Serum potassium increased	0/9 (0%)	0	1/11 (9.1%)	1	1/40 (2.5%)	1
Serum sodium decreased	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/9 (11.1%)	2	0/11 (0%)	0	2/40 (5%)	3
Arthritis	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Back pain	1/9 (11.1%)	4	1/11 (9.1%)	2	3/40 (7.5%)	5
Bone pain	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	2
Muscle weakness lower limb	0/9 (0%)	0	1/11 (9.1%)	2	0/40 (0%)	0
Musculoskeletal disorder	0/9 (0%)	0	0/11 (0%)	0	2/40 (5%)	4
Myalgia	1/9 (11.1%)	1	0/11 (0%)	0	1/40 (2.5%)	1
Neck pain	0/9 (0%)	0	1/11 (9.1%)	2	1/40 (2.5%)	1
Upper extremity dysfunction	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	2
Nervous system disorders
Dizziness	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Headache	2/9 (22.2%)	2	1/11 (9.1%)	3	2/40 (5%)	4
Neuralgia	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Neurological disorder NOS	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Syncope	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Tremor	0/9 (0%)	0	1/11 (9.1%)	2	0/40 (0%)	0
Psychiatric disorders
Anxiety	0/9 (0%)	0	1/11 (9.1%)	2	1/40 (2.5%)	1
Confusion	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	4
Depression	1/9 (11.1%)	1	4/11 (36.4%)	24	1/40 (2.5%)	1
Insomnia	1/9 (11.1%)	3	2/11 (18.2%)	5	2/40 (5%)	2
Renal and urinary disorders
Bladder pain	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Urogenital disorder	0/9 (0%)	0	1/11 (9.1%)	1	0/40 (0%)	0
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/9 (11.1%)	1	1/11 (9.1%)	1	2/40 (5%)	2
Bronchospasm	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Cough	0/9 (0%)	0	2/11 (18.2%)	2	1/40 (2.5%)	1
Dyspnea	1/9 (11.1%)	5	5/11 (45.5%)	14	5/40 (12.5%)	5
Hypoxia	1/9 (11.1%)	1	0/11 (0%)	0	0/40 (0%)	0
Pharyngolaryngeal pain	1/9 (11.1%)	1	0/11 (0%)	0	1/40 (2.5%)	2
Respiratory disorder	0/9 (0%)	0	1/11 (9.1%)	2	0/40 (0%)	0
Sinus pain	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	3
Voice alteration	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Skin and subcutaneous tissue disorders
Erythema multiforme	0/9 (0%)	0	1/11 (9.1%)	1	0/40 (0%)	0
Rash desquamating	2/9 (22.2%)	6	2/11 (18.2%)	6	2/40 (5%)	2
Skin disorder	0/9 (0%)	0	1/11 (9.1%)	2	3/40 (7.5%)	4
Skin ulceration	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1
Sweating	0/9 (0%)	0	2/11 (18.2%)	3	1/40 (2.5%)	2
Vascular disorders
Hot flashes	0/9 (0%)	0	1/11 (9.1%)	1	2/40 (5%)	4
Hypertension	1/9 (11.1%)	1	0/11 (0%)	0	2/40 (5%)	2
Hypotension	2/9 (22.2%)	2	0/11 (0%)	0	2/40 (5%)	2
Thrombosis	0/9 (0%)	0	0/11 (0%)	0	1/40 (2.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.