A Study Of Inotuzumab Ozogamicin Plus Rituximab For Relapsed/Refractory Aggressive Non-Hodgkin Lymphoma Patients Who Are Not Candidates For Intensive High-Dose Chemotherapy

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01232556
• Collaborator: UCB Pharma (Industry)
• Enrollment: 338
• Locations: 177
• Arms: 2
• Actual Duration (Months): 35.8
• Patients Per Site: 1.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy of inotuzumab ozogamicin plus rituximab in relapsed/refractory aggressive Non-Hodgkin lymphoma patients who are not candidates for intensive high-dose chemotherapy. Specifically, the goal is to demonstrate the superiority of this combination compared with an active comparator arm (investigator's choice of rituximab+bendamustine or rituximab+gemcitabine) using the primary endpoint of overall survival.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Non-Hodgkin	Drug: Inotuzumab ozogamicin; Drug: Rituximab; Drug: rituximab + gemcitabine; Drug: rituximab +bendamustine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 338 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: AN OPEN-LABEL, RANDOMIZED, PHASE 3 STUDY OF INOTUZUMAB OZOGAMICIN ADMINISTERED IN COMBINATION WITH RITUXIMAB COMPARED TO DEFINED INVESTIGATOR'S CHOICE THERAPY IN SUBJECTS WITH RELAPSED OR REFRACTORY CD22-POSITIVE AGGRESSIVE NON-HODGKIN LYMPHOMA WHO ARE NOT CANDIDATES FOR INTENSIVE HIGH-DOSE CHEMOTHERAPY
• Actual Study Start Date: Apr 4, 2011
• Actual Primary Completion Date: Mar 28, 2014
• Actual Study Completion Date: Mar 28, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Inotuzumab ozogamicin+rituximab	Drug: Inotuzumab ozogamicin; 1.8 mg/m2 on day 2 every 28 days by IV infusion, 3 to 6 cycles; Other Names: CMC-544 ; Drug: Rituximab; 375 mg/m2 on day 1 every 28 days by IV infusion, 3 to 6 cycles
Active Comparator: 2 Investigator's choice of (1) rituximab+gemcitabine, or (2) rituximab+bendamustine	Drug: rituximab + gemcitabine; rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1, and day 1 of cycles 2 to 6, every 28 days by IV infusion, 3 to 6 cycles; gemcitabine 1000 mg/m2 on days 1, 8, and 15 every 28 days, 3 to 6 cycles; Drug: rituximab +bendamustine; rituximab 375 mg/m2 on day 1 every 28 days by IV infusion, 3 to 6 cycles; bendamustine 120 mg/m2 on days 1 and 2 by IV infusion every 28 days, 3 to 6 cycles

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From randomization up to 5 years after last dose or up to final study visit, whichever occurs first.]

   Overall Survival (OS) was defined as the time from randomization to death due to any cause, censoring at the date of last contact or the end of the study. The Kaplan-Meier method was used to determine OS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.

2. Percentage of Participants With a Treatment Emergent Adverse Event (TEAE) (Safety Population) [Up to 20 weeks after the first dose of study drug]

   Includes all TEAEs: Any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration..

Secondary Outcome Measures

1. Progression-Free Survival (PFS) [From randomization up to 2 years or final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.]

   PFS is defined as time from date of randomization to date of progressive disease (PD, including investigator's claim of clinical progression), date of death from any cause, or initiation of a new treatment for the lymphoma due to persistent/refractory disease. The Kaplan-Meier method was used to determine PFS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression. PD requires the following: Appearance of any new lesion more than 1.5 cm in any axis during or at the end of treatment, even if other lesions are decreasing in size. At least a 50% increase from nadir in the sum of the product diameters of any previously involved nodes, or in a single involved node, or the size of other lesions. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.

2. Percentage of Participants With A Best Overall Response of CR or Partial Response (PR) Per NCI International Response Criteria for NHL [Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.]

   CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment). Partial Response (PR) requires the following: ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. No new sites of disease. The 95% CI was determined using the exact method based on binomial distribution.

3. Percentage of Participants With A Best Overall Response of CR, Unconfirmed CR (unCR), PR, or Unconfirmed PR (unPR) Per NCI International Response Criteria for NHL [Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.]

   CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment). Partial Response (PR) requires the following: ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. No new sites of disease. unCR and unPR means didn't have confirmatory assessment (including bone marrow assessment for CR). The 95% CI was determined using the exact method based on binomial distribution.

4. Duration of Response [Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.]

   The duration of overall response is measured from the first date of response until the first date that the progressive disease (PD) or death is objectively documented. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.

5. Health Status as Assessed by the European Quality of Life 5 Dimension (EQ-5D) Questionnaire [Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported]

   EQ-5D consists of a descriptive system and an EQ visual analogue scale. The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. The scale, the best state is marked 100 and the worst state is marked 0, is to help the participant to say how good or bad a health state is. EQ-5D index, which was reported, was derived based on US weight. The range of EQ-5D index is -0.109 to 1.00. Higher scores mean better outcomes. The average post-baseline scores for EQ-5D index were computed at approximately Week 12. The overall treatment comparisons were estimated at approximately Week 12.

6. Health Related Quality of Life as Assessed by the Functional Assessment of Cancer Therapy for Lymphoma (FACT-Lym) Questionnaire [Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported]

   FACT-Lym is a questionnaire that begins with 27 items covering four core Health-Related Quality of Life subscales: Physical Well-being (7 items), Social/Family Well-being (7), Emotional Well-being (6), and Functional Well-being (7). The FACT-Lym also includes an additional concerns subscale (15 items). It also asks participants about their concerns about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. The participants were requested to circle one number on a 0 to 4 points scale per line to indicate how true each statement has been for him/her during the past 7 days. FACT-Lym total score, which was reported, was derived based on FACT-Lym scoring guideline (Version 4). The range of FACT-Lym total score is 0 to 168. Higher scores mean better outcomes. The average post-baseline FACT-Lym total scores were computed at approximately Week 12. The overall treatment comparisons were estimated at approximately Week 12.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Exclusion Criteria:

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Disney Family Cancer Center at Providence St Joseph Medical Center	Burbank	California	United States	91505
2	Providence St Joseph Medical Center	Burbank	California	United States	91505
3	Hematology-Oncology Medical Group of Fresno Inc	Fresno	California	United States	93720
4	Ronald Reagan UCLA Medical Center Drug Information Center Department of Pharmaceutical Services	Los Angeles	California	United States	90095-6981
5	Clinical Research Unit	Los Angeles	California	United States	90095
6	Peter Morton Medical Plaza	Los Angeles	California	United States	90095
7	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
8	Sansum Clinic	Santa Barbara	California	United States	93105
9	UCLA Santa Monica Hematology Oncology	Santa Monica	California	United States	90404
10	Sansum Clinic	Solvang	California	United States	93463
11	Howard University Hospital	Washington	District of Columbia	United States	20060
12	Mount Sinai Comprehensive Cancer Center at Aventura	Aventura	Florida	United States	33180
13	University Cancer Institute	Boynton Beach	Florida	United States	33426
14	21st Century Oncology of Jacksonville, LLC	Fernandina Beach	Florida	United States	32034
15	Davis Cancer Pavilion and Shands Medical Plaza	Gainesville	Florida	United States	32608
16	Shands Cancer Hospital at the University of Florida	Gainesville	Florida	United States	32608
17	UF Health Davis Cancer Pavillion and Shands Med Plaza	Gainesville	Florida	United States	32608
18	UF Health Shands Cancer Hospital	Gainesville	Florida	United States	32608
19	Shands Hospital at the University of Florida	Gainesville	Florida	United States	32610
20	UF Health Shands Hospital	Gainesville	Florida	United States	32610
21	21st Century Oncology of Jacksonville, LLC	Jacksonville	Florida	United States	32205
22	21st Century Oncology of Jacksonville, LLC	Jacksonville	Florida	United States	32207
23	Baptist Cancer Institute	Jacksonville	Florida	United States	32207
24	Baptist Medical Center	Jacksonville	Florida	United States	32207
25	21st Century Oncology of Jacksonville, LLC	Jacksonville	Florida	United States	32256
26	21st Century Oncology of Jacksonville, Inc.	Jacksonville	Florida	United States	32258
27	Medical Specialists Of The Palm Beaches	Lake Worth	Florida	United States	33467
28	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida	United States	33140
29	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
30	Advanced Medical Specialties	Miami	Florida	United States	33133
31	Mercy Hospital	Miami	Florida	United States	33133
32	Mercy Research Institute	Miami	Florida	United States	33133
33	21st Century Oncology of Jacksonville, LLC	Orange Park	Florida	United States	32073
34	Georgia Regents Medical Cancer Pharmacy	Augusta	Georgia	United States	30912
35	Georgia Regents University	Augusta	Georgia	United States	30912
36	Kootenai Cancer Center	Coeur d'Alene	Idaho	United States	83814
37	Kootenai Cancer Center	Post Falls	Idaho	United States	083854
38	Decatur Memorial Hospital (DMH)	Decatur	Illinois	United States	62526
39	Floyd Memorial Cancer Center of Indiana	New Albany	Indiana	United States	47150
40	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
41	University of Kansas Cancer Center and Medical Pavilion	Westwood	Kansas	United States	66205
42	University of Kentucky A.B. Chandler Medical Center	Lexington	Kentucky	United States	40536
43	University of Kentucky Markey Cancer Center	Lexington	Kentucky	United States	40536
44	Tulane University Hospital and Clinic	New Orleans	Louisiana	United States	70112
45	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
46	Barbara Ann Karmanos Cancer Institute at farmington Hills	Farmington Hills	Michigan	United States	48334
47	Park Nicollet Frauenshuh Cancer Center	Saint Louis Park	Minnesota	United States	55426
48	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
49	Washington University in St Louis	Saint Louis	Missouri	United States	63110
50	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
51	Washington University	Saint Louis	Missouri	United States	63110
52	Barnes-Jewish St. Peters	Saint Peters	Missouri	United States	63376
53	Southeast Nebraska Hematology & Oncology Consultants, P.C. d/b/a Southeast Nebraska Cancer Center	Lincoln	Nebraska	United States	68510
54	Beth Israel Medical Center;	New York	New York	United States	10003
55	Beth Israel Comprehensive Cancer Center	New York	New York	United States	10011-5903
56	St Luke's- Roosevelt Hospital Center	New York	New York	United States	10019
57	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
58	Stony Brook University Medical Center, The Cancer Center	Stony Brook	New York	United States	11794
59	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
60	University Hospital	Cincinnati	Ohio	United States	45219
61	West Chester Hospital Medical Building	West Chester	Ohio	United States	45069
62	OU Medical Center Presbyterian Professional Building	Oklahoma City	Oklahoma	United States	73104
63	OU Medical Center Presbyterian Tower	Oklahoma City	Oklahoma	United States	73104
64	Peggy and Charles Stephenson Cancer Center (chemo & infusion)	Oklahoma City	Oklahoma	United States	73104
65	Peggy and Charles Stephenson Cancer Center (clinic location)	Oklahoma City	Oklahoma	United States	73104
66	Good Samaritan Hospital Corvallis	Corvallis	Oregon	United States	97330
67	Good Samaritan Hospital, Corvallis	Corvallis	Oregon	United States	97330
68	Samaritan Ambulatory Infusion Services	Corvallis	Oregon	United States	97330
69	Samaritan Pacific Coast Hospital	Newport	Oregon	United States	97365
70	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033
71	Guthrie Clinic, Ltd.	Sayre	Pennsylvania	United States	18840
72	Robert Packer Hospital	Sayre	Pennsylvania	United States	18840
73	Thompson Oncology Group	Knoxville	Tennessee	United States	37916
74	Thompson Oncology Group	Knoxville	Tennessee	United States	37932
75	Thompson Oncology Group	Maryville	Tennessee	United States	37804
76	Thompson Oncology Group	Sevierville	Tennessee	United States	37862
77	University Hospital - St. Paul	Dallas	Texas	United States	75235
78	University Hospital - Zale Lipshy	Dallas	Texas	United States	75235
79	Baylor University Medical Center	Dallas	Texas	United States	75246
80	Baylor: Charles A. Sammons Cancer Center	Dallas	Texas	United States	75246
81	Simmons Comprehensive Cancer Center	Dallas	Texas	United States	75390
82	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
83	Universitaire Ziekenhuizen Leuven	Leuven	Vlaams Brabant	Belgium	3000
84	Institut Jules Bordet	Bruxelles		Belgium	1000
85	Grand Hopital de Charleroi	Charleroi		Belgium	6000
86	H.-Hartziekenhuis Roeselare-Menen	Roeselare		Belgium	8800
87	St Augustinus Ziekenhuis	Wilrijk		Belgium	2610
88	Cliniques universitaires UCL de Mont-Godinne,	Yvoir		Belgium	5530
89	UMBAL Sveti Georgi, Klinika po hematologia	Plovdiv		Bulgaria	4002
90	SBAL na Hematologichnichni Zabolyavania,CTH Sofia	Sofia		Bulgaria	1756
91	Spetsializirana Bolnitsa za Aktivno Lechenie na Hematologichni Zabolyavania, CTH Sofia	Sofia		Bulgaria	1756
92	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
93	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
94	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3 M5
95	Centre Hospitalier Universitaire de Sherbrooke (CHUS), Hopital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
96	University Hospital Zagreb	Zagreb		Croatia	10000
97	University Hospital Dubrava Department of Internal Medicine Division of Hematology	Zagreb		Croatia	10010
98	Fakultni nemocnice Kralovske Vinohrady	Praha 10	Czech Republic	Czechia	100 34
99	Fakultni nemocnice Brno	Brno		Czechia	62500
100	Département Pharmacie	Marseille	Bouches-du-rhône	France	Cedex 09 13273
101	Institut Paoli Calmettes	Marseille	Cedex 09	France	13273
102	Hospital Universitaire Andre Mignot	Le Chesnay Cedex	Yvelines	France	78157
103	Hopital Andre Mignot	Le Chesnay	Yvelines	France	78157
104	Centre Leon Berard	Lyon		France	69373
105	CHU Saint Eloi	Montpellier		France	34295Cedex5
106	Hopital du haut Leveque	Pessac		France	33600
107	Centre Henri Becquerel	Rouen		France	76038
108	Universitaetsklinikum Aachen	Aachen		Germany	52074
109	Sozialstiftung Bamberg	Bamberg		Germany	96049
110	Charite Campus Benjamin Franklin	Berlin		Germany	10117
111	Charite Campus Virchow-Klinikum	Berlin		Germany	13353
112	Universitaetsklinikum Mainz	Mainz		Germany	55101
113	TU Muenchen III. Medizinische Klinik	Muenchen		Germany	81675
114	Universitaetsklinik Ulm	Ulm		Germany	89081
115	Egyesitett Szent Istvan es Szent Laszlo Korhaz /	Budapest		Hungary	1097
116	DEOEC, Belgyogyaszati Intezet	Debrechen		Hungary	4032
117	Somongy Megyei Kaposi Mor Okato Korhaz/ Belgyogyaszati osztaly	Kaposvar		Hungary	7400
118	Kodlikeri Memorial Hospital	Aurangabad	Maharashtra	India	431 005
119	Sahyadri Clinical Research and Development Center	Pune	Maharashtra	India	411 004
120	OEC Record Management Company Pvt. Ltd.,	Pune	Maharashtra	India	411004
121	Sahyadri Speciality Hospital	Pune	Maharashtra	India	411004
122	Bon Secours Hospital	Cork		Ireland
123	Nagoya Daini Red Cross Hospital	Nagoya	Aichi	Japan	4668650
124	National Cancer Center Hospital East	Kashiwa	Chiba	Japan	277-8577
125	Ehime University Hospital	Toon-shi	Ehime	Japan	791-0295
126	Gunma University Hospital	Maebashi-city	Gunma	Japan	371-8511
127	Tohoku University Hospital	Sendai	Miyagi	Japan	980-8574
128	Matsushita Memorial Hospital	Moriguchi	Osaka	Japan	570-8540
129	Shizuoka Cancer Center	Sunto-gun	Shizuoka	Japan	411-8777
130	National Cancer Center Hospital	Chuo-ku	Tokyo	Japan	104-0045
131	Cancer Institute Hospital, Japanese Foundation For Cancer Research	Koto-Ku	Tokyo	Japan	135-8550
132	Akita University Hospital	Akita		Japan	010-8543
133	National Kyushu Cancer Center	Fukuoka		Japan	811-1395
134	Tokai University Hospital	Kanagawa		Japan	259-1193
135	University Hospital, Kyoto Prefectural University of Medicine	Kyoto		Japan	602-8566
136	Klaipeda Seamen's Hospital, Public Institution, department of Oncology	Klaipeda		Lithuania	92288
137	Instituto Biomédico de Investigación A.C.	Aguascalientes	Aguascalientes. Mexico	Mexico	20127
138	Niepubliczny Zaklad Opieki Zdrowotnej AVI Diagnostyka Obrazowa	Warszawa		Poland	00-728
139	Klinika Nowotworow Ukladu Chlonnego	Warszawa		Poland	02-781
140	Advanced Infusion Services	Catano		Puerto Rico	00962
141	Hospital Espanol Auxilio Mutuo de Puerto Rico Inc	San Juan		Puerto Rico	00918
142	Federal State Budgetary Institution Hematology Scientific Centre of Ministry of	Moscow		Russian Federation	125167
143	Moscow State Healthcare Institution City clinical hospital S.P. Botkin	Moscow		Russian Federation	125284
144	Institute of Pediatric Hematology and Transplantology R.M.Gorbacheva	Saint-Petersburg		Russian Federation	197022
145	National University Hospital	Singapore		Singapore	119074
146	Singapore General Hospital	Singapore		Singapore	169608
147	Narodny onkologicky ustav	Bratislava		Slovakia	833 10
148	Hospital Virgen Del Rocio	Sevilla	Andalucia	Spain	41013
149	Hospital Universitario De Salamanca	Salamanca	Castille AND LION	Spain	37007
150	Hospital Clinic de Barcelona	Barcelona		Spain	08036
151	Hospital Clinic Universitari de Barcelona	Barcelona		Spain	08036
152	Institut Catala d'Oncologia-L'Hospitalet	L'Hospitalet De Llobregat (bcn)		Spain	08907
153	Hospital Universitario de Canarias	La Laguna (Tenerife)		Spain	38320
154	Hospital de la Princesa	Madrid		Spain	28006
155	Universitetssjukhuset	Linkoping		Sweden	58185
156	Skanes Universitetssjukhus i Lund	Lund		Sweden	221 85
157	Chang Gung Medical Foundation - Linkou Branch	Kuei-Shan Hsiang	Taoyuan County	Taiwan	333
158	Taichung Veterans General Hospital	Taichung		Taiwan	40705
159	National Taiwan University Hospital, Department of Internal Medicine	Taipei		Taiwan	100
160	Taipei Veterans General Hospital	Taipei		Taiwan	11217
161	Hematology Division Department of Medicine Faculty of Medicine Siriraj Hospital Mahidol University	Bangkoknoi	Bangkok	Thailand	10700
162	Chiang Mai University	Chiang Mai		Thailand	50200
163	Regional Treatment and Diagnostic Hematology Center Communal Establishment	Cherkasy		Ukraine	18009
164	Department of Oncology and Medical Radiology of State Institution	Dnipropetrovsk		Ukraine	49102
165	SI"Research Center for Radiation Medicine of NAMS of Ukraine"	Kyiv		Ukraine	03115
166	Barts Cancer Centre Dept Haemato-oncology St. Bartholomew's Hospital Barts Health NHS Trust	London		United Kingdom	EC1A 7BE
167	Chemotherapy Preparative Unit St. Bartholomew's Hospital	London		United Kingdom	EC1A 7BE
168	Department of Medical Oncology St. Bartholomew's Hospital	London		United Kingdom	EC1A 7BE
169	The Christie NHS Foundation Trust - Christie Hospital	Manchester		United Kingdom	M20 4BX
170	Department of Clinical Pathology Newcastle upon Tyne Hospitals NHS Foundation Trust Royal Victoria I	Newcastle upon Tyne		United Kingdom	NE1 4LP
171	Department of Clinical Biochemistry Newcastle upon Tyne Hospitals	Newcastle upon Tyne		United Kingdom	NE7 7DN
172	Northern Centre for Cancer Care	Newcastle upon Tyne		United Kingdom	NE7 7DN
173	Nottingham University Hospital	Nottingham		United Kingdom	NG5 1PB
174	Pathology Department Nottingham University Hospital - City Hospital Campus	Nottingham		United Kingdom	NG5 1PB
175	Pharmacy Nottingham University Hospital - City Hospital Campus	Nottingham		United Kingdom	NG5 1PB
176	Local Laboratory Nottingham University Hospital - City Hospital Campus	Nottingham		United Kingdom	NG51PB
177	New Cross Hospital	Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Pfizer
• UCB Pharma

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01232556
• Other Study ID Numbers: B1931008; 3129K5-3303; 2010-020147-12
• First Posted: Nov 2, 2010
• Last Update Posted: Jan 8, 2019
• Last Verified: Dec 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Pfizer: inotuzumab ozogamicin; aggressive Non-Hodgkin lymphoma; diffuse large b-cell lymphoma; relapsed/refractory lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Aggression; Gemcitabine; Rituximab; Inotuzumab Ozogamicin; Bendamustine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Inotuzumab Ozogamicin Plus (+) Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) via intravenous (IV) infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Period Title: Overall Study
STARTED	166	172
Treated	165	167
COMPLETED	7	1
NOT COMPLETED	159	171

Baseline Characteristics

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine	Total
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.	Total of all reporting groups
Overall Participants	166	172	338
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	68.6 (12.29)	66.9 (11.40)	67.7 (11.86)
Sex: Female, Male (Count of Participants)
Female	75 45.2%	75 43.6%	150 44.4%
Male	91 54.8%	97 56.4%	188 55.6%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was defined as the time from randomization to death due to any cause, censoring at the date of last contact or the end of the study. The Kaplan-Meier method was used to determine OS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time Frame	From randomization up to 5 years after last dose or up to final study visit, whichever occurs first.

Outcome Measure Data

Analysis Population Description

ITT Population.

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	166	172
Median (95% Confidence Interval) [Months]	9.5	9.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
	Comments	Primary null hypothesis: Equality of survival distributions. Sample size sufficient to have power 0.96 for an experimental/control hazard ratio of 0.6.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.708
	Comments	A one sided 0.025 level testing plan was specified with two interim analyses and final testing level at one-sided 0.023.
	Method	Log Rank
	Comments	From one sided stratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.083
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.44
	Parameter Dispersion	Type: Value:
	Estimation Comments	From stratified Cox proportional hazards model. The stratification factors are are pre-randomization investigator choice, baseline Secondary International Prognostic Index (sIPI), and best response to most recent chemo therapy.

2. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS is defined as time from date of randomization to date of progressive disease (PD, including investigator's claim of clinical progression), date of death from any cause, or initiation of a new treatment for the lymphoma due to persistent/refractory disease. The Kaplan-Meier method was used to determine PFS. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression. PD requires the following: Appearance of any new lesion more than 1.5 cm in any axis during or at the end of treatment, even if other lesions are decreasing in size. At least a 50% increase from nadir in the sum of the product diameters of any previously involved nodes, or in a single involved node, or the size of other lesions. At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.
Time Frame	From randomization up to 2 years or final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	166	172
Median (95% Confidence Interval) [Months]	3.7	3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
	Comments	Second comparison in hierarchical testing strategy was used for power calculation.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.271
	Comments	An hierarchical testing strategy was specified for OS, PFS and response. PFS could be tested at the 0.023 level if the OS test result were positive. Response could be tested if both the OS and PFS test results were positive.
	Method	Log Rank
	Comments	From one sided stratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.924
	Confidence Interval	(2-Sided) 95%; 0.72 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments	From stratified Cox proportional hazards model. The stratification factors are are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.

3. Secondary Outcome

Title	Percentage of Participants With A Best Overall Response of CR or Partial Response (PR) Per NCI International Response Criteria for NHL
Description	CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment). Partial Response (PR) requires the following: ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. No new sites of disease. The 95% CI was determined using the exact method based on binomial distribution.
Time Frame	Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	166	172
Number (95% Confidence Interval) [Percentage of Participants]	29.5 17.8%	29.7 17.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
	Comments	Third comparison in hierarchical testing strategy was used for power calculation.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.843
	Comments	An hierarchical testing strategy was specified for OS, PFS and response. PFS could be tested at the 0.023 level if the OS test result were positive. Response could be tested if both the OS and PFS test results were positive.
	Method	Cochran-Mantel-Haenszel
	Comments	The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.

4. Secondary Outcome

Title	Percentage of Participants With A Best Overall Response of CR, Unconfirmed CR (unCR), PR, or Unconfirmed PR (unPR) Per NCI International Response Criteria for NHL
Description	CR is defined as disappearance of all detectable clinical evidence of disease (including cleared infiltrate on repeat bone marrow aspirate/biopsy if lymphoma involvement of bone marrow before treatment). Partial Response (PR) requires the following: ≥50 % decrease in SPD of the six largest dominant nodes or nodal masses. No increase in the size of other nodes, liver, or spleen. Splenic and hepatic nodules must regress by ≥50% in the SPD, or for single nodules, in the greatest transverse diameter. With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present. No new sites of disease. unCR and unPR means didn't have confirmatory assessment (including bone marrow assessment for CR). The 95% CI was determined using the exact method based on binomial distribution.
Time Frame	Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	166	172
Number (95% Confidence Interval) [Percentage of Participants]	41.0 24.7%	43.6 25.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
	Comments	Third comparison in hierarchical testing strategy was used for power calculation.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.714
	Comments	An hierarchical testing strategy was specified for OS, PFS and response. PFS could be tested at the 0.023 level if the OS test result were positive. Response could be tested if both the OS and PFS test results were positive.
	Method	Cochran-Mantel-Haenszel
	Comments	The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.

5. Secondary Outcome

Title	Duration of Response
Description	The duration of overall response is measured from the first date of response until the first date that the progressive disease (PD) or death is objectively documented. The hazard ratio and corresponding 95% 2-sided confidence interval were calculated using stratified Cox proportional hazard regression.
Time Frame	Up to 2 years from first study drug dose or up to final study visit, whichever occurs first, including but not limited to planned assessments scheduled approximately every 12 weeks.

Outcome Measure Data

Analysis Population Description

ITT population; only participants with a CR, unCR, PR, or unPR were included in the analysis

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	166	172
Median (95% Confidence Interval) [Months]	11.56	6.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
	Comments	DOR was not part of the formal hypothesis testing strategy.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.142
	Comments
	Method	Log Rank
	Comments	From one sided stratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	From stratified Cox proportional hazards model. The stratification factors are pre-randomization investigator choice, baseline sIPI, and best response to most recent chemo therapy.

6. Secondary Outcome

Title	Health Status as Assessed by the European Quality of Life 5 Dimension (EQ-5D) Questionnaire
Description	EQ-5D consists of a descriptive system and an EQ visual analogue scale. The descriptive system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. The scale, the best state is marked 100 and the worst state is marked 0, is to help the participant to say how good or bad a health state is. EQ-5D index, which was reported, was derived based on US weight. The range of EQ-5D index is -0.109 to 1.00. Higher scores mean better outcomes. The average post-baseline scores for EQ-5D index were computed at approximately Week 12. The overall treatment comparisons were estimated at approximately Week 12.
Time Frame	Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	166	172
Mean (95% Confidence Interval) [Unit on a scale]	0.79	0.77

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2892
	Comments
	Method	Mixed Models Analysis
	Comments	Repeated measures mixed effects model with treatment, time, treatment-by-time interaction, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Health Related Quality of Life as Assessed by the Functional Assessment of Cancer Therapy for Lymphoma (FACT-Lym) Questionnaire
Description	FACT-Lym is a questionnaire that begins with 27 items covering four core Health-Related Quality of Life subscales: Physical Well-being (7 items), Social/Family Well-being (7), Emotional Well-being (6), and Functional Well-being (7). The FACT-Lym also includes an additional concerns subscale (15 items). It also asks participants about their concerns about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. The participants were requested to circle one number on a 0 to 4 points scale per line to indicate how true each statement has been for him/her during the past 7 days. FACT-Lym total score, which was reported, was derived based on FACT-Lym scoring guideline (Version 4). The range of FACT-Lym total score is 0 to 168. Higher scores mean better outcomes. The average post-baseline FACT-Lym total scores were computed at approximately Week 12. The overall treatment comparisons were estimated at approximately Week 12.
Time Frame	Assessed at Day 1 of each cycle and 6-9 weeks after the last dose, Cycle 3 (Week 12) reported

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	166	172
Mean (95% Confidence Interval) [Unit on a scale]	120.07	116.96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inotuzumab Ozogamicin+Rituximab, Rituximab+Gemcitabine or Rituximab+Bendamustine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1879
	Comments
	Method	Mixed Models Analysis
	Comments	Repeated measures mixed effects model with treatment, time, treatment-by-time interaction, and baseline as covariate.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.11
	Confidence Interval	(2-Sided) 95%; -1.52 to 7.74
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Primary Outcome

Title	Percentage of Participants With a Treatment Emergent Adverse Event (TEAE) (Safety Population)
Description	Includes all TEAEs: Any event that occurred after the first dose of study drug and was not present prior to study drug administration or worsened in severity after study drug administration..
Time Frame	Up to 20 weeks after the first dose of study drug

Outcome Measure Data

Analysis Population Description

Safety Population - included all participants who received at least 1 dose of test article (either inotuzumab ozogamicin administrated in combination with rituximab or investigator's choice). This population only excluded participants who never received any test article.

Arm/Group Title	Inotuzumab Ozogamicin+Rituximab	Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.	Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
Measure Participants	164	167
% participants with a TEAE	98.8 59.5%	100.0 58.1%
% participants with serious TEAE	37.2 22.4%	37.7 21.9%
% participants with Grade 3 or 4 TEAE	79.9 48.1%	79.6 46.3%
% participants with Grade 5 TEAE	14.6 8.8%	13.8 8%
% participants for study drug discontinuation	25.0 15.1%	18.0 10.5%
% participants with dose reductions due to TEAEs	27.4 16.5%	29.3 17%
% participants for study drug stopped temporarily	31.1 18.7%	46.1 26.8%

Adverse Events

Time Frame	Up to 22 weeks after the informed consent
Adverse Event Reporting Description	Adverse Events calculated using safety population. One subject in the rituximab+ inotuzumab ozogamicin arm received rituximab only, and was excluded from the safety population analysis. AE summaries below are inclusive of AEs from first dose date up to 56 days after last dose of study drug.
Arm/Group Title	Inotuzumab Ozogamicin+Rituximab		Rituximab+Gemcitabine or Rituximab+Bendamustine
Arm/Group Description	Participants received rituximab 375 mg/m^2 via IV infusion on Day 1 and inotuzumab ozogamicin 1.8 mg/m^2 via IV infusion on Day 2 of each 28-day cycle for a maximum of 6 cycles.		Participants received either R-bendamustine (rituximab 375 mg/m^2 via IV infusion on Day 1 and bendamustine 120 mg/m^2 via IV infusion on Days 1 and 2 in 28-day cycles for a maximum of 6 cycles) or R-gemcitabine (rituximab 375 mg/m^2 via IV infusion on Days 1, 8, 15 and 22 of Cycle 1 and on Day 1 for all other cycles, and gemcitabine 1000 mg/m^2 via IV infusion on Days 1, 8 and 15 of each 28-day cycle for a maximum of 6 cycles). Choice of therapy was at the discretion of the investigator.
All Cause Mortality
	Inotuzumab Ozogamicin+Rituximab		Rituximab+Gemcitabine or Rituximab+Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Inotuzumab Ozogamicin+Rituximab		Rituximab+Gemcitabine or Rituximab+Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/164 (37.2%)		63/167 (37.7%)
Blood and lymphatic system disorders
Anaemia	0/164 (0%)		1/167 (0.6%)
Febrile bone marrow aplasia	0/164 (0%)		1/167 (0.6%)
Febrile neutropenia	5/164 (3%)		7/167 (4.2%)
Neutropenia	0/164 (0%)		1/167 (0.6%)
Pancytopenia	1/164 (0.6%)		1/167 (0.6%)
Splenic infarction	0/164 (0%)		1/167 (0.6%)
Thrombocytopenia	2/164 (1.2%)		2/167 (1.2%)
Cardiac disorders
Angina unstable	0/164 (0%)		1/167 (0.6%)
Atrial fibrillation	2/164 (1.2%)		0/167 (0%)
Atrial flutter	0/164 (0%)		1/167 (0.6%)
Atrial tachycardia	0/164 (0%)		1/167 (0.6%)
Myocardial infarction	0/164 (0%)		1/167 (0.6%)
Sinus tachycardia	0/164 (0%)		1/167 (0.6%)
Gastrointestinal disorders
Abdominal pain	1/164 (0.6%)		1/167 (0.6%)
Abdominal wall haematoma	0/164 (0%)		1/167 (0.6%)
Colitis ulcerative	1/164 (0.6%)		0/167 (0%)
Diarrhoea	0/164 (0%)		2/167 (1.2%)
Dysphagia	1/164 (0.6%)		1/167 (0.6%)
Enteritis	0/164 (0%)		1/167 (0.6%)
Gastrointestinal haemorrhage	2/164 (1.2%)		0/167 (0%)
Ileus	1/164 (0.6%)		1/167 (0.6%)
Intestinal obstruction	0/164 (0%)		1/167 (0.6%)
Nausea	0/164 (0%)		1/167 (0.6%)
Pancreatitis acute	1/164 (0.6%)		0/167 (0%)
Small intestinal obstruction	1/164 (0.6%)		0/167 (0%)
Vomiting	0/164 (0%)		1/167 (0.6%)
General disorders
Asthenia	3/164 (1.8%)		2/167 (1.2%)
Disease progression	15/164 (9.1%)		20/167 (12%)
Fatigue	1/164 (0.6%)		1/167 (0.6%)
General physical health deterioration	1/164 (0.6%)		0/167 (0%)
Oedema due to hepatic disease	1/164 (0.6%)		0/167 (0%)
Pain	1/164 (0.6%)		0/167 (0%)
Pyrexia	5/164 (3%)		4/167 (2.4%)
Sudden death	0/164 (0%)		1/167 (0.6%)
Hepatobiliary disorders
Hepatitis	1/164 (0.6%)		0/167 (0%)
Hepatitis acute	1/164 (0.6%)		0/167 (0%)
Hyperbilirubinaemia	1/164 (0.6%)		0/167 (0%)
Venoocclusive liver disease	2/164 (1.2%)		0/167 (0%)
Infections and infestations
Bacteraemia	0/164 (0%)		1/167 (0.6%)
Bronchitis	1/164 (0.6%)		0/167 (0%)
Cellulitis	0/164 (0%)		2/167 (1.2%)
Clostridium difficile colitis	1/164 (0.6%)		0/167 (0%)
Clostridium difficile infection	1/164 (0.6%)		0/167 (0%)
Cytomegalovirus infection	0/164 (0%)		1/167 (0.6%)
Cytomegalovirus viraemia	0/164 (0%)		1/167 (0.6%)
Device related infection	1/164 (0.6%)		1/167 (0.6%)
Gastroenteritis viral	0/164 (0%)		1/167 (0.6%)
Infection	1/164 (0.6%)		1/167 (0.6%)
Infectious pleural effusion	1/164 (0.6%)		0/167 (0%)
Influenza	2/164 (1.2%)		0/167 (0%)
Lung infection	0/164 (0%)		1/167 (0.6%)
Meningitis	0/164 (0%)		1/167 (0.6%)
Oesophageal candidiasis	0/164 (0%)		1/167 (0.6%)
Oral candidiasis	0/164 (0%)		1/167 (0.6%)
Pneumocystis jirovecii pneumonia	0/164 (0%)		1/167 (0.6%)
Pneumonia	8/164 (4.9%)		1/167 (0.6%)
Pneumonia fungal	0/164 (0%)		1/167 (0.6%)
Pyelonephritis	1/164 (0.6%)		0/167 (0%)
Respiratory tract infection	1/164 (0.6%)		0/167 (0%)
Salmonella sepsis	0/164 (0%)		1/167 (0.6%)
Sepsis	1/164 (0.6%)		2/167 (1.2%)
Sinusitis	1/164 (0.6%)		0/167 (0%)
Staphylococcal infection	1/164 (0.6%)		1/167 (0.6%)
Staphylococcal sepsis	0/164 (0%)		1/167 (0.6%)
Staphylococcal skin infection	1/164 (0.6%)		0/167 (0%)
Streptococcal bacteraemia	1/164 (0.6%)		0/167 (0%)
Upper respiratory tract infection	0/164 (0%)		1/167 (0.6%)
Urinary tract infection	2/164 (1.2%)		2/167 (1.2%)
Viral infection	0/164 (0%)		1/167 (0.6%)
Viral upper respiratory tract infection	1/164 (0.6%)		0/167 (0%)
Injury, poisoning and procedural complications
Fall	1/164 (0.6%)		0/167 (0%)
Femoral neck fracture	0/164 (0%)		1/167 (0.6%)
Infusion related reaction	1/164 (0.6%)		0/167 (0%)
Overdose	0/164 (0%)		1/167 (0.6%)
Spinal fracture	0/164 (0%)		2/167 (1.2%)
Transfusion reaction	1/164 (0.6%)		0/167 (0%)
Investigations
Alanine aminotransferase increased	2/164 (1.2%)		0/167 (0%)
Aspartate aminotransferase increased	2/164 (1.2%)		0/167 (0%)
Blood bilirubin increased	1/164 (0.6%)		0/167 (0%)
Metabolism and nutrition disorders
Decreased appetite	2/164 (1.2%)		2/167 (1.2%)
Dehydration	3/164 (1.8%)		0/167 (0%)
Hypercalcaemia	3/164 (1.8%)		1/167 (0.6%)
Hyperkalaemia	0/164 (0%)		1/167 (0.6%)
Hyperuricaemia	0/164 (0%)		1/167 (0.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/164 (0.6%)		0/167 (0%)
Back pain	0/164 (0%)		1/167 (0.6%)
Groin pain	1/164 (0.6%)		0/167 (0%)
Muscular weakness	1/164 (0.6%)		0/167 (0%)
Pain in extremity	0/164 (0%)		1/167 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphoma	1/164 (0.6%)		0/167 (0%)
Myelodysplastic syndrome transformation	1/164 (0.6%)		0/167 (0%)
Prostate cancer	0/164 (0%)		1/167 (0.6%)
Nervous system disorders
Carotid artery stenosis	0/164 (0%)		1/167 (0.6%)
Cognitive disorder	1/164 (0.6%)		0/167 (0%)
Depressed level of consciousness	0/164 (0%)		1/167 (0.6%)
Dizziness	1/164 (0.6%)		0/167 (0%)
Dysarthria	0/164 (0%)		1/167 (0.6%)
IIIrd nerve paralysis	0/164 (0%)		1/167 (0.6%)
Paraplegia	1/164 (0.6%)		0/167 (0%)
Presyncope	1/164 (0.6%)		1/167 (0.6%)
Syncope	0/164 (0%)		1/167 (0.6%)
Tremor	0/164 (0%)		1/167 (0.6%)
VIIth nerve paralysis	0/164 (0%)		1/167 (0.6%)
Psychiatric disorders
Confusional state	0/164 (0%)		1/167 (0.6%)
Delirium febrile	1/164 (0.6%)		0/167 (0%)
Mental status changes	0/164 (0%)		1/167 (0.6%)
Suicide attempt	0/164 (0%)		1/167 (0.6%)
Renal and urinary disorders
Haematuria	0/164 (0%)		1/167 (0.6%)
Renal failure	2/164 (1.2%)		2/167 (1.2%)
Renal failure acute	0/164 (0%)		1/167 (0.6%)
Renal impairment	0/164 (0%)		1/167 (0.6%)
Urinary retention	1/164 (0.6%)		0/167 (0%)
Urinary tract obstruction	0/164 (0%)		1/167 (0.6%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/164 (0.6%)		0/167 (0%)
Cough	1/164 (0.6%)		0/167 (0%)
Dyspnoea	1/164 (0.6%)		3/167 (1.8%)
Pneumonitis	0/164 (0%)		1/167 (0.6%)
Pulmonary embolism	0/164 (0%)		1/167 (0.6%)
Vascular disorders
Haematoma	1/164 (0.6%)		0/167 (0%)
Hypotension	0/164 (0%)		3/167 (1.8%)
Other (Not Including Serious) Adverse Events
	Inotuzumab Ozogamicin+Rituximab		Rituximab+Gemcitabine or Rituximab+Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	155/164 (94.5%)		158/167 (94.6%)
Blood and lymphatic system disorders
Anaemia	24/164 (14.6%)		43/167 (25.7%)
Leukopenia	37/164 (22.6%)		54/167 (32.3%)
Lymphopenia	28/164 (17.1%)		39/167 (23.4%)
Neutropenia	57/164 (34.8%)		81/167 (48.5%)
Thrombocytopenia	101/164 (61.6%)		64/167 (38.3%)
Gastrointestinal disorders
Abdominal pain	14/164 (8.5%)		13/167 (7.8%)
Constipation	38/164 (23.2%)		33/167 (19.8%)
Diarrhoea	22/164 (13.4%)		31/167 (18.6%)
Nausea	50/164 (30.5%)		54/167 (32.3%)
Vomiting	23/164 (14%)		32/167 (19.2%)
General disorders
Asthenia	13/164 (7.9%)		14/167 (8.4%)
Chills	5/164 (3%)		9/167 (5.4%)
Fatigue	55/164 (33.5%)		42/167 (25.1%)
Oedema peripheral	17/164 (10.4%)		15/167 (9%)
Pyrexia	37/164 (22.6%)		35/167 (21%)
Hepatobiliary disorders
Hyperbilirubinaemia	12/164 (7.3%)		3/167 (1.8%)
Infections and infestations
Nasopharyngitis	9/164 (5.5%)		6/167 (3.6%)
Urinary tract infection	9/164 (5.5%)		12/167 (7.2%)
Investigations
Alanine aminotransferase increased	28/164 (17.1%)		17/167 (10.2%)
Aspartate aminotransferase increased	44/164 (26.8%)		18/167 (10.8%)
Blood alkaline phosphatase increased	24/164 (14.6%)		16/167 (9.6%)
Blood bilirubin increased	10/164 (6.1%)		4/167 (2.4%)
Blood creatinine increased	5/164 (3%)		13/167 (7.8%)
Blood lactate dehydrogenase increased	9/164 (5.5%)		4/167 (2.4%)
Gamma-glutamyltransferase increased	38/164 (23.2%)		16/167 (9.6%)
Haemoglobin decreased	4/164 (2.4%)		10/167 (6%)
Platelet count decreased	9/164 (5.5%)		7/167 (4.2%)
Weight decreased	4/164 (2.4%)		11/167 (6.6%)
White blood cell count decreased	4/164 (2.4%)		12/167 (7.2%)
Metabolism and nutrition disorders
Decreased appetite	28/164 (17.1%)		31/167 (18.6%)
Hypercalcaemia	9/164 (5.5%)		6/167 (3.6%)
Hypokalaemia	11/164 (6.7%)		14/167 (8.4%)
Hypophosphataemia	12/164 (7.3%)		12/167 (7.2%)
Musculoskeletal and connective tissue disorders
Arthralgia	9/164 (5.5%)		4/167 (2.4%)
Back pain	10/164 (6.1%)		17/167 (10.2%)
Pain in extremity	6/164 (3.7%)		10/167 (6%)
Nervous system disorders
Dizziness	8/164 (4.9%)		13/167 (7.8%)
Dysgeusia	10/164 (6.1%)		8/167 (4.8%)
Headache	8/164 (4.9%)		11/167 (6.6%)
Psychiatric disorders
Insomnia	7/164 (4.3%)		9/167 (5.4%)
Respiratory, thoracic and mediastinal disorders
Cough	24/164 (14.6%)		13/167 (7.8%)
Dyspnoea	9/164 (5.5%)		14/167 (8.4%)
Skin and subcutaneous tissue disorders
Pruritus	6/164 (3.7%)		10/167 (6%)
Rash	8/164 (4.9%)		13/167 (7.8%)

Limitations/Caveats

Interpretation of the results is limited by the small number of subjects analyzed and follow-up period was shortened due to the early termination of the study. Adverse Events were calculated using the safety populations.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.