Study of SyB L-0501 in Combination With Rituximab to Treat Relapsed/Refractory Diffuse Large B-Cell Lymphoma

• Sponsor: SymBio Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01118845
• Collaborator: (none)
• Enrollment: 63
• Locations: 25
• Arm: 1
• Duration (Months): 18
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy of SyB L-0501 in combination with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Non-Hodgkin's Lymphoma; Lymphoma, Large Cell; Diffuse, Mantle Cell Lymphoma, Lymphoma; Follicular Lymphoma; Large B-Cell, Diffuse	Drug: SyB L-0501; Drug: Rituximab	Phase 2

Detailed Description

Primary Objective is to determine the efficacy, as measured by overall response rate on the basis of Revised Response Criteria for Malignant Lymphoma, of SyB L-0501 at 120 mg/m^{2/day on day2 and 3 in combination with rituximab at 375 mg/m}2 on day 1 of each 21-day cycle in patients with relapsed/refractory diffuse large B-cell lymphoma.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multinational, Multicenter, Open-Label Phase II Study of SyB L-0501 in Combination With Rituximab in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: SyB L-0501

Drug: SyB L-0501; The administration of SyB L-0501 at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. SyB L-0501 60 mg/m^2, 90 mg/m^2 or 120 mg/m^2/day on Day 2 and Day 3 will be followed by 18 days of observation.; Other Names: Bendamustine hydrochloride ; Drug: Rituximab; The administration of rituximab at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.

Outcome Measures

Primary Outcome Measures

1. The Overall Response Rate [Complete Response (CR) + Partial Response (PR)] Determined on the Basis of Revised Response Criteria for Malignant Lymphoma [up to 30 weeks]

   CR: Disappearance of all evidence of disease. PR: Regression of measurable disease and no new sites. For the criteria for CR, See Outcome measure 2 description. The criteria for PR is as below. Nodal Masses: more than 50% decrease in sum of the product of the perpendicular diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site Variably FDG-avid or PET negative; regression on CT Spleen, Liver: more than 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen Bone Marrow: Irrelevant if positive prior to therapy; cell type should be specified

Secondary Outcome Measures

1. The Complete Response (CR) Rate Determined on the Basis of Revised Response Criteria for Malignant Lymphoma [up to 30 weeks]

   The criteria for CR is as below Nodal Masses: fluorodeoxy glucose (FDG)-avid or positron emission tomography (PET) positive prior to therapy; mass of any size permitted if PET negative Variably FDG-avid or PET negative; regression to normal size on computed tomography (CT) Spleen, Liver: Not palpable, nodules disappeared Bone Marrow: Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative

2. Progression Free Survival (PFS) [up to 30 weeks]

   PFS = day of the first PFS event - day of start of study treatment + 1 The definitions of PFS event are as below. PD according to overall response on the basis of Revised Response Criteria for Malignant Lymphoma PD: Any new lesion or increase by ≥50% of previously involved sites from nadir. Nodal masses; Appearance of a new lesion(s) >1.5 cm in any axis, ≥50% increase in SPD of more than one node, or ≥50% increase in longest diameter of a previously identified node >1 cm in short axis. Lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy. Spleen, Liver; ≥50% increase from nadir in the SPD of any previous lesions. Bone marrow; New or recurrent involvement Disease progression during treatment period Disease progression during follow up period Start of treatment of new lesion Occurrence of other multiple malignant tumors Death

3. Number of Subjects With Adverse Event [up to 30 weeks]

4. Number of Adverse Events [up to 30 weeks]

5. Number of Subjects With Abnormality (Grade ≥3) in Laboratory Test Values [up to 30 weeks]

   Abnormalities in laboratory test values in overall study period were analyzed. Severity of abnormalities were evaluated using Common Terminology Criteria for Adverse Events (CTCAE). grade 1 : mild grade 2 : moderate grade 3 : severe grade 4 : life threatening or disabling grade 5 : death related to adverse event

6. Number of Subjects With Grade ≥3 Physical Examination Finding [up to 30 weeks]

7. Concomitant Medication Usage [up to 30 weeks]

8. The Maximum Concentration (Cmax) of Unchanged SyB L-0501 in Japan [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

9. The Maximum Drug Concentration Time (Tmax) of Unchanged SyB L-0501 in Japan [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

10. The Area Under the Curve (AUC) for Unchanged SyB L-0501 in Japan [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

11. The Half-life Period (t1/2) of Unchanged SyB L-0501 in Japan [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

12. The Maximum Concentration (Cmax) of Unchanged SyB L-0501 in Korea [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

13. The Maximum Drug Concentration Time (Tmax) of Unchanged SyB L-0501 in Korea [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

14. The Area Under the Curve (AUC) for Unchanged SyB L-0501 in Korea [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

15. The Half-life Period (t1/2) of Unchanged SyB L-0501 in Korea [Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with documented Cluster of differentiation 20 (CD20)-positive for lymphoma cells

• Patients with measurable lesions

• Patients with measurable lesions >1.5 cm in major axes

• Relapsed or refractory after 1 to 3 prior therapeutic treatments for diffuse large B-cell lymphoma.

• Patients who are expected to survive for at least 3 months

• Patients aged from 20 to 75 years at the time informed consent is obtained

• Performance Status (P.S.) of 0 to 1 at initial administration of the study drug

• Patients with adequately maintained organ functions

• Patients capable of personally giving voluntary informed consent in writing to participate in the study

Exclusion Criteria:

• Patients who have been without treatment for less than 3 weeks after prior treatment

• Patients who can be candidates for autologous peripheral blood stem cell transplantation at the discretion of the investigator.

• Patients who received adequate prior treatments and did not respond to any of them.

• Patients with central nervous system (CNS) involvement or patients with clinical symptoms suggestive of CNS involvement.

• Patients with serious, active infections

• Patients with serious complications

• Patients with complications or medical history of serious cardiac disease

• Patients with serious gastrointestinal symptoms

• Patients with malignant pleural effusion, cardiac effusion, or ascites retention

• Patients positive for hepatitis B surface (HBs) antigen, hepatitis C virus (HCV) antibody, or HIV antibody

• Patients with serious bleeding tendencies

• Patients with a fever of 38.0°C or higher

• Patients with, or confirmed in the past to have had, interstitial pneumonia, pulmonary fibrosis, or pulmonary emphysema

• Patients with active multiple primary cancer or patients with a history of other malignant cancer within the past 5 years, except for basal cell cancer of the skin, squamous cell cancer, or cervical cancer in situ

• Patients with, or confirmed in the past to have had, autoimmune hemolytic anemia

• Patients who received SyB L-0501 in the past

• Patients who received cytokine preparation such as erythropoietin or granulocyte colony-stimulating factor (G-CSF) or blood transfusions within 2 weeks before the examination at registration for this study

• Patients who received other investigational products or unapproved medication within 3 months before registration in this study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya	Aichi	Japan
2		Matsuyama	Ehime	Japan
3		Kurume	Fukuoka	Japan
4		Maebashi	Gunma	Japan
5		Sapporo	Hokkaido	Japan
6		Kanazawa	Ishikawa	Japan
7		Isehara	Kanagawa	Japan
8		Ninomaru	Kumamoto	Japan
9		Sendai	Miyagi	Japan
10		Kita-ku	Okayama	Japan
11		Kurashiki	Okayama	Japan
12		Hidaka	Saitama	Japan
13		Izumo	Shimane	Japan
14		Chuo-ku	Tokyo	Japan
15		Akita		Japan
16		Fukuoka		Japan
17		Kagoshima		Japan
18		Kyoto		Japan
19		Seo-gu	Busan	Korea, Republic of
20		Jung-gu	Daegu	Korea, Republic of
21		Goyang-si	Gyeonggi-do	Korea, Republic of
22		Hwasun-gun	Jeonnam	Korea, Republic of
23		Gangnam-gu	Seoul	Korea, Republic of
24		Seodaemun-gu	Seoul	Korea, Republic of
25		Songpa-gu	Seoul	Korea, Republic of

Sponsors and Collaborators

• SymBio Pharmaceuticals

Investigators

• Study Chair: Kensei Tobinai, MD, Ph D, National Cancer Center Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01118845
• Other Study ID Numbers: 2010001
• First Posted: May 7, 2010
• Last Update Posted: Jul 4, 2013
• Last Verified: May 1, 2013

• Keywords provided by , ,: Non-Hodgkin's lymphoma; Lymphoma, Large B-Cell; Diffuse, Mantle cell lymphoma, Lymphoma; Follicular, Lymphoma; Large B-Cell, Diffuse
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma, Large B-Cell, Diffuse; Rituximab; Bendamustine Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	Among the 63 subjects enrolled in the study, 59 subjects received study drug and four subjects were excluded before the first study drug administration. The reasons for exclusion were adverse events and major protocol deviation/violation for two subjects each.

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Period Title: Overall Study
STARTED	59
COMPLETED	17
NOT COMPLETED	42

Baseline Characteristics

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Overall Participants	59
Age (Year) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Year]	64.2 (9.2)
Age, Customized (Percentage of participants) [Number]
20-29 years	0.0 0%
30-39 years	1.7 2.9%
40-49 years	8.5 14.4%
50-59 years	16.9 28.6%
60-69 years	39.0 66.1%
70-75 years	33.9 57.5%
Age, Customized (Percentage of participants) [Number]
<65 years	37.3 63.2%
≥65 years	62.7 106.3%
Sex/Gender, Customized (percentage of participants) [Number]
Male	42.4 71.9%
Female	57.6 97.6%
Diagnosis of Relapsed/Refractory Diffuse Large B-Cell Lymphoma (percentage of participants) [Number]
Number [percentage of participants]	100.0 169.5%
Clinical Stage (Ann Arbor staging) (Percentage of participants) [Number]
Stage I	5.1 8.6%
Stage I-E	3.4 5.8%
Stage II	27.1 45.9%
Stage II-E	3.4 5.8%
Stage III	25.4 43.1%
Stage III-S	6.8 11.5%
Stage III-E	3.4 5.8%
Stage III-SE	0.0 0%
Stage IV	25.4 43.1%
Unknown	0.0 0%
Systemic symptoms (B symptoms) (Ann Arbor staging) (Percentage of participants) [Number]
Asymptomatic	86.4 146.4%
Symptomatic	13.6 23.1%
Unknown	0.0 0%
Medical history of diffuse large B-cell lymphoma (DLBCL) (Percentage of participants) [Number]
No	40.7 69%
Yes	59.3 100.5%
Complications of DLBCL (Percentage of participants) [Number]
No	6.8 11.5%
Yes	93.2 158%
Prior medication/therapy for DLBCL (Percentage of participants) [Number]
No	8.5 14.4%
Yes	91.5 155.1%
Prior medication/therapy for DLBCL (Transplant) (Percentage of participants) [Number]
No	86.4 146.4%
Yes	13.6 23.1%
Prior treatment for DLBCL (Percentage of participants) [Number]
No	0.0 0%
Yes	100.0 169.5%
Number of regimens (Percentage of participants) [Number]
1	64.4 109.2%
2	22.0 37.3%
3	13.6 23.1%
P.S.(performance status)[the Eastern Cooperative Oncology Group (ECOG) criteria] (Percentage of Participants) [Number]
0	66.1 112%
1	33.9 57.5%
Tumor diameter (Percentage of Participants) [Number]
<5 cm	71.2 120.7%
≥5 cm	28.8 48.8%
Tumor diameter (Percentage of Participants) [Number]
<7 cm	86.4 146.4%
≥7 cm	13.6 23.1%
lactate dehydrogenase (LDH) (Percentage of Participants) [Number]
Within normal range	44.1 74.7%
Elevated	55.9 94.7%
LDH (Percentage of Participants) [Number]
<240 IU/L	39.0 66.1%
≥240 IU/L	61.0 103.4%
Site of disease (Percentage of Participants) [Number]
<4 nodular sites	47.5 80.5%
≥4 nodular sites	52.5 89%
Site of disease (Percentage of Participants) [Number]
<2 extranodular sites	93.2 158%
≥4 extranodular sites	6.8 11.5%
Bone marrow involvement (Percentage of Participants) [Number]
Positive	3.4 5.8%
Negative	94.9 160.8%
Indeterminate	0.0 0%
Unknown	1.7 2.9%
Response to prior treatment (Percentage of Participants) [Number]
Responder	100.0 169.5%
Non-Responder	0.0 0%
Unknown	0.0 0%
Time from prior treatment (Percentage of Participants) [Number]
<12 months	15.3 25.9%
≥12 months	49.2 83.4%
Unknown	0.0 0%
International Prognostic Index risk category (Percentage of Participants) [Number]
Low (score=0-1)	33.9 57.5%
Low-Intermediate (score=2)	35.6 60.3%
High-Intermediate (score=3)	23.6 40%
High(score=4-5)	6.8 11.5%
Unknown	0.0 0%
International Prognostic Index risk category (Percentage of Participants) [Number]
Low-Intermediate (score<3)	69.5 117.8%
High-Intermediate (score≥3)	30.5 51.7%
Unknown	0.0 0%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	158.25 (8.59)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	57.64 (12.85)
Body Surface Area（BSA） (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.537 (0.184)

Outcome Measures

1. Primary Outcome

Title	The Overall Response Rate [Complete Response (CR) + Partial Response (PR)] Determined on the Basis of Revised Response Criteria for Malignant Lymphoma
Description	CR: Disappearance of all evidence of disease. PR: Regression of measurable disease and no new sites. For the criteria for CR, See Outcome measure 2 description. The criteria for PR is as below. Nodal Masses: more than 50% decrease in sum of the product of the perpendicular diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site Variably FDG-avid or PET negative; regression on CT Spleen, Liver: more than 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen Bone Marrow: Irrelevant if positive prior to therapy; cell type should be specified
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
Number (95% Confidence Interval) [Percentage of Participants]	62.7 106.3%

2. Secondary Outcome

Title	The Complete Response (CR) Rate Determined on the Basis of Revised Response Criteria for Malignant Lymphoma
Description	The criteria for CR is as below Nodal Masses: fluorodeoxy glucose (FDG)-avid or positron emission tomography (PET) positive prior to therapy; mass of any size permitted if PET negative Variably FDG-avid or PET negative; regression to normal size on computed tomography (CT) Spleen, Liver: Not palpable, nodules disappeared Bone Marrow: Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
Number (95% Confidence Interval) [Percentage of participants]	37.3 63.2%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS = day of the first PFS event - day of start of study treatment + 1 The definitions of PFS event are as below. PD according to overall response on the basis of Revised Response Criteria for Malignant Lymphoma PD: Any new lesion or increase by ≥50% of previously involved sites from nadir. Nodal masses; Appearance of a new lesion(s) >1.5 cm in any axis, ≥50% increase in SPD of more than one node, or ≥50% increase in longest diameter of a previously identified node >1 cm in short axis. Lesions PET positive if FDG-avid lymphoma or PET positive prior to therapy. Spleen, Liver; ≥50% increase from nadir in the SPD of any previous lesions. Bone marrow; New or recurrent involvement Disease progression during treatment period Disease progression during follow up period Start of treatment of new lesion Occurrence of other multiple malignant tumors Death
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
Median (95% Confidence Interval) [Days]	200.0

4. Secondary Outcome

Title	Number of Subjects With Adverse Event
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
Subjects with adverse event	59 100%
Subjects with serious adverse event	14 23.7%

5. Secondary Outcome

Title	Number of Adverse Events
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
Adverse events	1848
Serious adverse events	23

6. Secondary Outcome

Title	Number of Subjects With Abnormality (Grade ≥3) in Laboratory Test Values
Description	Abnormalities in laboratory test values in overall study period were analyzed. Severity of abnormalities were evaluated using Common Terminology Criteria for Adverse Events (CTCAE). grade 1 : mild grade 2 : moderate grade 3 : severe grade 4 : life threatening or disabling grade 5 : death related to adverse event
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
Subjects with grade 3 abnormality	2 3.4%
Subjects with grade 4 abnormality	54 91.5%

7. Secondary Outcome

Title	Number of Subjects With Grade ≥3 Physical Examination Finding
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
Subjects with grade 3 Physical Findings	1 1.7%
Subjects with grade 4 Physical Findings	22 37.3%

8. Secondary Outcome

Title	Concomitant Medication Usage
Time Frame	up to 30 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	59
concomitant medications for adverse events	58 98.3%
concomitant medications for complications	50 84.7%
concomitant medications for supportive therapy	59 100%
concomitant medications for other reasons	59 100%

9. Secondary Outcome

Title	The Maximum Concentration (Cmax) of Unchanged SyB L-0501 in Japan
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	10
Mean (Standard Deviation) [ng/mL]	8365.82 (3522.73)

10. Secondary Outcome

Title	The Maximum Drug Concentration Time (Tmax) of Unchanged SyB L-0501 in Japan
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	10
Median (Standard Deviation) [hour]	1.0 (0.0)

11. Secondary Outcome

Title	The Area Under the Curve (AUC) for Unchanged SyB L-0501 in Japan
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	10
Mean (Standard Deviation) [ng・h/mL]	10394.39 (5368.77)

12. Secondary Outcome

Title	The Half-life Period (t1/2) of Unchanged SyB L-0501 in Japan
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	10
Median (Standard Deviation) [hour]	0.39 (0.1)

13. Secondary Outcome

Title	The Maximum Concentration (Cmax) of Unchanged SyB L-0501 in Korea
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	4
Mean (Standard Deviation) [ng/mL]	8095.99 (4339.74)

14. Secondary Outcome

Title	The Maximum Drug Concentration Time (Tmax) of Unchanged SyB L-0501 in Korea
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	4
Median (Standard Deviation) [hour]	0.9 (0.3)

15. Secondary Outcome

Title	The Area Under the Curve (AUC) for Unchanged SyB L-0501 in Korea
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	4
Mean (Standard Deviation) [ng・h/mL]	9218.56 (6696.81)

16. Secondary Outcome

Title	The Half-life Period (t1/2) of Unchanged SyB L-0501 in Korea
Time Frame	Prior to and 30 min after start of administration, and 0, 30, 60, 120 min after completion of administration on Day 2 of the 1st cycle

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
Measure Participants	4
Median (Standard Deviation) [hour]	0.48 (0.18)

Adverse Events

Time Frame	up to 30 weeks
Arm/Group Title	SyB L-0501
Arm/Group Description	SyB L-0501 was administered in combination with rituximab. SyB L-0501 was administered at 120 mg/m^2/day by intravenous infusion on day 2 and 3 of each 21-day cycle with up to 6 cycles. Dose modifications are permitted from 2nd cycle according to dose reduction schedule. Rituximab was administered at 375 mg/m^2/day by intravenous infusion on day 1 of each 21-day cycle with up to 6 cycles. Dose modifications are not permitted.
All Cause Mortality
	SyB L-0501
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	SyB L-0501
	Affected / at Risk (%)	# Events
Total	14/59 (23.7%)
Blood and lymphatic system disorders
Neutropenia	1/59 (1.7%)
Thrombocytopenia	1/59 (1.7%)
Gastrointestinal disorders
Constipation	2/59 (3.4%)
Diarrhoea	1/59 (1.7%)
General disorders
Asthenia	2/59 (3.4%)
Death	1/59 (1.7%)
Mucosal inflammation	1/59 (1.7%)
Infections and infestations
Cytomegalovirus infection	3/59 (5.1%)
Infection	1/59 (1.7%)
Pneumonia	3/59 (5.1%)
Pneumonia cytomegaloviral	1/59 (1.7%)
Gastric cancer	1/59 (1.7%)
Renal and urinary disorders
Urinary retention	1/59 (1.7%)
Respiratory, thoracic and mediastinal disorders
Cough	1/59 (1.7%)
Dyspnoea	1/59 (1.7%)
Respiratory failure	1/59 (1.7%)
Vascular disorders
Shock haemorrhagic	1/59 (1.7%)
Other (Not Including Serious) Adverse Events
	SyB L-0501
	Affected / at Risk (%)	# Events
Total	59/59 (100%)
Blood and lymphatic system disorders
Anaemia	30/59 (50.8%)
Febrile neutropenia	4/59 (6.8%)
Leukocytosis	1/59 (1.7%)
Leukopenia	12/59 (20.3%)
Lymphopenia	14/59 (23.7%)
Neutropenia	18/59 (30.5%)
Thrombocytopenia	16/59 (27.1%)
Cardiac disorders
Arrhythmia supraventricular	1/59 (1.7%)
Palpitations	1/59 (1.7%)
Sinus tachycardia	1/59 (1.7%)
Supraventricular extrasystoles	1/59 (1.7%)
Eye disorders
Conjunctival haemorrhage	1/59 (1.7%)
Lacrimation increased	1/59 (1.7%)
Vision blurred	1/59 (1.7%)
Vitreous floaters	1/59 (1.7%)
Gastrointestinal disorders
Abdominal discomfort	5/59 (8.5%)
Abdominal pain	2/59 (3.4%)
Abdominal pain upper	1/59 (1.7%)
Anal ulcer	1/59 (1.7%)
Cheilitis	1/59 (1.7%)
Constipation	29/59 (49.2%)
Diarrhoea	8/59 (13.6%)
Dysphagia	1/59 (1.7%)
Enterocolitis	1/59 (1.7%)
Glossitis	1/59 (1.7%)
Nausea	20/59 (33.9%)
Oral discomfort	1/59 (1.7%)
Oral pain	1/59 (1.7%)
Periodontitis	1/59 (1.7%)
Stomatitis	12/59 (20.3%)
Vomiting	6/59 (10.2%)
Epigastric discomfort	1/59 (1.7%)
Oral mucosa erosion	1/59 (1.7%)
Thirst	1/59 (1.7%)
General disorders
Application site reaction	1/59 (1.7%)
Asthenia	7/59 (11.9%)
Chest discomfort	1/59 (1.7%)
Chills	1/59 (1.7%)
Face oedema	2/59 (3.4%)
Fatigue	13/59 (22%)
Feeling hot	3/59 (5.1%)
Generalised oedema	1/59 (1.7%)
Influenza like illness	1/59 (1.7%)
Injection site erythema	1/59 (1.7%)
Injection site pain	1/59 (1.7%)
Injection site phlebitis	1/59 (1.7%)
Injection site reaction	3/59 (5.1%)
Malaise	14/59 (23.7%)
Mucosal inflammation	4/59 (6.8%)
Multi-organ failure	1/59 (1.7%)
Oedema	4/59 (6.8%)
Oedema peripheral	6/59 (10.2%)
Pyrexia	15/59 (25.4%)
Infusion site reaction	1/59 (1.7%)
Inflammation	1/59 (1.7%)
Hepatobiliary disorders
Jaundice	1/59 (1.7%)
Liver disorder	1/59 (1.7%)
Liver injury	1/59 (1.7%)
Immune system disorders
Hypersensitivity	1/59 (1.7%)
Infections and infestations
Bronchitis	1/59 (1.7%)
Cystitis	1/59 (1.7%)
Cytomegalovirus infection	2/59 (3.4%)
Gastrointestinal infection	1/59 (1.7%)
Herpes zoster	4/59 (6.8%)
Infection	2/59 (3.4%)
Nasopharyngitis	4/59 (6.8%)
Oral candidiasis	3/59 (5.1%)
Sinusitis	1/59 (1.7%)
Upper respiratory tract infection	3/59 (5.1%)
Urinary tract infection	2/59 (3.4%)
Enterocolitis infectious	1/59 (1.7%)
Oral herpes	4/59 (6.8%)
Injury, poisoning and procedural complications
Fall	1/59 (1.7%)
Tooth injury	1/59 (1.7%)
Open wound	1/59 (1.7%)
Investigations
Alanine aminotransferase increased	19/59 (32.2%)
Aspartate aminotransferase increased	22/59 (37.3%)
Blood albumin decreased	1/59 (1.7%)
Blood bilirubin increased	2/59 (3.4%)
Blood chloride increased	1/59 (1.7%)
Blood creatinine increased	8/59 (13.6%)
Blood immunoglobulin A decreased	24/59 (40.7%)
Blood immunoglobulin G decreased	26/59 (44.1%)
Blood lactate dehydrogenase increased	20/59 (33.9%)
Blood potassium increased	2/59 (3.4%)
Blood urea decreased	4/59 (6.8%)
Blood urea increased	6/59 (10.2%)
Blood uric acid decreased	1/59 (1.7%)
Blood uric acid increased	1/59 (1.7%)
C-reactive protein increased	23/59 (39%)
CD4 lymphocytes decreased	41/59 (69.5%)
Eosinophil count increased	1/59 (1.7%)
Gamma-glutamyltransferase increased	16/59 (27.1%)
Glucose urine present	3/59 (5.1%)
Glycosylated haemoglobin increased	1/59 (1.7%)
Blood urine present	1/59 (1.7%)
Haemoglobin decreased	2/59 (3.4%)
Liver function test abnormal	2/59 (3.4%)
Lymphocyte count decreased	33/59 (55.9%)
Neutrophil count decreased	34/59 (57.6%)
Platelet count decreased	26/59 (44.1%)
Protein total decreased	16/59 (27.1%)
Red blood cell count decreased	5/59 (8.5%)
Weight decreased	11/59 (18.6%)
Weight increased	4/59 (6.8%)
White blood cell count decreased	37/59 (62.7%)
White blood cell count increased	27/59 (45.8%)
Blood bilirubin decreased	1/59 (1.7%)
Platelet count increased	1/59 (1.7%)
Basophil percentage increased	1/59 (1.7%)
Eosinophil percentage decreased	1/59 (1.7%)
Eosinophil percentage increased	3/59 (5.1%)
Monocyte percentage decreased	2/59 (3.4%)
Monocyte percentage increased	2/59 (3.4%)
Blood alkaline phosphatase increased	11/59 (18.6%)
Hepatitis B virus test positive	1/59 (1.7%)
Blood immunoglobulin M decreased	25/59 (42.4%)
Neutrophil count increased	22/59 (37.3%)
Metabolism and nutrition disorders
Dehydration	1/59 (1.7%)
Hyperglycaemia	3/59 (5.1%)
Hyperkalaemia	8/59 (13.6%)
Hyperuricaemia	2/59 (3.4%)
Hypoalbuminaemia	13/59 (22%)
Hypocalcaemia	4/59 (6.8%)
Hypoglycaemia	2/59 (3.4%)
Hypokalaemia	4/59 (6.8%)
Hyponatraemia	7/59 (11.9%)
Hypoproteinaemia	1/59 (1.7%)
Hypouricaemia	2/59 (3.4%)
Decreased appetite	20/59 (33.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/59 (1.7%)
Back pain	2/59 (3.4%)
Musculoskeletal pain	2/59 (3.4%)
Pain in extremity	2/59 (3.4%)
Musculoskeletal stiffness	1/59 (1.7%)
Bone pain	3/59 (5.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	1/59 (1.7%)
Tumour haemorrhage	1/59 (1.7%)
Nervous system disorders
Burning sensation	1/59 (1.7%)
Dizziness	4/59 (6.8%)
Dysgeusia	6/59 (10.2%)
Headache	10/59 (16.9%)
Hypoaesthesia	1/59 (1.7%)
Peripheral sensory neuropathy	1/59 (1.7%)
Tremor	1/59 (1.7%)
Psychiatric disorders
Delirium	3/59 (5.1%)
Insomnia	14/59 (23.7%)
Major depression	1/59 (1.7%)
Renal and urinary disorders
Haematuria	2/59 (3.4%)
Pollakiuria	2/59 (3.4%)
Proteinuria	4/59 (6.8%)
Respiratory, thoracic and mediastinal disorders
Asthma	1/59 (1.7%)
Cough	5/59 (8.5%)
Dyspnoea	3/59 (5.1%)
Haemoptysis	1/59 (1.7%)
Hiccups	6/59 (10.2%)
Interstitial lung disease	1/59 (1.7%)
Productive cough	4/59 (6.8%)
Respiratory disorder	1/59 (1.7%)
Rhinorrhoea	3/59 (5.1%)
Oropharyngeal discomfort	1/59 (1.7%)
Oropharyngeal pain	2/59 (3.4%)
Skin and subcutaneous tissue disorders
Alopecia	2/59 (3.4%)
Dermatitis exfoliative	1/59 (1.7%)
Drug eruption	1/59 (1.7%)
Dry skin	2/59 (3.4%)
Erythema	1/59 (1.7%)
Hyperhidrosis	1/59 (1.7%)
Nail discolouration	1/59 (1.7%)
Pain of skin	1/59 (1.7%)
Pruritus	4/59 (6.8%)
Rash	10/59 (16.9%)
Rash maculo-papular	5/59 (8.5%)
Skin depigmentation	1/59 (1.7%)
Skin erosion	1/59 (1.7%)
Urticaria	2/59 (3.4%)
Photodermatosis	1/59 (1.7%)
Vascular disorders
Flushing	1/59 (1.7%)
Hypertension	1/59 (1.7%)
Hypotension	4/59 (6.8%)
Phlebitis	1/59 (1.7%)
Vasculitis	2/59 (3.4%)
Haemorrhage	1/59 (1.7%)
Angiopathy	3/59 (5.1%)
Hot flush	5/59 (8.5%)

Limitations/Caveats

[Not Specified]

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.