A Study of Bevacizumab (Avastin) in Combination With Rituximab (MabThera) and CHOP (Cyclophosphamide, Hydroxydaunorubicin [Doxorubicin], Oncovin [Vincristine], Prednisone) Chemotherapy in Patients With Diffuse Large B-cell Lymphoma

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00486759
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 787
• Locations: 266
• Arms: 2
• Actual Duration (Months): 52.2
• Patients Per Site: 3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This 2-arm study was designed to compare the efficacy and safety of bevacizumab (Avastin) in combination with rituximab (MabThera) and CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) chemotherapy (R-CHOP) versus rituximab plus CHOP chemotherapy (R-CHOP) in previously untreated patients with CD20-positive diffuse large B-cell lymphoma (DLBCL). Patients were randomized to receive 8 cycles of treatment with R-CHOP plus bevacizumab or R-CHOP plus placebo. Treatment with bevacizumab/placebo and R-CHOP was given either on a 2-week or 3-week schedule and bevacizumab was given at a weekly average dose of 5 mg/kg (10 mg/kg for 2-week cycles and 15 mg/kg for 3-week cycles).

Condition or Disease	Intervention/Treatment	Phase
B-cell Lymphoma	Drug: Bevacizumab; Drug: Rituximab; Drug: CHOP; Drug: Placebo	Phase 3

Detailed Description

An independent Data and Safety Monitoring Board (DSMB) was established to review safety data collected during the study on an ongoing basis. At its meeting in December 2009, the DSMB noted a trend for increased cardiac toxicity in the experimental arm (R-CHOP + bevacizumab) compared with the control arm (R-CHOP + placebo). Additional efficacy analyses of data from 720 randomized patients were presented at a DSMB meeting on May 22, 2010; they indicated no improvement in efficacy with the addition of bevacizumab to R-CHOP. It was noted, however, that there was an apparent increase in the risk of cardiotoxicity, premature treatment withdrawal, serious adverse events (SAEs), fatal adverse events (AEs), and perforation/ulcer in the experimental arm. Based on its assessment of an increased risk with unlikely benefit for patients randomized to the experimental arm, the DSMB recommended that further enrollment in the study be permanently halted and that bevacizumab be discontinued for any patients randomized to the experimental arm. On May 31, 2010, the sponsor took the decision to stop enrollment into the study and the bevacizumab treatment was terminated with immediate effect as recommended by the DSMB.

The study protocol was amended. The primary objective of the study was changed from evaluation of efficacy to evaluation of safety and the study was extended to include an 18-month safety follow-up period. Because enrollment was terminated prematurely resulting in fewer enrolled patients than planned, the outcome measure data are premature due to fewer than expected events.

The time frame for the reporting of serious adverse events was modified. Serious adverse events (SAE) unrelated to study treatment were reported until 1 year post-treatment or until new anti-lymphoma treatment was initiated. SAEs judged to be related to study treatment and congestive heart failure events were reported at any time during the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 787 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled Phase III Trial Comparing the Efficacy of Bevacizumab in Combination With Rituximab and CHOP (R-CHOP + Bevacizumab) Versus Rituximab and CHOP (R-CHOP) in Previously Untreated Patients With CD20-positive Diffuse Large B-cell Lymphoma (DLBCL)
• Actual Study Start Date: Jul 26, 2007
• Actual Primary Completion Date: Nov 30, 2011
• Actual Study Completion Date: Nov 30, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bevacizumab + rituximab + CHOP Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Drug: Bevacizumab; Bevacizumab was administered at a dose of 15 mg/kg IV on Day 1 of each 21-day cycle for 8 cycles or at a dose 10 mg/kg IV on Day 1 of each 14-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.; Other Names: Avastin ; Drug: Rituximab; Rituximab was administered at a dose of 375 mg/m^2 IV on Day 1 of each 14- or 21-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.; Other Names: MabThera ; Drug: CHOP; Cyclophosphamide was administered at a dose of 750 mg/m^2 IV on Day 1 of each cycle. Doxorubicin was administered at a dose of 50 mg/m^2 IV on Day 1 of each cycle. Vincristine was administered at a dose of 1.4 mg/m^2 IV (maximum of 2 mg) on Day 1 of each cycle. Prednisone was administered at a dose of 100 mg orally on Days 1-5 of each cycle. All 4 drugs were administered either every 21 days for 8 cycles or every 14 days for 6 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.
Active Comparator: Placebo + rituximab + CHOP Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Drug: Rituximab; Rituximab was administered at a dose of 375 mg/m^2 IV on Day 1 of each 14- or 21-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.; Other Names: MabThera ; Drug: CHOP; Cyclophosphamide was administered at a dose of 750 mg/m^2 IV on Day 1 of each cycle. Doxorubicin was administered at a dose of 50 mg/m^2 IV on Day 1 of each cycle. Vincristine was administered at a dose of 1.4 mg/m^2 IV (maximum of 2 mg) on Day 1 of each cycle. Prednisone was administered at a dose of 100 mg orally on Days 1-5 of each cycle. All 4 drugs were administered either every 21 days for 8 cycles or every 14 days for 6 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.; Drug: Placebo; Placebo to bevacizumab was administered on Day 1 of each 14- or 21-day cycle for 8 cycles. The cycle duration (14- or 21-day) was chosen by each center prior to initiation of the study and was the same for all patients enrolled at that center.

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [Baseline to end of the study (up to 4 years, 4 months)]

   PFS was defined as the time from the date of randomization to the date of disease progression (PD)/relapse, as determined by the investigator, or death from any cause, whichever occurred earlier. A patient with PD/relapse must meet at least 1 of the following criteria: (1) Appearance of any new lesion > 1.0 cm in the short axis during or at the end of therapy. (2) ≥ 50 % increase from nadir in the sum of the products of diameters (SPD, maximum diameter of a tumor x largest diameter perpendicular to the maximum diameter) of any previously involved nodes, in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered progressive disease, a lymph node with a diameter of the short axis < 1.0 cm must increase by ≥ 50% to a size of 1.5 x 1.5 cm or > 1.5 cm in the long axis. (3) ≥ 50 % increase in the greatest diameter of any previously identified node > 1.0 cm in its short axis or in the SPD of more than 1 node.

Secondary Outcome Measures

1. Overall Survival [Baseline to end of the study (up to 4 years, 4 months)]

   Overall survival was defined as the time from the date of randomization to the date of death due to any cause.

2. Overall Response (OR) Assessed According to the Revised Response Criteria for Malignant Lymphoma [At the end of treatment (Cycle 8, up to 12 months)]

   OR = a complete response (CR), an unconfirmed CR, or a partial response (PR). CR = Complete disappearance of disease and disease-related symptoms. All lymph nodes and nodal masses regressed on computed tomography (CT) to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on physical examination, normal size by imaging, and disappearance of nodules related to lymphoma. If bone marrow was involved prior to therapy, infiltrate must have cleared on repeat biopsy. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or, for single nodules, in the greatest transverse diameter. No new sites of disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 79 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients, ≥ 18 and < 80 years of age.

• CD20-positive diffuse large B-cell lymphoma.

• Low-intermediate, high-intermediate, or high risk disease and/or bulky tumor (largest diameter ≥ 7.5 cm).

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

Exclusion Criteria:

• Prior treatment for diffuse large B-cell lymphoma.

• Types of non-Hodgkin's lymphoma other than diffuse large B-cell lymphoma (DLBCL).

• Central nervous system (CNS) involvement of lymphoma.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Uni of California - San Diego; Cancer Center & Dept of Medicine	La Jolla	California	United States	92093
2	Kenmar Research Inst.	Whittier	California	United States	90603
3	University of Colorado Cancer Center Department of Hematology	Aurora	Colorado	United States	80045
4	Uni Medical Center; Division Of Hemotology/Oncology	Jacksonville	Florida	United States	32207
5	Florida Cancer Specialists	West Palm Beach	Florida	United States	33401
6	Northwest Georgia Oncology Centers	Marietta	Georgia	United States	30060
7	University of Kansas Medical Center; Department of Hematology	Kansas City	Kansas	United States	66160
8	St. Joseph Mercy Hospital; Department of Oncology	Ann Arbor	Michigan	United States	48106
9	Northeast Oncology Associates	Concord	North Carolina	United States	28025
10	Forsyth Regional Cancer Center; Piedmont Hematology/Oncology Associates	Winston-Salem	North Carolina	United States	27103
11	Providence Portland Medical Center	Portland	Oregon	United States	97213
12	Charleston Cancer Center	Charleston	South Carolina	United States	29406
13	Uni of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-9063
14	Cancer Therapy & Research Center	San Antonio	Texas	United States	78229
15	Northwest Medical Specialties B	Federal Way	Washington	United States	98003
16	Rainier Physicians	Puyallup	Washington	United States	98372
17	Northwest Medical Specialties	Tacoma	Washington	United States	98405
18	Hospital Italiano; Haemathology	Buenos Aires		Argentina	1425
19	Fundaleu; Haematology	Buenos Aires		Argentina	C1114AAN
20	Hospital Britanico; Haematology	Buenos Aires		Argentina	C1280AEB
21	HOSPITAL PRIVADO - CENTRO MEDICO DE CÓRDOBA; Dpto Oncología	Córdoba		Argentina	5016
22	Greenslopes Private Hospital; Gallipoli Research Centre	Greenslopes	Queensland	Australia	4120
23	Princess Alexandra Hospital Woolloongabba; Clinical Hematology and Medical Oncology	Woolloongabba	Queensland	Australia	4102
24	Royal Adelaide Hospital; Haematology, Institute of Medical Veterinary Science	Adelaide	South Australia	Australia	5000
25	Ashford Cancer Center Research	Kurralta Park	South Australia	Australia	5037
26	Frankston Hospital; Oncology/Haematology	Frankston	Victoria	Australia	3199
27	Peter Maccallum Cancer Institute; Medical Oncology	Melbourne	Victoria	Australia	3000
28	Alfred Hospital; Bone Marrow Transplant Unit	Melbourne	Victoria	Australia	3181
29	Border Medical Oncology; Murray Valley Private Hospital	Wodonga	Victoria	Australia	3690
30	Fremantle Hospital; Haematology	Fremantle	Western Australia	Australia	6160
31	Lkh-Univ. Klinikum Graz; Klinik Für Innere Medizin I	Graz		Austria	8036
32	Lkh Salzburg - Univ. Klinikum Salzburg; Iii. Medizinische Abt.	Salzburg		Austria	5020
33	Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Hämatologie & Hämostaseologie	Wien		Austria	1090
34	Centro Goiano de Oncologia - CGO	Goiania	GO	Brazil	74140-050
35	Hospital de Caridade de Ijui; Oncologia	Ijui	RS	Brazil	98700-000
36	Hospital das Clinicas - UFRGS; Hematologia	Porto Alegre	RS	Brazil	90035-903
37	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS	Brazil	91350-200
38	Hospital das Clinicas - UNICAMP	Campinas	SP	Brazil	13083-888
39	Faculdade de Medicina do ABC - FMABC; Oncologia e Hematologia	Santo Andre	SP	Brazil	09060-650
40	Santa Casa de Misericordia de Sao Paulo; Hematologia e Hemoterapia	Sao Paulo	SP	Brazil	01221-020
41	Hospital das Clinicas - FMUSP; Hematologia	Sao Paulo	SP	Brazil	05403-000
42	Tom Baker Cancer Centre; Dept of Medicine	Calgary	Alberta	Canada	T2N 4N2
43	Cross Cancer Institute ; Dept of Medical Oncology	Edmonton	Alberta	Canada	T6G 1Z2
44	Cancer Care Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
45	Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
46	Health Science Centre	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
47	QEII HSC; Oncology	Halifax	Nova Scotia	Canada	B3H 2Y9
48	Cancer Centre of Southeastern Ontario; Kingston General Hospital	Kingston	Ontario	Canada	K7L 5P9
49	Credit Valley Hospital/Carlo Fidani Peel Regional Cancer Centre	Mississauga	Ontario	Canada	L5M 2N1
50	Toronto Sunnybrook Regional Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
51	University Health Network; Princess Margaret Hospital; Medical Oncology Dept	Toronto	Ontario	Canada	M5G 2M9
52	Windsor Regional Cancer Centre	Windsor	Ontario	Canada	N8W 2X3
53	Hopital Charles Lemoyne; Centre Integre de Lutte Contre Le Cancer de La Monteregie	Greenfield Park	Quebec	Canada	J4V 2H1
54	Mcgill University - Royal Victoria Hospital; Oncology	Montreal	Quebec	Canada	H3A 1A1
55	McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology	Montreal	Quebec	Canada	H3T 1E2
56	Hopital de L'Enfant-Jesus; Hematology	Quebec City	Quebec	Canada	G1J 1Z4
57	Chuq - Hopital Hotel Dieu de Quebec; Oncology	Quebec City	Quebec	Canada	G1R 2J6
58	Allan Blair Cancer Centre	Regina	Saskatchewan	Canada	S4T 7T1
59	Saskatoon Cancer Centre; Uni of Saskatoon Campus	Saskatoon	Saskatchewan	Canada	S7N 4H4
60	Cancer Hospital Chinese Academy of Medical Sciences.	Beijing		China	100021
61	Beijing Cancer Hospital	Beijing		China	100142
62	Beijing Union Hospital	Beijing		China	100730
63	General Hospital of Chinese PLA; Department of Hematology	Beijing		China	100853
64	Fujian Cancer Hospital	Fuzhou		China	350014
65	Fudan University Shanghai Cancer Center	Shanghai		China	200032
66	Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	Shanghai		China	200127
67	Changhai Hospital of Shanghai	Shanghai		China	200433
68	The Second Affiliated Hospital of Soochow University	Suzhou		China	215004
69	First Affiliated Hospital of Soochow University	Suzhou		China	215006
70	Tianjin Institute of Hematology & Blood Diseases Hospital	Tianjin		China	300020
71	The First Affiliated Hospital of The Fourth Military Medical University (Xijing Hospital)	Xi'an		China	710032
72	Organizacion Sanitas Internacional	Bogota		Colombia
73	Hospital Pablo Tobon Uribe	Medellin-Antioquia		Colombia
74	Instituto Cancerologia Medellin; Clinica Las Americas	Medellin		Colombia	2A-80
75	Oncólogos de Occidente	Pereira		Colombia	600004
76	Fakultni nemocnice Brno; Interni hematoonkologicka klinika	Brno		Czechia	625 00
77	Fn Hr. Kralove; IV. Interni Hematologicka Klinika	Hradec Kralove		Czechia	500 05
78	Fakultni nemocnice Olomouc; Hemato-onkologicka klinika	Olomouc		Czechia	775 20
79	Fakultni Nemocnice Plzen, Hematologicko-Onkologicke Oddeleni	Plzen - Lochotin		Czechia	304 60
80	VshEOBECNÁ FAKULTNÍ NEMOCNICE; I. INTERNI KLINIKA	Praha 2		Czechia	128 08
81	Fakultní Nemocnice Královské Vinohrady; Hematologická Klinika	Praha		Czechia	100 34
82	Teodoro Maldonado Carbo Hospital; Oncology Service	Guayaquil		Ecuador	EC090150
83	Hospital Carlos Andrade Marin; Servicio de Oncología	Quito		Ecuador	2569
84	Hospital Solca Quito; Oncologia	Quito		Ecuador	EC170124
85	Clinique Claude Bernard; Onco Hematologie	Albi		France	81030
86	Centre Hospitalier Uni Ire; Service de Medecine D	Angers		France	49033
87	Institut Bergonie; Hematologie Oncologie	Bordeaux		France	33076
88	Polyclinique Bordeaux Nord Aquitaine; Chimiotherapie Radiotherapie	Bordeaux		France	33077
89	Centre Francois Baclesse; Comite 2	Caen		France	14076
90	Chu Estaing; Cons Hemato Medecine Interne	Clermont Ferrand		France	63003
91	Chu Site Du Bocage;Hematologie Clinique	Dijon		France	21079
92	CH Dptal Les Oudairies; Hematologie Oncologie	La Roche Sur Yon		France	85925
93	Hopital Albert Michallon; Oncologie	La Tronche		France	38700
94	Clinique Victor Hugo; Chimiotherapie	Le Mans		France	72015
95	Hopital Claude Huriez; Hematologie	Lille		France	59037
96	Hopital Uni Ire Dupuytren; Hematologie	Limoges		France	87042
97	Centre Leon Berard; Departement Oncologie Medicale	Lyon		France	69373
98	Institut J Paolii Calmettes; Onco Hematologie 1	Marseille		France	13273
99	Clinique Pont de Chaume; Oncologie Et Radiotherapie	Montauban		France	82017
100	Hopital Saint Eloi; Hematologie Oncologie Medicale	Montpellier		France	34295
101	Hopital de L'Archet; Hematologie Clinique	Nice		France	06202
102	Polyclinique Kenval ; Radiotherapie Oncologie	Nimes		France	30900
103	Institut Curie; Oncologie Medicale	Paris		France	75231
104	Hopital Saint Louis ; Service d Oncologie Medicale Fougere 6 (Pr Misset)	Paris		France	75475
105	Hopital Pitie Salpetriere; Hematologie Clinique	Paris		France	75651
106	Hopital Saint Jean; Hematologie	Perpignan		France	66046
107	Hopital De Haut Leveque; Hematologie Clinique	Pessac		France	33604
108	Ch Lyon Sud; Hemato Secteur Jules Courmont	Pierre Benite		France	69495
109	Hopital De La Miletrie; Hematologie Et Oncologie Medicale	Poitiers		France	86021
110	Ch Jacques Puel;Oncologie Medicale	Rodez		France	12027
111	ICL; Hematologie	Saint-Priest en Jarez		France	42271
112	Hopital Sud; Hematologie Clinique	Salouel		France	80480
113	Hopital Purpan; Hematologie Clinique	Toulouse		France	31059
114	Clinique Pasteur; Oncologie Medicale	Toulouse		France	31076
115	Hopital Bretonneau; Hematologie Therapie Cellulaire	Tours		France	37044
116	Hopitaux De Brabois; Hematologie Medecine Interne	Vandoeuvre Les Nancy		France	54511
117	Institut Gustave Roussy; Unite D'Hematologie	Villejuif		France	94805
118	Gesundheitszentrum St. Marien GmbH; Med. II, Hämatologie/Onkologie	Amberg		Germany	92224
119	Charité-Universitätsm. Berlin; Med. Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunolo.	Berlin		Germany	10117
120	Charité; Onkologie & Hämatologie	Berlin		Germany	10117
121	DIAKO Ev. Diakonie-Krankenhaus Bremen GmbH; Med. Klinik II; Hämatologie und internistische Onkologie	Bremen		Germany	28239
122	Carl-Thiem-Klinik Cottbus; Medizinische Klinik	Cottbus		Germany	03048
123	Klinikzentrum Mitte; Medizinische Klinik Gastroenterologie Haematologie / Onkologie	Dortmund		Germany	44137
124	St. Johannes Hospital; Abt. Innere Medizin	Dortmund		Germany	44137
125	St Antonius Hospital; Haematologie/Onkologie	Eschweiler		Germany	52249
126	Krankenhaus Nordwest Medizinische Klinik	Frankfurt		Germany	60488
127	Klinik Fulda; Abt. Itz	Fulda		Germany	36043
128	Universitätsklinikum Greifswald Klinik für Innere Medizin C und Poliklinik	Greifswald		Germany	17475
129	Georg-August-Uniklinik ; Zentrum Innere Medizin Abt. Hämatologie & Onkologie	Göttingen		Germany	37075
130	Kath.Krankenhaus Hagen gem.GmbH St.-Marien-Hospital	Hagen		Germany	58095
131	Asklepios Klinik St. Georg; Allgemeine Innere Medizin	Hamburg		Germany	20099
132	Facharztzentrum Eppendorf, Studien GbR	Hamburg		Germany	20249
133	Evang.Krankenhaus Abt. Hämatologie und Onkologie	Hamm		Germany	59063
134	St.-Marien-Hospital Klinik Knappenstraße; Klinik für Hämatologie und Onkologie	Hamm		Germany	59071
135	KRH Klinikum Siloah Medizinische Klinik III	Hannover		Germany	30449
136	St. Bernward-Krankenhaus	Hildesheim		Germany	31134
137	Universitaetsklinikum des Saarlandes; medizinische Klinik und Poliklinik; Innere Medizin I	Homburg/Saar		Germany	66421
138	Städtisches Klinikum Karlsruhe gGmbH, II. Medizinische Klinik	Karlsruhe		Germany	76133
139	St. Vincentius Kliniken Ag; Medizinische Klinik Abt. 2	Karlsruhe		Germany	76137
140	Tagesklinik Landshut; Hämatologie/Onkologie	Landshut		Germany	84028
141	Universitätsklinikum Leipzig Medizinische Klinik II Gastroenterolog. u. Hepatolog.	Leipzig		Germany	04103
142	Klinikum St.Georg gGmbH Klinik für Internistische Onkologie und Hämotologie	Leipzig		Germany	04129
143	Klinikum der Stadt Ludwigshafen; Medizinische Klinik A	Ludwigshafen		Germany	67063
144	Universitätsklinikum Schleswig-Holstein / Campus Lübeck, Med. Klinik I, Hämatologie/Onkologie	Lübeck		Germany	23562
145	Märkische Kliniken GmbH, Klinikum Lüdenscheid; Hämatologie / Onkologie	Lüdenscheid		Germany	58515
146	Otto von Guericke Uni Magdeburg Uniklinik; Hämatologie/Onkologie	Magdeburg		Germany	39120
147	Klinikum Magdeburg gemeinnützige GmbH; Klinik Haematologie und Onkologie	Magdeburg		Germany	39130
148	Klinikum Mannheim III. Medizinische Klinik	Mannheim		Germany	68167
149	Klinikum der Universitaet Muenchen; Campus Großhadern; Medizinische Klinik III und Poliklinik	Muenchen		Germany	81377
150	Westfälische Wilhelms-Universität Münster, Medizinische Klinik und Poliklinik A	Münster		Germany	48149
151	Klinikum Oldenburg gGmbH; Klinik für Onkologie und Hämatologie	Oldenburg		Germany	26133
152	Prosper-Hospital, Medizinische Klinik I	Recklinghausen		Germany	45659
153	St Marien Krankenhaus; Medizinische Klinik Iii	Siegen		Germany	57072
154	Klinikum Mutterhaus der Borromaeerinnen gGmbH; Haematologie/Onkologie	Trier		Germany	54290
155	Krankenhaus der Barmherzigen Brüder Trier; Innere Medizin I, Hämatologie / Internistische Onkologie	Trier		Germany	54292
156	Eberhard-Karls-Universität Tübingen; Medizinische Klinik I	Tübingen		Germany	72076
157	Universitätsklinikum Ulm; Medizinische Uni-Klinik III Abt. Innere Medizin III Hämatologie u. Onkolo.	Ulm		Germany	89081
158	HSK Dr.-Horst-Schmidt-Kliniken; Innere Medizin I Kardiologie; Angiologie und Intensivmedizin	Wiesbaden		Germany	65199
159	Helios Klinik Wuppertal; Medizinische Klinik I	Wuppertal		Germany	42283
160	Kliniken St. Antonius; Zentrum Für Innere Medizin, Haematologie/Onkologie	Wuppertal		Germany	42283
161	Georgios Papanikolaou Hospital; Hematology Department	Thessaloniki		Greece	570 10
162	Queen Elizabeth Hospital; Clinical Oncology	Hong Kong		Hong Kong
163	Queen Mary Hospital; Dept of Medicine	Hong Kong		Hong Kong
164	Fov. Onk. Egyesitett Szent Istvan es Szent Laszlo Korhaz; Dept Of Bone Marrow Transplant	Budapest		Hungary	1097
165	National Institute of Oncology, A Dept of Internal Medicine	Budapest		Hungary	1122
166	University of Debrecen Medical and Health Science Center, Institute of Internal Medicine, Hematology	Debrecen		Hungary	4032
167	A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna	Bologna	Emilia-Romagna	Italy	40138
168	Ospedale Regionale Di Parma; Divisione Di Oncologia Medica	Parma	Emilia-Romagna	Italy	43100
169	Az. Osp. Arcispedale S. Maria Nuova; U.O. Di Ematologia	Reggio Emilia	Emilia-Romagna	Italy	42100
170	Irccs Centro Di Riferimento Oncologico (CRO); Dipartimento Di Oncologia Medica	Aviano	Friuli-Venezia Giulia	Italy	33081
171	A.O. Universitaria S. Maria Della Misericordia Di Udine; Oncologia; Clinica Ematologica	Udine	Friuli-Venezia Giulia	Italy	33100
172	Univ. Cattolica La Sapienza; Cattedra Di Ematologia	Roma	Lazio	Italy	00161
173	ASST DI MONZA; Ematologia	Monza	Lombardia	Italy	20052
174	Irccs Policlinico San Matteo; Divisione Di Ematologia	Pavia	Lombardia	Italy	27100
175	Ospedale Gen.Le Prov.Le 'C.G.Mazzoni'; Ematologia	Ascoli Piceno	Marche	Italy	63100
176	Università Cattolica Del Sacro Cuore S.S. Giovanni Paolo Ii; Uoc Di Onco-Ematologia	Campobasso	Molise	Italy	86100
177	Az. Osp. S. Luigi Gonzaga; Malattie Apparato Respiratorio 5 Ad Indirizzo Oncologico	Orbassano	Piemonte	Italy	10043
178	A.O. Universitaria S. Giovanni Battista-Molinette Di Torino; Ematologia 1	Torino	Piemonte	Italy	10126
179	Irccs Ist. Tumori Giovanni Paolo Ii; Dipartimento Oncologia Medica	Bari	Puglia	Italy	70124
180	Ospedale Ferrarotto; Divisione Di Ematologia	Via S. Sofia 78	Sicilia	Italy	95123
181	Ospedale Santa Chiara; Unita Operativa Di Ematologia	Pisa	Toscana	Italy	56100
182	Samsung Medical Centre; Oncology	Seoul		Korea, Republic of	135-170
183	Asan Medical Center, Uni Ulsan Collegemedicine; Dept.Internal Medicine / Divisionhematology/Oncology	Seoul		Korea, Republic of	138-736
184	Korean Cancer Center Hospital; Oncology	Seoul		Korea, Republic of	139-709
185	Severance Hospital - Yonsei University; Medicine Dept.	Seoul		Korea, Republic of
186	Seamen' Hospital' Dept. of haematology	Klaipeda		Lithuania	92288
187	Uni Hospital Santariskiu Clinic; Haematology	Vilnius		Lithuania	08661
188	Hospital Pulau Pinang	Penang		Malaysia	10990
189	Instituto Biomedico De Investigacion A.C.	Aguascalientes		Mexico	20127
190	Hospital Español; Hematología Sala 19	Mexico City		Mexico	11520
191	Col Instituto Tecnologico Y Estudios Superiores de Monterrey	Monterrey		Mexico	00000
192	Hospital Universitario Dr. Jose E. Gonzalez; Haematology	Monterrey		Mexico	64460
193	North Shore Hospital; Haematolgy	Auckland		New Zealand	1309
194	Uni of Auckland; Dept of Molecular Medicine & Haematology	Auckland		New Zealand
195	Christchurch Hospital; Canterbury Health Laboratories	Christchurch		New Zealand
196	Centro Hemato Oncologico Paitilla	Panama City		Panama	083200752
197	Hospital Nacional Almanzor Aguinaga Asenjo; Unidad De Investigacion Del Servicio De Oncologia Medica	Chiclayo		Peru	CIX
198	Hospital Nacional Edgardo Rebagliati Martins; Oncologia	Lima		Peru	11
199	Hospital Nacional Guillermo Almenara Irigoyen; Oncology	Lima		Peru	13
200	Instituto Nacional de Enfermedades Neoplasicas	Lima		Peru	34
201	Hospital Nacional LNS dela Policia Nacional del Perú. Unidad Onco; Deapartamento de Oncología	Lima		Peru	Lima11
202	Cebu Cancer Institute; Perpetual Succour Hospital	Cebu		Philippines	6000
203	National Kidney and Transplant Institute; Chemotherapy Unit	Diliman, Quezon City		Philippines	1100
204	St Luke'S Medical Centre; Oncology	Quezon City		Philippines	1114
205	Szpital Specjalistyczny Podkarpacki Ośrodek Onkologiczny	Brzozów		Poland	36-200
206	Szpital Uniwersytecki W Krakowie; Klinika Hematologii	Krakow		Poland	31-501
207	Medical University School; Dept. of Haematology	Lodz		Poland	93-510
208	Katedra i Klinika Hematoonkologii i Transplantacji Szpiku; Uniwersytetu Medycznego w Lublinie	Lublin		Poland	20-081
209	Zaklad Opieki Zdrowotnej Mswia; Oddzial Chemioterapii	Olsztyn		Poland	10-228
210	Samodzielny Publiczny Centralny Szpital Kliniczny; Haematology Dept.	Warszawa		Poland	02-097
211	Centralny Szpital Kliniczny Mswia; Klinika onkologii, hematologii i chorob wewnetrznych	Warszawa		Poland	02-507
212	Centrum Onkologii - Inst.Im. Marii Sklodowskiej-Curie; Lymphoma Dept.	Warszawa		Poland	02-781
213	HUC; Servico de Hematologia	Coimbra		Portugal	3000-075
214	IPO de Lisboa; Servico de Hematologia	Lisboa		Portugal	1099-166
215	Hospital de Sao Joao; Servico de Hematologia Clinica	Porto		Portugal	4200-319
216	Republican Clinical Oncologic Dispensary of Republic Of Tatarstan	Kazan		Russian Federation	420029
217	N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis	Moscow		Russian Federation	115478
218	Haematology Research Center; Haematology	Moscow		Russian Federation	125167
219	Semashko Central Clinical Hospital Moscow; Hematology	Moscow		Russian Federation	129128
220	Research Inst. of Hematology & Blood Transfusion ; Hematology	St Petersburg		Russian Federation	191024
221	National Cancer Inst. ; Dept. of Chemotherapy	Bratislava		Slovakia	833 10
222	Hospital Mutua de Terrassa; Servicio de Hematologia	Terrassa	Barcelona	Spain	08221
223	Hospital Universitario Marques de Valdecilla; Servicio de Hematologia	Santander	Cantabria	Spain	39008
224	Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Hematologia	La Coruna	La Coruña	Spain	15006
225	Hospital Universitario de Canarias;servicio de Oncologia	La Laguna	Tenerife	Spain	38320
226	Hospital de Basurto; Servicio de Hematologia	Bilbao	Vizcaya	Spain	48013
227	Hospital de Galdakano	Galdakano	Vizcaya	Spain	48960
228	Hospital de la Santa Creu i Sant Pau; Servicio de Hematologia	Barcelona		Spain	08025
229	Hospital Universitari Vall d'Hebron; Servicio de Hematologia	Barcelona		Spain	08035
230	Hospital Clínic i Provincial; Servicio de Hematología y Oncología	Barcelona		Spain	08036
231	Hospital Duran i Reynals; Servicio de Hematologia	Barcelona		Spain	08907
232	Complejo Hospitalario de Jaen- Hospital Universitario Medico Quirurgico; Servicio de Hematologia	Jaen		Spain	23007
233	Hospital Universitario Clínico San Carlos; Servicio de Hematología	Madrid		Spain	28040
234	Hospital Universitario la Paz; Servicio de Hematologia	Madrid		Spain	28046
235	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga		Spain	29010
236	Hospital Clinico Universitario de Salamanca;Servicio de Hematologia	Salamanca		Spain	37007
237	Hospital Universitario Virgen del Rocio; Servicio de Hematologia	Sevilla		Spain	41013
238	Hospital Universitario la Fe; Servicio de Medicina Intena	Valencia		Spain	46009
239	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia		Spain	46010
240	Hospital Universitario Miguel Servet; Servicio Hematologia	Zaragoza		Spain	50009
241	Skånes University Hospital, Skånes Department of Onclology	Lund		Sweden	22185
242	Skånes Universitetssjukhus; Kliniska Forskningsenheten Onkologimottagning medicinsk behandling	Malmö		Sweden	205 02
243	Länssjukhuset; Medicinkliniken	Sundsvall		Sweden	85186
244	Akademiska sjukhuset, Onkologkliniken	Uppsala		Sweden	75185
245	Universitätsspital Zürich; Klinik für Onkologie	Zürich		Switzerland	8091
246	Veterans General Hospital; Division of Oncology	Taipei		Taiwan	00112
247	Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology	Taipei		Taiwan	112
248	Chang Gung Medical Foundation-Taipei	Taoyuan		Taiwan	333
249	King Chulalongkorn Memorial Hospital; Division of Hematology, Department of Medicine	Bangkok		Thailand	10330
250	National Cancer Inst.	Bangkok		Thailand	10400
251	Rajavithi Hospital; Medicine	Bangkok		Thailand	10400
252	Siriraj Hospital; Division of Hematology, Department of Medicine	Bangkok		Thailand	10700
253	Chiang Mai Uni Hospital; Division of Hematology,Dept of Medicine,Faculty of Medicine	Chiang Mai		Thailand	50200
254	Srinagarind Hospital, Khon Kaen Uni ; Dept of Medicine	Khon Kaen		Thailand	40002
255	Birmingham Heartlands Hospital; Department of Haematology	Birmingham		United Kingdom	B9 5SS
256	Bradford Royal Infirmary; Haematology Department	Bradford		United Kingdom	BD9 6RJ
257	North Hampshire Hospital; Dept. of Haematology	Hampshire		United Kingdom	RG24 9NA
258	Princess Alexandra Hospital; Department of Haematology	Harlow		United Kingdom	CM20 1QX
259	Leicester Royal Infirmary; Dept. of Medical Oncology	Leicester		United Kingdom	LE1 5WW
260	Royal Liverpool Uni Hospital; Haematology	Liverpool		United Kingdom	L7 8XP
261	St. George'S Hospital; Haematology	London		United Kingdom	SW17 0QT
262	Hillingdon Hospital	Middx		United Kingdom	UB8 3NN
263	Churchill Hospital; Oxford Cancer and Haematology Centre	Oxford		United Kingdom	OX3 7LJ
264	Royal Hallamshire Hospital; Haematology Dept	Sheffield		United Kingdom	S10 2JF
265	Weston Park Hospital; Cancer Clinical Trials Centre	Sheffield		United Kingdom	S10 2SJ
266	The Royal Wolverhampton Hospitals NHS Trust; Department of Haematology	Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Hoffmann-La Roche
• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00486759
• Other Study ID Numbers: BO20603
• First Posted: Jun 15, 2007
• Last Update Posted: Jul 25, 2017
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Bevacizumab; Rituximab

Study Results

Participant Flow

Arm/Group Title	Bevacizumab + Rituximab + CHOP	Placebo + Rituximab + CHOP
Arm/Group Description	Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).
Period Title: Treatment
STARTED	390	397
COMPLETED	203	260
NOT COMPLETED	187	137
Period Title: Treatment
STARTED	203	260
COMPLETED	64	142
NOT COMPLETED	139	118

Baseline Characteristics

Arm/Group Title	Bevacizumab + Rituximab + CHOP	Placebo + Rituximab + CHOP	Total
Arm/Group Description	Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Total of all reporting groups
Overall Participants	390	397	787
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.89 (14.256)	56.98 (15.399)	57.44 (14.841)
Sex: Female, Male (Count of Participants)
Female	207 53.1%	193 48.6%	400 50.8%
Male	183 46.9%	204 51.4%	387 49.2%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as the time from the date of randomization to the date of disease progression (PD)/relapse, as determined by the investigator, or death from any cause, whichever occurred earlier. A patient with PD/relapse must meet at least 1 of the following criteria: (1) Appearance of any new lesion > 1.0 cm in the short axis during or at the end of therapy. (2) ≥ 50 % increase from nadir in the sum of the products of diameters (SPD, maximum diameter of a tumor x largest diameter perpendicular to the maximum diameter) of any previously involved nodes, in a single involved node, or the size of other lesions (eg, splenic or hepatic nodules). To be considered progressive disease, a lymph node with a diameter of the short axis < 1.0 cm must increase by ≥ 50% to a size of 1.5 x 1.5 cm or > 1.5 cm in the long axis. (3) ≥ 50 % increase in the greatest diameter of any previously identified node > 1.0 cm in its short axis or in the SPD of more than 1 node.
Time Frame	Baseline to end of the study (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless whether or not they had actually received the assigned treatments.

Arm/Group Title	Bevacizumab + Rituximab + CHOP	Placebo + Rituximab + CHOP
Arm/Group Description	Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).
Measure Participants	390	397
Median (Inter-Quartile Range) [Months]	40.2	42.9

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from the date of randomization to the date of death due to any cause.
Time Frame	Baseline to end of the study (up to 4 years, 4 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless whether or not they had actually received the assigned treatments.

Arm/Group Title	Bevacizumab + Rituximab + CHOP	Placebo + Rituximab + CHOP
Arm/Group Description	Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).
Measure Participants	390	397
Median (Inter-Quartile Range) [Months]	NA	NA

3. Secondary Outcome

Title	Overall Response (OR) Assessed According to the Revised Response Criteria for Malignant Lymphoma
Description	OR = a complete response (CR), an unconfirmed CR, or a partial response (PR). CR = Complete disappearance of disease and disease-related symptoms. All lymph nodes and nodal masses regressed on computed tomography (CT) to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on physical examination, normal size by imaging, and disappearance of nodules related to lymphoma. If bone marrow was involved prior to therapy, infiltrate must have cleared on repeat biopsy. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or, for single nodules, in the greatest transverse diameter. No new sites of disease.
Time Frame	At the end of treatment (Cycle 8, up to 12 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients, regardless whether or not they had actually received the assigned treatments.

Arm/Group Title	Bevacizumab + Rituximab + CHOP	Placebo + Rituximab + CHOP
Arm/Group Description	Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).	Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).
Measure Participants	390	397
Number [Percentage of patients]	63.1	70.5

Adverse Events

Time Frame	All adverse events (AE) were reported starting from the first dose up to 92 days after the last dose of study drug. AEs of special interest were reported up to 6 months after the last dose.
Adverse Event Reporting Description	Safety analysis population: All patients who received at least 1 dose of study drug whether withdrawn prematurely or not. Bevacizumab (B) 395=390 randomized-2 no treatment+7 randomized to placebo who received B. Placebo to B 386=397 randomized-5 no treatment-7 received B+1 randomized to B who received placebo but no B.
Arm/Group Title	Bevacizumab + Rituximab + CHOP		Placebo + Rituximab + CHOP
Arm/Group Description	Patients received bevacizumab 5 mg/kg/week on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).		Patients received placebo to bevacizumab on Day 1 of each cycle + rituximab 375 mg/m^2 intravenously (IV) on Day 1 of each cycle + CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone).
All Cause Mortality
	Bevacizumab + Rituximab + CHOP		Placebo + Rituximab + CHOP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Bevacizumab + Rituximab + CHOP		Placebo + Rituximab + CHOP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	224/395 (56.7%)		173/386 (44.8%)
Blood and lymphatic system disorders
Febrile neutorpenia	63/395 (15.9%)		48/386 (12.4%)
Neutropenia	12/395 (3%)		17/386 (4.4%)
Leukopenia	6/395 (1.5%)		5/386 (1.3%)
Anaemia	8/395 (2%)		1/386 (0.3%)
Thrombocytopenia	5/395 (1.3%)		4/386 (1%)
Agranulocytosis	3/395 (0.8%)		2/386 (0.5%)
Febrile bone marrow aplasia	0/395 (0%)		3/386 (0.8%)
Pancytopenia	2/395 (0.5%)		1/386 (0.3%)
Lymphopenia	2/395 (0.5%)		0/386 (0%)
Splenic vein thrombosis	1/395 (0.3%)		0/386 (0%)
Splenomegaly	1/395 (0.3%)		0/386 (0%)
Cardiac disorders
Left ventricular dysfunction	15/395 (3.8%)		5/386 (1.3%)
Cardiac failure	6/395 (1.5%)		4/386 (1%)
Cardiac failure congestive	5/395 (1.3%)		2/386 (0.5%)
Atrial fibrillation	2/395 (0.5%)		4/386 (1%)
Angina pectoris	1/395 (0.3%)		1/386 (0.3%)
Cardiovascular disorder	1/395 (0.3%)		1/386 (0.3%)
Restrictive cardiomyopathy	1/395 (0.3%)		1/386 (0.3%)
Angina unstable	0/395 (0%)		1/386 (0.3%)
Arrhythmia	1/395 (0.3%)		0/386 (0%)
Atrioventricular block complete	1/395 (0.3%)		0/386 (0%)
Cardiac disorder	1/395 (0.3%)		0/386 (0%)
Cardiomyopathy	1/395 (0.3%)		0/386 (0%)
Cardiotoxicity	0/395 (0%)		1/386 (0.3%)
Congestive cardiomyopathy	1/395 (0.3%)		0/386 (0%)
Sick sinus syndrome	1/395 (0.3%)		0/386 (0%)
Sinus tachycardia	0/395 (0%)		1/386 (0.3%)
Supraventricular tachycardia	1/395 (0.3%)		0/386 (0%)
Tachyarrhythmia	0/395 (0%)		1/386 (0.3%)
Ventricular hypokinesia	1/395 (0.3%)		0/386 (0%)
Congenital, familial and genetic disorders
Aplasia	1/395 (0.3%)		0/386 (0%)
Endocrine disorders
Hyperthyroidism	0/395 (0%)		1/386 (0.3%)
Toxic nodular goitre	1/395 (0.3%)		0/386 (0%)
Eye disorders
Retinal detachment	0/395 (0%)		1/386 (0.3%)
Retinal haemorrhage	0/395 (0%)		1/386 (0.3%)
Retinal vein thrombosis	0/395 (0%)		1/386 (0.3%)
Gastrointestinal disorders
Abdominal pain	4/395 (1%)		5/386 (1.3%)
Diarrhoea	6/395 (1.5%)		3/386 (0.8%)
Ascites	4/395 (1%)		0/386 (0%)
Constipation	2/395 (0.5%)		2/386 (0.5%)
Gastric perforation	3/395 (0.8%)		0/386 (0%)
Nausea	3/395 (0.8%)		0/386 (0%)
Stomatitis	2/395 (0.5%)		1/386 (0.3%)
Abdominal pain upper	1/395 (0.3%)		1/386 (0.3%)
Gastrointestinal haemorrhage	1/395 (0.3%)		1/386 (0.3%)
Upper gastrointestinal haemorrhage	2/395 (0.5%)		0/386 (0%)
Abdominal pain lower	1/395 (0.3%)		0/386 (0%)
Anal fissure	1/395 (0.3%)		0/386 (0%)
Enteritis	0/395 (0%)		1/386 (0.3%)
Gastrointestinal hypomotility	0/395 (0%)		1/386 (0.3%)
Haemorrhoidal haemorrhage	1/395 (0.3%)		0/386 (0%)
Haemorrhoids	1/395 (0.3%)		0/386 (0%)
Ileal perforation	1/395 (0.3%)		0/386 (0%)
Ileus paralytic	1/395 (0.3%)		0/386 (0%)
Impaired gastric emptying	0/395 (0%)		1/386 (0.3%)
Inguinal hernia	1/395 (0.3%)		0/386 (0%)
Inguinal hernia, obstructive	0/395 (0%)		1/386 (0.3%)
Intestinal perforation	1/395 (0.3%)		0/386 (0%)
Melaena	0/395 (0%)		1/386 (0.3%)
Periodontitis	1/395 (0.3%)		0/386 (0%)
Rectal ulcer	0/395 (0%)		1/386 (0.3%)
Small intestinal obstruction	0/395 (0%)		1/386 (0.3%)
Small intestinal perforation	1/395 (0.3%)		0/386 (0%)
Subileus	1/395 (0.3%)		0/386 (0%)
Volvulus	1/395 (0.3%)		0/386 (0%)
Vomiting	1/395 (0.3%)		0/386 (0%)
General disorders
Pyrexia	14/395 (3.5%)		15/386 (3.9%)
Asthenia	4/395 (1%)		2/386 (0.5%)
Chest pain	0/395 (0%)		3/386 (0.8%)
Death	1/395 (0.3%)		2/386 (0.5%)
General physical health deterioration	3/395 (0.8%)		0/386 (0%)
Fatigue	1/395 (0.3%)		1/386 (0.3%)
Mucosal inflammation	2/395 (0.5%)		0/386 (0%)
Catheter site haemorrhage	1/395 (0.3%)		0/386 (0%)
Effusion	1/395 (0.3%)		0/386 (0%)
Hyperthermia	1/395 (0.3%)		0/386 (0%)
Impaired healing	1/395 (0.3%)		0/386 (0%)
Influenza like illness	0/395 (0%)		1/386 (0.3%)
Local swelling	0/395 (0%)		1/386 (0.3%)
Medical device complication	1/395 (0.3%)		0/386 (0%)
Multi-organ failure	1/395 (0.3%)		0/386 (0%)
Oedema peripheral	0/395 (0%)		1/386 (0.3%)
Pain	0/395 (0%)		1/386 (0.3%)
Hepatobiliary disorders
Acute hepatic failure	1/395 (0.3%)		0/386 (0%)
Bile duct stone	1/395 (0.3%)		0/386 (0%)
Cholangitis	1/395 (0.3%)		0/386 (0%)
Cholecystitis acute	1/395 (0.3%)		0/386 (0%)
Hepatitis	1/395 (0.3%)		0/386 (0%)
Jaundice cholestatic	1/395 (0.3%)		0/386 (0%)
Immune system disorders
Hypersensitivity	1/395 (0.3%)		2/386 (0.5%)
Anaphylactic reaction	1/395 (0.3%)		0/386 (0%)
Infections and infestations
Pneumonia	22/395 (5.6%)		16/386 (4.1%)
Septic shock	6/395 (1.5%)		4/386 (1%)
Infection	3/395 (0.8%)		6/386 (1.6%)
Urinary tract infection	6/395 (1.5%)		3/386 (0.8%)
Bronchopneumonia	2/395 (0.5%)		6/386 (1.6%)
Gastroenteritis	2/395 (0.5%)		4/386 (1%)
Neutropenic sepsis	5/395 (1.3%)		1/386 (0.3%)
Sepsis	2/395 (0.5%)		4/386 (1%)
Neutropenic infection	1/395 (0.3%)		4/386 (1%)
Device related infection	2/395 (0.5%)		1/386 (0.3%)
Lower respiratory tract infection	1/395 (0.3%)		2/386 (0.5%)
Anal abscess	2/395 (0.5%)		0/386 (0%)
Appendicitis	1/395 (0.3%)		1/386 (0.3%)
Bronchitis	1/395 (0.3%)		1/386 (0.3%)
Cellulitis	0/395 (0%)		2/386 (0.5%)
Cystitis	1/395 (0.3%)		1/386 (0.3%)
Erysipelas	0/395 (0%)		2/386 (0.5%)
Escherichia sepsis	0/395 (0%)		2/386 (0.5%)
Herpes zoster	1/395 (0.3%)		1/386 (0.3%)
Oesophageal candidiasis	2/395 (0.5%)		0/386 (0%)
Pharyngitis	1/395 (0.3%)		1/386 (0.3%)
Pneumocystis jiroveci pneumonia	0/395 (0%)		2/386 (0.5%)
Respiratory tract infection	2/395 (0.5%)		0/386 (0%)
Abdominal abscess	1/395 (0.3%)		0/386 (0%)
Acute tonsillitis	1/395 (0.3%)		0/386 (0%)
Amoebiasis	1/395 (0.3%)		0/386 (0%)
Appendiceal abscess	0/395 (0%)		1/386 (0.3%)
Bronchitis bacterial	1/395 (0.3%)		0/386 (0%)
Bronchopulmonary aspergillosis	0/395 (0%)		1/386 (0.3%)
Enterococcal infection	0/395 (0%)		1/386 (0.3%)
Fungal oesophagitis	0/395 (0%)		1/386 (0.3%)
Gastroenteritis norovirus	0/395 (0%)		1/386 (0.3%)
Gastrointestinal fungal infection	0/395 (0%)		1/386 (0.3%)
Gastrointestinal infection	1/395 (0.3%)		0/386 (0%)
H1N1 influenza	0/395 (0%)		1/386 (0.3%)
Infectious peritonitis	1/395 (0.3%)		0/386 (0%)
Influenza	0/395 (0%)		1/386 (0.3%)
Localised infection	1/395 (0.3%)		0/386 (0%)
Lung infection	1/395 (0.3%)		0/386 (0%)
Lymph gland infection	1/395 (0.3%)		0/386 (0%)
Lymphadenitis bacterial	0/395 (0%)		1/386 (0.3%)
Meningitis cryptococcal	0/395 (0%)		1/386 (0.3%)
Mucosal infection	0/395 (0%)		1/386 (0.3%)
Oral candidiasis	1/395 (0.3%)		0/386 (0%)
Oral infection	0/395 (0%)		1/386 (0.3%)
Orchitis	0/395 (0%)		1/386 (0.3%)
Otitis media	0/395 (0%)		1/386 (0.3%)
Paronychia	0/395 (0%)		1/386 (0.3%)
Perirectal abscess	1/395 (0.3%)		0/386 (0%)
Pneumocystis jiroveci infection	0/395 (0%)		1/386 (0.3%)
Pneumonia viral	1/395 (0.3%)		0/386 (0%)
Pulmonary sepsis	1/395 (0.3%)		0/386 (0%)
Pyelonephritis	0/395 (0%)		1/386 (0.3%)
Pyelonephritis acute	1/395 (0.3%)		0/386 (0%)
Respiratory syncytial virus infection	0/395 (0%)		1/386 (0.3%)
Sinusitis	0/395 (0%)		1/386 (0.3%)
Splenic abscess	1/395 (0.3%)		0/386 (0%)
Staphylococcal infection	0/395 (0%)		1/386 (0.3%)
Systemic candida	1/395 (0.3%)		0/386 (0%)
Tooth abscess	1/395 (0.3%)		0/386 (0%)
Tuberculous pleurisy	0/395 (0%)		1/386 (0.3%)
Upper respiratory tract infection	0/395 (0%)		1/386 (0.3%)
Urosepsis	0/395 (0%)		1/386 (0.3%)
Injury, poisoning and procedural complications
Cervical vertebral fracture	1/395 (0.3%)		0/386 (0%)
Chemical injury	1/395 (0.3%)		0/386 (0%)
Fall	0/395 (0%)		1/386 (0.3%)
Femoral neck fracture	1/395 (0.3%)		0/386 (0%)
Head injury	0/395 (0%)		1/386 (0.3%)
Injury	1/395 (0.3%)		0/386 (0%)
Laceration	0/395 (0%)		1/386 (0.3%)
Lower limb fracture	1/395 (0.3%)		0/386 (0%)
Lumbar vertebral fracture	0/395 (0%)		1/386 (0.3%)
Post lumbar puncture syndrome	1/395 (0.3%)		0/386 (0%)
Road traffic accident	1/395 (0.3%)		0/386 (0%)
Spinal compression fracture	1/395 (0.3%)		0/386 (0%)
Subdural haematoma	0/395 (0%)		1/386 (0.3%)
Traumatic lung injury	1/395 (0.3%)		0/386 (0%)
Ulna fracture	1/395 (0.3%)		0/386 (0%)
Investigations
Ejection fraction decreased	4/395 (1%)		3/386 (0.8%)
C-reactive protein increased	1/395 (0.3%)		1/386 (0.3%)
Alanine aminotransferase increased	1/395 (0.3%)		0/386 (0%)
Aspartate aminotransferase increased	1/395 (0.3%)		0/386 (0%)
General physical condition abnormal	1/395 (0.3%)		0/386 (0%)
Hepatic enzyme increased	1/395 (0.3%)		0/386 (0%)
Multiple gated acquisition scan abnormal	1/395 (0.3%)		0/386 (0%)
Metabolism and nutrition disorders
Dehydration	2/395 (0.5%)		4/386 (1%)
Hyperglycaemia	3/395 (0.8%)		1/386 (0.3%)
Hypokalaemia	1/395 (0.3%)		3/386 (0.8%)
Diabetes mellitus inadequate control	0/395 (0%)		1/386 (0.3%)
Hypoglycaemia	1/395 (0.3%)		0/386 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/395 (0.3%)		1/386 (0.3%)
Arthralgia	0/395 (0%)		1/386 (0.3%)
Bone pain	1/395 (0.3%)		0/386 (0%)
Muscle atrophy	1/395 (0.3%)		0/386 (0%)
Myofascial pain syndrome	1/395 (0.3%)		0/386 (0%)
Osteoporosis	0/395 (0%)		1/386 (0.3%)
Spinal osteoarthritis	1/395 (0.3%)		0/386 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever	2/395 (0.5%)		0/386 (0%)
Gastrointestinal stromal tumour	1/395 (0.3%)		0/386 (0%)
Infected neoplasm	1/395 (0.3%)		0/386 (0%)
Thyroid cancer	1/395 (0.3%)		0/386 (0%)
Nervous system disorders
Headache	2/395 (0.5%)		3/386 (0.8%)
Syncope	0/395 (0%)		4/386 (1%)
Cerebrovascular accident	1/395 (0.3%)		2/386 (0.5%)
Convulsion	2/395 (0.5%)		0/386 (0%)
Dizziness	2/395 (0.5%)		0/386 (0%)
Transient ischaemic attack	1/395 (0.3%)		1/386 (0.3%)
Extrapyramidal disorder	0/395 (0%)		1/386 (0.3%)
Haemorrhage intracranial	0/395 (0%)		1/386 (0.3%)
Lethargy	1/395 (0.3%)		0/386 (0%)
Loss of consciousness	0/395 (0%)		1/386 (0.3%)
Nervous system disorder	0/395 (0%)		1/386 (0.3%)
Neuralgia	1/395 (0.3%)		0/386 (0%)
Partial seizures	0/395 (0%)		1/386 (0.3%)
Peripheral motor neuropathy	0/395 (0%)		1/386 (0.3%)
Polyneuropathy	1/395 (0.3%)		0/386 (0%)
Psychiatric disorders
Confusional state	1/395 (0.3%)		0/386 (0%)
Major depression	1/395 (0.3%)		0/386 (0%)
Suicidal ideation	0/395 (0%)		1/386 (0.3%)
Suicide attempt	1/395 (0.3%)		0/386 (0%)
Renal and urinary disorders
Proteinuria	0/395 (0%)		1/386 (0.3%)
Renal colic	1/395 (0.3%)		0/386 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	4/395 (1%)		4/386 (1%)
Dyspnoea	4/395 (1%)		3/386 (0.8%)
Interstitial lung disease	3/395 (0.8%)		2/386 (0.5%)
Lung disorder	1/395 (0.3%)		1/386 (0.3%)
Pneumonitis	1/395 (0.3%)		1/386 (0.3%)
Acute pulmonary oedema	1/395 (0.3%)		0/386 (0%)
Acute respiratory distress syndrome	0/395 (0%)		1/386 (0.3%)
Bronchiectasis	1/395 (0.3%)		0/386 (0%)
Bronchospasm	0/395 (0%)		1/386 (0.3%)
Cough	1/395 (0.3%)		0/386 (0%)
Haemoptysis	1/395 (0.3%)		0/386 (0%)
Organising pneumonia	0/395 (0%)		1/386 (0.3%)
Pleural effusion	0/395 (0%)		1/386 (0.3%)
Pleuritic pain	0/395 (0%)		1/386 (0.3%)
Pulmonary oedema	1/395 (0.3%)		0/386 (0%)
Respiratory failure	1/395 (0.3%)		0/386 (0%)
Skin and subcutaneous tissue disorders
Hidradenitis	1/395 (0.3%)		0/386 (0%)
Skin ulcer	1/395 (0.3%)		0/386 (0%)
Vascular disorders
Hypertension	6/395 (1.5%)		1/386 (0.3%)
Deep vein thrombosis	2/395 (0.5%)		4/386 (1%)
Hypertensive crisis	2/395 (0.5%)		0/386 (0%)
Circulatory collapse	0/395 (0%)		1/386 (0.3%)
Haematoma	1/395 (0.3%)		0/386 (0%)
Jugular vein thrombosis	0/395 (0%)		1/386 (0.3%)
Shock haemorrhagic	1/395 (0.3%)		0/386 (0%)
Thrombosis	1/395 (0.3%)		0/386 (0%)
Other (Not Including Serious) Adverse Events
	Bevacizumab + Rituximab + CHOP		Placebo + Rituximab + CHOP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	346/395 (87.6%)		331/386 (85.8%)
Blood and lymphatic system disorders
Neutropenia	88/395 (22.3%)		119/386 (30.8%)
Anaemia	66/395 (16.7%)		96/386 (24.9%)
Leukopenia	42/395 (10.6%)		49/386 (12.7%)
Thrombocytopenia	24/395 (6.1%)		30/386 (7.8%)
Gastrointestinal disorders
Nausea	107/395 (27.1%)		106/386 (27.5%)
Diarrhoea	95/395 (24.1%)		81/386 (21%)
Constipation	88/395 (22.3%)		70/386 (18.1%)
Vomiting	56/395 (14.2%)		70/386 (18.1%)
Stomatitis	33/395 (8.4%)		36/386 (9.3%)
Dyspepsia	23/395 (5.8%)		35/386 (9.1%)
Abdominal pain	32/395 (8.1%)		25/386 (6.5%)
Abdominal pain upper	17/395 (4.3%)		32/386 (8.3%)
Haemorrhoids	23/395 (5.8%)		12/386 (3.1%)
General disorders
Fatigue	71/395 (18%)		71/386 (18.4%)
Pyrexia	71/395 (18%)		55/386 (14.2%)
Asthenia	59/395 (14.9%)		60/386 (15.5%)
Mucosal inflammation	61/395 (15.4%)		45/386 (11.7%)
Oedema peripheral	24/395 (6.1%)		29/386 (7.5%)
Infections and infestations
Nasopharyngitis	30/395 (7.6%)		22/386 (5.7%)
Urinary tract infection	24/395 (6.1%)		23/386 (6%)
Upper respiratory tract infection	25/395 (6.3%)		17/386 (4.4%)
Investigations
Weight decreased	24/395 (6.1%)		21/386 (5.4%)
Metabolism and nutrition disorders
Decreased appetite	60/395 (15.2%)		46/386 (11.9%)
Hypokalaemia	21/395 (5.3%)		17/386 (4.4%)
Musculoskeletal and connective tissue disorders
Back pain	37/395 (9.4%)		37/386 (9.6%)
Arthralgia	35/395 (8.9%)		19/386 (4.9%)
Pain in extremity	22/395 (5.6%)		19/386 (4.9%)
Bone pain	23/395 (5.8%)		17/386 (4.4%)
Nervous system disorders
Headache	59/395 (14.9%)		59/386 (15.3%)
Neuropathy peripheral	38/395 (9.6%)		38/386 (9.8%)
Paraesthesia	42/395 (10.6%)		31/386 (8%)
Peripheral sensory neuropathy	25/395 (6.3%)		28/386 (7.3%)
Dizziness	24/395 (6.1%)		21/386 (5.4%)
Psychiatric disorders
Insomnia	29/395 (7.3%)		30/386 (7.8%)
Respiratory, thoracic and mediastinal disorders
Cough	52/395 (13.2%)		43/386 (11.1%)
Epistaxis	47/395 (11.9%)		10/386 (2.6%)
Dyspnoea	19/395 (4.8%)		27/386 (7%)
Oropharyngeal pain	27/395 (6.8%)		19/386 (4.9%)
Rhinorrhoea	24/395 (6.1%)		14/386 (3.6%)
Dysphonia	29/395 (7.3%)		7/386 (1.8%)
Skin and subcutaneous tissue disorders
Alopecia	96/395 (24.3%)		80/386 (20.7%)
Rash	22/395 (5.6%)		23/386 (6%)
Vascular disorders
Hypertension	54/395 (13.7%)		12/386 (3.1%)

Limitations/Caveats

Due to premature termination of the study, the efficacy results should be interpreted with caution.

More Information

Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.