S0801 Iodine I 131 Tositumomab, Rituximab, and Combination Chemotherapy in Previously Untreated Stage II, Stage III, or Stage IV Follicular Non-Hodgkin Lymphoma

• Sponsor: Southwest Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00770224
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 87
• Locations: 114
• Arm: 1
• Duration (Months): 124
• Patients Per Site: 0.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Radiolabeled monoclonal antibodies, such as iodine I 131 tositumomab, can find cancer cells and carry cancer-killing substances to them without harming normal cells. 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. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving a radiolabeled monoclonal antibody together with rituximab and combination chemotherapy may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects of giving iodine I 131 tositumomab together with rituximab and combination chemotherapy and to see how well it works in treating patients with previously untreated stage II, stage III, or stage IV follicular non-Hodgkin lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: rituximab; Biological: tositumomab; Drug: cyclophosphamide; Drug: doxorubicin; Drug: prednisone; Drug: vincristine; Radiation: tositumomab	Phase 2

Detailed Description

OBJECTIVES:

• To evaluate the response rate in patients with previously untreated stage II-IV follicular non-Hodgkin lymphoma treated with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) in combination with iodine I 131 tositumomab.

• To evaluate the toxicity of this regimen in these patients.

• To estimate the 3-year progression-free survival rate in patients treated with this regimen.

• To estimate the 5-year progression-free and overall survival rate in patients treated with this regimen.

• To assess the safety profile of this regimen in these patients.

OUTLINE: This is a multicenter study.

• Induction therapy: Patients receive R-CHOP* comprising rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 1 and oral prednisone once daily on days 1-5. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with at least stable disease then proceed to consolidation therapy.

NOTE: *Patients receive R-CHOP in courses 1-4 and CHOP alone in courses 5 and 6.

• Consolidation therapy: Within 12 weeks after completion of induction therapy, patients receive tositumomab IV over 1 hour followed by a dosimetric dose of iodine I 131 tositumomab IV over 20 minutes. Patients then undergo whole body gamma camera scans over a 1-week period to determine the rate of total body clearance of radioactivity and the therapeutic dose of iodine I 131 tositumomab. Within 7-14 days after the dosimetric dose, patients receive tositumomab IV over 1 hour followed by a therapeutic dose of iodine I 131 tositumomab IV over 20 minutes. Patients with at least stable disease then proceed to maintenance therapy.

• Maintenance therapy: Beginning approximately 1 year after study entry and no more than 28 days after restaging, patients receive rituximab IV every 3 months for up to 4 years (16 courses) in the absence of disease progression or unacceptable toxicity.

After completion of maintenance therapy, patients are followed annually for up to 7 years. Patients who do not complete maintenance therapy are followed every 6 months for 2 years and then annually for up to 7 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Iodine-131-Labeled Tositumomab in Combination With Cyclophosphamide, Doxorubicin, Vincristine, Prednisone and Rituximab Therapy for Patients With Advanced Stage Follicular Non-Hodgkin's Lymphoma
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Apr 1, 2017
• Actual Study Completion Date: Aug 1, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: R-CHOP, tositumomab and rituximab Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody. Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.

Biological: rituximab; Biological: tositumomab; Drug: cyclophosphamide; Drug: doxorubicin; Drug: prednisone; Drug: vincristine; Radiation: tositumomab; Other Names: iodine I 131 tositumomab

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With 3-year Progression-free Survival (PFS) [0-3 years]

   Measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is ≥ 50% increase in the sum of products of greatest diameters (SPD) of target measurable nodal lesions over the smallest sum observed (over baseline if no decrease during therapy), or ≥ 50% increase in the greatest transverse diameter (GTD) of any node > 1 cm in shortest axis, or ≥ 50% increase in the SPD of other target measurable lesions (e.g., splenic or hepatic nodules) over the smallest sum observed. Appearance of any new bone marrow involvement; appearance of a new lesion/site; lymph nodes with the long axis is > 1.5 cm, or if the both the long and short axes are > 1 cm; in patients with no pretreatment PET scan or when the PET scan was positive before therapy, lesions should be PET positive; or death due to disease without prior documentation of progression.

Secondary Outcome Measures

1. 5-year Progression-free Survival [0-5 years]

   Measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is ≥ 50% increase in the sum of products of greatest diameters (SPD) of target measurable nodal lesions over the smallest sum observed (over baseline if no decrease during therapy), or ≥ 50% increase in the greatest transverse diameter (GTD) of any node > 1 cm in shortest axis, or ≥ 50% increase in the SPD of other target measurable lesions (e.g., splenic or hepatic nodules) over the smallest sum observed. Appearance of any new bone marrow involvement; appearance of a new lesion/site; lymph nodes with the long axis is > 1.5 cm, or if the both the long and short axes are > 1 cm; in patients with no pretreatment PET scan or when the PET scan was positive before therapy, lesions should be PET positive; or death due to disease without prior documentation of progression.

2. 5-year Overall Survival [0-5 years]

   Measured from date of registration to date of death due to any cause. Patients last known to be alive and are censored at date of last contact.

3. Response Rate [up to 5 years (1 year induction + 4 years maintenance therapy) or time of disease progression]

   Complete (CR), complete unconfirmed (CRU) and partial responses (PR). CR is complete disappearance of all measurable and non-measurable disease with the exception of the following. Positron emission tomography (PET) must be negative if no pre-treatment PET scan or when the PET was positive before therapy. If the PET scan was negative before therapy, all nodal masses must have regressed. no new lesions; previously enlarged organs must have regressed in size; and if bone marrow positive at baseline, it must be negative. PR is ≥ 50% decrease in sum of products of greatest diameters (SPD) for up to six identified dominant lesions identified at baseline; no new lesions; no increase in the size of liver, spleen or other nodes; and splenic and hepatic nodules must have regressed in size by at least 50% in SPD. In patients with no pre-treatment PET scan or when the PET scan was positive before therapy, PET should be positive in at least one previously involved site.

4. Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug [up to 5 years (1 year induction + 4 years maintenance therapy) or time of disease progression.]

   Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically confirmed* grade 1, 2, or 3 follicular B-cell non-Hodgkin lymphoma meeting the following criteria:

• Bulky stage II or stage III or IV disease

• Diffuse large cell component must be < 25% of the biopsy

• Confirmed cluster of differentiation antigen 20 (CD20) antigen-positive disease NOTE: *Needle aspiration or cytology are not considered adequate for pathology review

• Patient must have unilateral or bilateral bone marrow aspirate and biopsy performed within 42 days

• Positive biopsy performed > 42 days but < 6 months allowed

• Previously untreated disease

• Bidimensionally measurable disease

• No clinical evidence of central nervous system (CNS) involvement by lymphoma

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-2

• Cardiac ejection fraction ≥ 45% by multigated acquisition scan (MUGA) or ECHO

• No significant cardiac abnormalities

• No known HIV positivity

• No requirement for continuous supplemental oxygen therapy

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer from which the patient is currently in complete remission

• Not pregnant or nursing

• Fertile patients must use effective contraception during and for 12 months after completion of maintenance therapy

PRIOR CONCURRENT THERAPY:

• No prior chemotherapy, radiotherapy, or antibody therapy for lymphoma

• No prior solid organ transplantation

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence Cancer Center at Providence Hospital	Mobile	Alabama	United States	36608
2	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona	United States	85724-5024
3	Saint Anthony's Hospital at Saint Anthony's Health Center	Alton	Illinois	United States	62002
4	Cancer Care Center of Decatur	Decatur	Illinois	United States	62526
5	Decatur Memorial Hospital Cancer Care Institute	Decatur	Illinois	United States	62526
6	Crossroads Cancer Center	Effingham	Illinois	United States	62401
7	Cardinal Bernardin Cancer Center at Loyola University Medical Center	Maywood	Illinois	United States	60153
8	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
9	Regional Cancer Center at Memorial Medical Center	Springfield	Illinois	United States	62781-0001
10	St. Francis Hospital and Health Centers - Beech Grove Campus	Beech Grove	Indiana	United States	46107
11	Reid Hospital & Health Care Services	Richmond	Indiana	United States	47374
12	Cancer Center of Kansas, PA - Chanute	Chanute	Kansas	United States	66720
13	Cancer Center of Kansas, PA - Dodge City	Dodge City	Kansas	United States	67801
14	Cancer Center of Kansas, PA - El Dorado	El Dorado	Kansas	United States	67042
15	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
16	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
17	Cancer Center of Kansas, PA - Kingman	Kingman	Kansas	United States	67068
18	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
19	Cancer Center of Kansas, PA - Newton	Newton	Kansas	United States	67114
20	Cancer Center of Kansas, PA - Parsons	Parsons	Kansas	United States	67357
21	Cancer Center of Kansas, PA - Pratt	Pratt	Kansas	United States	67124
22	Cancer Center of Kansas, PA - Salina	Salina	Kansas	United States	67401
23	Tammy Walker Cancer Center at Salina Regional Health Center	Salina	Kansas	United States	67401
24	Cotton-O'Neil Cancer Center	Topeka	Kansas	United States	66606
25	Cancer Center of Kansas, PA - Wellington	Wellington	Kansas	United States	67152
26	Associates in Womens Health, PA - North Review	Wichita	Kansas	United States	67208
27	Cancer Center of Kansas, PA - Medical Arts Tower	Wichita	Kansas	United States	67208
28	Cancer Center of Kansas, PA - Wichita	Wichita	Kansas	United States	67214
29	CCOP - Wichita	Wichita	Kansas	United States	67214
30	Via Christi Cancer Center at Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
31	Wesley Medical Center	Wichita	Kansas	United States	67214
32	Cancer Center of Kansas, PA - Winfield	Winfield	Kansas	United States	67156
33	Alvin and Lois Lapidus Cancer Institute at Sinai Hospital	Baltimore	Maryland	United States	21215
34	Battle Creek Health System Cancer Care Center	Battle Creek	Michigan	United States	49017
35	Mecosta County Medical Center	Big Rapids	Michigan	United States	49307
36	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan	United States	49503
37	CCOP - Grand Rapids	Grand Rapids	Michigan	United States	49503
38	Lacks Cancer Center at Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
39	Mercy General Health Partners	Muskegon	Michigan	United States	49443
40	Munson Medical Center	Traverse City	Michigan	United States	49684
41	Metro Health Hospital	Wyoming	Michigan	United States	49519
42	University of Mississippi Cancer Clinic	Jackson	Mississippi	United States	39216
43	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
44	Midwest Hematology Oncology Group, Incorporated	Saint Louis	Missouri	United States	63109
45	CCOP - St. Louis-Cape Girardeau	Saint Louis	Missouri	United States	63141
46	David C. Pratt Cancer Center at St. John's Mercy	Saint Louis	Missouri	United States	63141
47	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
48	St. Vincent Healthcare Cancer Care Services	Billings	Montana	United States	59101
49	Hematology-Oncology Centers of the Northern Rockies - Billings	Billings	Montana	United States	59102
50	Billings Clinic - Downtown	Billings	Montana	United States	59107-7000
51	Bozeman Deaconess Cancer Center	Bozeman	Montana	United States	59715
52	St. James Healthcare Cancer Care	Butte	Montana	United States	59701
53	Great Falls Clinic - Main Facility	Great Falls	Montana	United States	59405
54	Sletten Cancer Institute at Benefis Healthcare	Great Falls	Montana	United States	59405
55	Northern Montana Hospital	Havre	Montana	United States	59501
56	St. Peter's Hospital	Helena	Montana	United States	59601
57	Glacier Oncology, PLLC	Kalispell	Montana	United States	59901
58	Kalispell Medical Oncology at KRMC	Kalispell	Montana	United States	59901
59	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
60	Montana Cancer Specialists at Montana Cancer Center	Missoula	Montana	United States	59807-7877
61	Montana Cancer Center at St. Patrick Hospital and Health Sciences Center	Missoula	Montana	United States	59807
62	Falck Cancer Center at Arnot Ogden Medical Center	Elmira	New York	United States	14905
63	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
64	Wayne Memorial Hospital, Incorporated	Goldsboro	North Carolina	United States	27534
65	Rutherford Hospital	Rutherfordton	North Carolina	United States	28139
66	Mary Rutan Hospital	Bellefontaine	Ohio	United States	43311
67	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
68	Riverside Methodist Hospital Cancer Care	Columbus	Ohio	United States	43214-3998
69	CCOP - Columbus	Columbus	Ohio	United States	43215
70	Grant Medical Center Cancer Care	Columbus	Ohio	United States	43215
71	Mount Carmel Health - West Hospital	Columbus	Ohio	United States	43222
72	Doctors Hospital at Ohio Health	Columbus	Ohio	United States	43228
73	Grandview Hospital	Dayton	Ohio	United States	45405
74	Good Samaritan Hospital	Dayton	Ohio	United States	45406
75	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio	United States	45409
76	Samaritan North Cancer Care Center	Dayton	Ohio	United States	45415
77	CCOP - Dayton	Dayton	Ohio	United States	45420
78	Grady Memorial Hospital	Delaware	Ohio	United States	43015
79	Blanchard Valley Medical Associates	Findlay	Ohio	United States	45840
80	Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
81	Wayne Hospital	Greenville	Ohio	United States	45331
82	Charles F. Kettering Memorial Hospital	Kettering	Ohio	United States	45429
83	Fairfield Medical Center	Lancaster	Ohio	United States	43130
84	Strecker Cancer Center at Marietta Memorial Hospital	Marietta	Ohio	United States	45750
85	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
86	Licking Memorial Cancer Care Program at Licking Memorial Hospital	Newark	Ohio	United States	43055
87	Community Hospital of Springfield and Clark County	Springfield	Ohio	United States	45505
88	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio	United States	45373-1300
89	Mount Carmel St. Ann's Cancer Center	Westerville	Ohio	United States	43081
90	Clinton Memorial Hospital	Wilmington	Ohio	United States	45177
91	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio	United States	45385
92	Genesis - Good Samaritan Hospital	Zanesville	Ohio	United States	43701
93	AnMed Cancer Center	Anderson	South Carolina	United States	29621
94	CCOP - Upstate Carolina	Spartanburg	South Carolina	United States	29303
95	Gibbs Regional Cancer Center at Spartanburg Regional Medical Center	Spartanburg	South Carolina	United States	29303
96	U.T. Medical Center Cancer Institute	Knoxville	Tennessee	United States	37920-6999
97	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah	United States	84112
98	St. Joseph Cancer Center	Bellingham	Washington	United States	98225
99	Olympic Hematology and Oncology	Bremerton	Washington	United States	98310
100	Columbia Basin Hematology	Kennewick	Washington	United States	99336
101	Skagit Valley Hospital Cancer Care Center	Mount Vernon	Washington	United States	98273
102	Harrison Poulsbo Hematology and Onocology	Poulsbo	Washington	United States	98370
103	Harborview Medical Center	Seattle	Washington	United States	98104
104	Minor and James Medical, PLLC	Seattle	Washington	United States	98104
105	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109
106	Group Health Central Hospital	Seattle	Washington	United States	98112
107	Swedish Cancer Institute at Swedish Medical Center - First Hill Campus	Seattle	Washington	United States	98122-4307
108	Polyclinic First Hill	Seattle	Washington	United States	98122
109	University Cancer Center at University of Washington Medical Center	Seattle	Washington	United States	98195
110	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
111	Evergreen Hematology and Oncology, PS	Spokane	Washington	United States	99218
112	Wenatchee Valley Medical Center	Wenatchee	Washington	United States	98801-2028
113	Rocky Mountain Oncology	Casper	Wyoming	United States	82609
114	Welch Cancer Center at Sheridan Memorial Hospital	Sheridan	Wyoming	United States	82801

Sponsors and Collaborators

• Southwest Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Jonathan W. Friedberg, MD, James P. Wilmot Cancer Center
• Study Chair: Oliver W. Press, MD, PhD, Fred Hutchinson Cancer Center
• Study Chair: Lisa Rimsza, MD, University of Arizona

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Jan 15, 2016

More Information

Publications

None provided.

• Responsible Party: Southwest Oncology Group
• ClinicalTrials.gov Identifier: NCT00770224
• Other Study ID Numbers: CDR0000615104; S0801; U10CA032102
• First Posted: Oct 9, 2008
• Last Update Posted: Aug 28, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Southwest Oncology Group: contiguous stage II grade 1 follicular lymphoma; contiguous stage II grade 2 follicular lymphoma; contiguous stage II grade 3 follicular lymphoma; noncontiguous stage II grade 1 follicular lymphoma; noncontiguous stage II grade 2 follicular lymphoma; noncontiguous stage II grade 3 follicular lymphoma; stage III grade 1 follicular lymphoma; stage III grade 2 follicular lymphoma; stage III grade 3 follicular lymphoma; stage IV grade 1 follicular lymphoma; stage IV grade 2 follicular lymphoma; stage IV grade 3 follicular lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, Follicular; Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Vincristine; Tositumomab I-131

Study Results

Participant Flow

Arm/Group Title	R-CHOP+I-131 Tositumomab	Rituximab Maintenance
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody.	Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.
Period Title: Step 1: Induction
STARTED	87	0
Eligible and Evaluable	84	0
COMPLETED	73	0
NOT COMPLETED	14	0
Period Title: Step 1: Induction
STARTED	0	71
Eligible and Evaluable	0	69
COMPLETED	0	41
NOT COMPLETED	0	30

Baseline Characteristics

Arm/Group Title	R-CHOP+I-131 Tositumomab
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody.
Overall Participants	84
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52.3
Sex: Female, Male (Count of Participants)
Female	44 52.4%
Male	40 47.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 2.4%
Not Hispanic or Latino	81 96.4%
Unknown or Not Reported	1 1.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	1 1.2%
Black or African American	3 3.6%
White	78 92.9%
More than one race	0 0%
Unknown or Not Reported	2 2.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With 3-year Progression-free Survival (PFS)
Description	Measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is ≥ 50% increase in the sum of products of greatest diameters (SPD) of target measurable nodal lesions over the smallest sum observed (over baseline if no decrease during therapy), or ≥ 50% increase in the greatest transverse diameter (GTD) of any node > 1 cm in shortest axis, or ≥ 50% increase in the SPD of other target measurable lesions (e.g., splenic or hepatic nodules) over the smallest sum observed. Appearance of any new bone marrow involvement; appearance of a new lesion/site; lymph nodes with the long axis is > 1.5 cm, or if the both the long and short axes are > 1 cm; in patients with no pretreatment PET scan or when the PET scan was positive before therapy, lesions should be PET positive; or death due to disease without prior documentation of progression.
Time Frame	0-3 years

Outcome Measure Data

Analysis Population Description

Eligible and evaluable patients were included in the analysis.

Arm/Group Title	R-CHOP+I-131 Tositumomab Followed by Rituximab Maintenance
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody. Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.
Measure Participants	84
Number (95% Confidence Interval) [percentage of participants]	90 107.1%

2. Secondary Outcome

Title	5-year Progression-free Survival
Description	Measured from date of registration to date of first observation of progressive disease or death due to any cause. Progressive disease is ≥ 50% increase in the sum of products of greatest diameters (SPD) of target measurable nodal lesions over the smallest sum observed (over baseline if no decrease during therapy), or ≥ 50% increase in the greatest transverse diameter (GTD) of any node > 1 cm in shortest axis, or ≥ 50% increase in the SPD of other target measurable lesions (e.g., splenic or hepatic nodules) over the smallest sum observed. Appearance of any new bone marrow involvement; appearance of a new lesion/site; lymph nodes with the long axis is > 1.5 cm, or if the both the long and short axes are > 1 cm; in patients with no pretreatment PET scan or when the PET scan was positive before therapy, lesions should be PET positive; or death due to disease without prior documentation of progression.
Time Frame	0-5 years

Outcome Measure Data

Analysis Population Description

Eligible and evaluable patients were included in the analysis.

Arm/Group Title	R-CHOP+I-131 Tositumomab Followed by Rituximab Maintenance
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody. Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.
Measure Participants	84
Number (95% Confidence Interval) [percentage of participants]	85 101.2%

3. Secondary Outcome

Title	5-year Overall Survival
Description	Measured from date of registration to date of death due to any cause. Patients last known to be alive and are censored at date of last contact.
Time Frame	0-5 years

Outcome Measure Data

Analysis Population Description

Eligible and evaluable patients were included in the analysis.

Arm/Group Title	R-CHOP+I-131 Tositumomab Followed by Rituximab Maintenance
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody. Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.
Measure Participants	84
Number (95% Confidence Interval) [percentage of participants]	94 111.9%

4. Secondary Outcome

Title	Response Rate
Description	Complete (CR), complete unconfirmed (CRU) and partial responses (PR). CR is complete disappearance of all measurable and non-measurable disease with the exception of the following. Positron emission tomography (PET) must be negative if no pre-treatment PET scan or when the PET was positive before therapy. If the PET scan was negative before therapy, all nodal masses must have regressed. no new lesions; previously enlarged organs must have regressed in size; and if bone marrow positive at baseline, it must be negative. PR is ≥ 50% decrease in sum of products of greatest diameters (SPD) for up to six identified dominant lesions identified at baseline; no new lesions; no increase in the size of liver, spleen or other nodes; and splenic and hepatic nodules must have regressed in size by at least 50% in SPD. In patients with no pre-treatment PET scan or when the PET scan was positive before therapy, PET should be positive in at least one previously involved site.
Time Frame	up to 5 years (1 year induction + 4 years maintenance therapy) or time of disease progression

Outcome Measure Data

Analysis Population Description

Eligible and evaluable patients were included in the analysis.

Arm/Group Title	R-CHOP+I-131 Tositumomab Followed by Rituximab Maintenance
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody. Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.
Measure Participants	84
Complete Response	61 72.6%
Patital Response	22 26.2%
Assessment Inadequate	1 1.2%

5. Secondary Outcome

Title	Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug
Description	Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.
Time Frame	up to 5 years (1 year induction + 4 years maintenance therapy) or time of disease progression.

Outcome Measure Data

Analysis Population Description

Eligible patients who had received any treatment were included in the adverse event summaries. Any CTCAE 4.0 event of Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) which deemed to be related to protocol treatment are included.

Arm/Group Title	R-CHOP+I-131 Tositumomab	Rituximab Maintenance
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody.	Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.
Measure Participants	84	69
Albumin, serum-low (hypoalbuminemia)	1 1.2%	0 NaN
Allergic reaction/hypersensitivity	2 2.4%	0 NaN
Anorexia	1 1.2%	0 NaN
Cough	1 1.2%	1 NaN
Diarrhea	1 1.2%	0 NaN
Dyspnea (shortness of breath)	1 1.2%	0 NaN
Enteritis (inflammation of the small bowel)	0 0%	1 NaN
Fatigue (asthenia, lethargy, malaise)	8 9.5%	1 NaN
Febrile neutropenia	14 16.7%	0 NaN
Fever in absence of neutropenia, ANC lt1.0x10e9/L	2 2.4%	0 NaN
Glucose, serum-high (hyperglycemia)	4 4.8%	0 NaN
Hemoglobin	6 7.1%	0 NaN
Hypotension	2 2.4%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Bladder	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Blood	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Catheter-rel	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Dental-tooth	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Lung	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Lymphatic	2 2.4%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Pharynx	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Skin	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - UTI	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Upper airway	1 1.2%	0 NaN
Inf (clin/microbio) w/Gr 3-4 neuts - Wound	1 1.2%	0 NaN
Inf w/normal ANC or Gr 1-2 neutrophils - Mid ear	0 0%	1 NaN
Inf w/normal ANC or Gr 1-2 neutrophils - Sinus	0 0%	1 NaN
Left ventricular systolic dysfunction	1 1.2%	1 NaN
Leukocytes (total WBC)	34 40.5%	0 NaN
Lymphopenia	25 29.8%	4 NaN
Mood alteration - anxiety	0 0%	1 NaN
Mood alteration - depression	0 0%	1 NaN
Muscle weakness, not d/t neuropathy - body/general	1 1.2%	1 NaN
Nasal cavity/paranasal sinus reactions	0 0%	1 NaN
Nausea	3 3.6%	0 NaN
Neuropathy: motor	1 1.2%	0 NaN
Neuropathy: sensory	6 7.1%	0 NaN
Neutrophils/granulocytes (ANC/AGC)	48 57.1%	1 NaN
Opportunistic inf associated w/gt=Gr 2 lymphopenia	1 1.2%	0 NaN
Pain - Abdomen NOS	1 1.2%	0 NaN
Pain - Bone	1 1.2%	0 NaN
Pain - Head/headache	1 1.2%	0 NaN
Pain - Muscle	1 1.2%	0 NaN
Pain-Other (Specify)	0 0%	1 NaN
Platelets	17 20.2%	0 NaN
Pulmonary hypertension	0 0%	1 NaN
Restrictive cardiomyopathy	0 0%	1 NaN
Secondary Malignancy-poss rel to cancer Tx	0 0%	1 NaN
Sodium, serum-low (hyponatremia)	1 1.2%	0 NaN
Syncope (fainting)	1 1.2%	0 NaN
Thrombosis/thrombus/embolism	1 1.2%	0 NaN
Valvular heart disease	0 0%	1 NaN
Vasovagal episode	0 0%	1 NaN
Vision-blurred vision	1 1.2%	0 NaN
Vomiting	2 2.4%	0 NaN
Weight loss	1 1.2%	0 NaN

Adverse Events

Time Frame	up to 5 years (1 year induction + 4 years maintenance therapy) or time of disease progression.
Arm/Group Title	R-CHOP+I-131 Tositumomab		Rituximab Maintenance
Arm/Group Description	Cyclophosphamide 750 mg/m2 IV Day 1 Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 Prednisone 100 mg PO Days 1-5 Rituximab 375 mg/m2 IV Day 1 Q 21 Days x 6 Cycles Patients are restaged by CT scan. Unlabeled tositumomab antibody 450 mg IV within 12 after Cycle 6 of CHOP. Dosimetric dose 35 mg IV after infusion of unlabeled tositumomab antibody. Unlabeled tositumomab antibody 450 mg IV 7-14 days after dosimetric dose. Therapeutic dose 35 mg IV after infusion of unlabeled tositumomab antibody.		Rituximab 375 mg/m2 IV q 3 months x 4 years beginning 1 year after registration.
All Cause Mortality
	R-CHOP+I-131 Tositumomab		Rituximab Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/84 (0%)		0/69 (0%)
Serious Adverse Events
	R-CHOP+I-131 Tositumomab		Rituximab Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/84 (0%)		1/69 (1.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Secondary Malignancy-poss rel to cancer Tx	0/84 (0%)		1/69 (1.4%)
Other (Not Including Serious) Adverse Events
	R-CHOP+I-131 Tositumomab		Rituximab Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/84 (100%)		66/69 (95.7%)
Blood and lymphatic system disorders
Febrile neutropenia	15/84 (17.9%)		0/69 (0%)
Hemoglobin	56/84 (66.7%)		18/69 (26.1%)
Cardiac disorders
Left ventricular systolic dysfunction	1/84 (1.2%)		4/69 (5.8%)
Palpitations	2/84 (2.4%)		4/69 (5.8%)
Endocrine disorders
Thyroid function, high	0/84 (0%)		4/69 (5.8%)
Thyroid function, low (hypothyroidism)	2/84 (2.4%)		7/69 (10.1%)
Eye disorders
Vision-blurred vision	6/84 (7.1%)		4/69 (5.8%)
Gastrointestinal disorders
Constipation	40/84 (47.6%)		9/69 (13%)
Diarrhea	18/84 (21.4%)		15/69 (21.7%)
Heartburn/dyspepsia	15/84 (17.9%)		5/69 (7.2%)
Mucositis/stomatitis (clinical exam) - Oral cavity	6/84 (7.1%)		0/69 (0%)
Mucositis/stomatitis (functional/symp) - Oral cav	10/84 (11.9%)		2/69 (2.9%)
Nausea	58/84 (69%)		16/69 (23.2%)
Pain - Abdomen NOS	23/84 (27.4%)		10/69 (14.5%)
Vomiting	21/84 (25%)		5/69 (7.2%)
General disorders
Edema: limb	12/84 (14.3%)		7/69 (10.1%)
Fatigue (asthenia, lethargy, malaise)	70/84 (83.3%)		42/69 (60.9%)
Fever in absence of neutropenia, ANC lt1.0x10e9/L	7/84 (8.3%)		3/69 (4.3%)
Pain-Other	9/84 (10.7%)		14/69 (20.3%)
Rigors/chills	15/84 (17.9%)		2/69 (2.9%)
Immune system disorders
Allergic reaction/hypersensitivity	14/84 (16.7%)		2/69 (2.9%)
Infections and infestations
Inf w/normal ANC or Gr 1-2 neutrophils - Bronchus	0/84 (0%)		4/69 (5.8%)
Inf w/normal ANC or Gr 1-2 neutrophils - Sinus	0/84 (0%)		12/69 (17.4%)
Inf w/normal ANC or Gr 1-2 neutrophils - Skin	3/84 (3.6%)		5/69 (7.2%)
Inf w/normal ANC or Gr 1-2 neutrophils - Up airway	7/84 (8.3%)		4/69 (5.8%)
Infection with unknown ANC - Sinus	0/84 (0%)		9/69 (13%)
Infection-Other	4/84 (4.8%)		7/69 (10.1%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	15/84 (17.9%)		11/69 (15.9%)
AST, SGOT	14/84 (16.7%)		10/69 (14.5%)
Alkaline phosphatase	9/84 (10.7%)		5/69 (7.2%)
Bilirubin (hyperbilirubinemia)	4/84 (4.8%)		8/69 (11.6%)
Creatinine	8/84 (9.5%)		10/69 (14.5%)
Leukocytes (total WBC)	60/84 (71.4%)		31/69 (44.9%)
Lymphopenia	36/84 (42.9%)		32/69 (46.4%)
Metabolic/Laboratory-Other	10/84 (11.9%)		10/69 (14.5%)
Neutrophils/granulocytes (ANC/AGC)	56/84 (66.7%)		9/69 (13%)
Platelets	58/84 (69%)		26/69 (37.7%)
Weight gain	7/84 (8.3%)		10/69 (14.5%)
Weight loss	8/84 (9.5%)		9/69 (13%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	14/84 (16.7%)		5/69 (7.2%)
Anorexia	25/84 (29.8%)		8/69 (11.6%)
Calcium, serum-low (hypocalcemia)	12/84 (14.3%)		6/69 (8.7%)
Dehydration	6/84 (7.1%)		2/69 (2.9%)
Glucose, serum-high (hyperglycemia)	35/84 (41.7%)		22/69 (31.9%)
Glucose, serum-low (hypoglycemia)	6/84 (7.1%)		4/69 (5.8%)
Magnesium, serum-low (hypomagnesemia)	7/84 (8.3%)		0/69 (0%)
Potassium, serum-high (hyperkalemia)	5/84 (6%)		4/69 (5.8%)
Potassium, serum-low (hypokalemia)	12/84 (14.3%)		7/69 (10.1%)
Sodium, serum-low (hyponatremia)	13/84 (15.5%)		5/69 (7.2%)
Musculoskeletal and connective tissue disorders
Muscle weakness, not d/t neuropathy - Extrem-lower	5/84 (6%)		1/69 (1.4%)
Muscle weakness, not d/t neuropathy - body/general	10/84 (11.9%)		3/69 (4.3%)
Pain - Back	12/84 (14.3%)		11/69 (15.9%)
Pain - Bone	11/84 (13.1%)		4/69 (5.8%)
Pain - Extremity-limb	6/84 (7.1%)		6/69 (8.7%)
Pain - Joint	13/84 (15.5%)		18/69 (26.1%)
Pain - Muscle	16/84 (19%)		11/69 (15.9%)
Nervous system disorders
Dizziness	15/84 (17.9%)		8/69 (11.6%)
Neuropathy: sensory	48/84 (57.1%)		15/69 (21.7%)
Pain - Head/headache	24/84 (28.6%)		8/69 (11.6%)
Taste alteration (dysgeusia)	16/84 (19%)		0/69 (0%)
Psychiatric disorders
Insomnia	24/84 (28.6%)		13/69 (18.8%)
Mood alteration - anxiety	18/84 (21.4%)		10/69 (14.5%)
Mood alteration - depression	7/84 (8.3%)		14/69 (20.3%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	9/84 (10.7%)		10/69 (14.5%)
Cough	18/84 (21.4%)		21/69 (30.4%)
Dyspnea (shortness of breath)	19/84 (22.6%)		8/69 (11.6%)
Pain - Throat/pharynx/larynx	6/84 (7.1%)		4/69 (5.8%)
Pulmonary/Upper Respiratory-Other	3/84 (3.6%)		9/69 (13%)
Skin and subcutaneous tissue disorders
Dermatology/Skin-Other	4/84 (4.8%)		5/69 (7.2%)
Hair loss/Alopecia (scalp or body)	46/84 (54.8%)		3/69 (4.3%)
Nail changes	5/84 (6%)		3/69 (4.3%)
Pruritus/itching	6/84 (7.1%)		1/69 (1.4%)
Rash/desquamation	8/84 (9.5%)		5/69 (7.2%)
Rash: acne/acneiform	5/84 (6%)		2/69 (2.9%)
Sweating (diaphoresis)	13/84 (15.5%)		10/69 (14.5%)
Vascular disorders
Hot flashes/flushes	9/84 (10.7%)		10/69 (14.5%)
Hypertension	3/84 (3.6%)		10/69 (14.5%)
Hypotension	7/84 (8.3%)		0/69 (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.