Clinical trial NCT04660799
Conditions: Lymphoma, Large B-Cell, Diffuse
Keywords: Mabthera, Rituximab, SC, Subcutaneous, DLBCL
Sponsor: Hoffmann-La Roche
Start date: 2021-02-24; Completion date: 2022-10-11
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter China-only study to investigate the PK, efficacy and safety of SC rituximab versus IV rituximab, both in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in previously untreated participants with CD20 positive DLBCL. Participants will be randomized to receive eight cycles of rituximab SC or rituximab IV combined with six or eight cycles of standard CHOP chemotherapy. After the end of study treatment, participants will be followed-up every 3 months for 6 months.

Detailed description:

Arms: arm 1: Participants will receive 8 cycles of IV rituximab in combination with 6 or 8 cycles of CHOP chemotherapy administered every 3 weeks. arm 2: Participants will receive 1 cycle of IV plus 7 cycles of SC rituximab in combination with 6 or 8 cycles of CHOP chemotherapy administered every 3 weeks.
Interventions: intervention 1: Rituximab IV intervention 2: Rituximab SC intervention 3: Rituximab IV intervention 4: Cyclophosphamide intervention 5: Doxorubicin intervention 6: Vincristine intervention 7: Prednisone intervention 8: Paracetamol intervention 9: Diphenhydramine hydrochloride or alternative antihistamine
Intervention descriptions: intervention 1: Rituximab will be administered intravenously through Cycle 1-8 at a standard dose of 375 mg/m\^2 (milligram per square meter). intervention 2: Rituximab will be administered subcutaneously through Cycle 2-8 at a dose of 1400 milligram (mg). intervention 3: Rituximab will be administered intravenously in Cycle 1 at a standard dose of 375 mg/m\^2. intervention 4: Cyclophosphamide will be administered IV at a dose of 750 mg/m\^2 intervention 5: Doxorubicin will be administered IV at a dose of 50 mg/m\^2 intervention 6: Vincristine will be administered IV at a dose of 1.4 mg/m\^2 intervention 7: Prednisone will be administered orally at a dose of 100 mg/day intervention 8: All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab intervention 9: All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab

Protocol documents:
Prot_000.pdf: 
Official Title: A Phase II Comparative, Open Label, Randomized, Multicenter, 
China-Only Study to Investigate the Pharmacokinetics, Efficacy and 
Safety of Subcutaneous Rituximab Versus Intravenous Rituximab, 
Both in Combination With CHOP in Previously Untreated Patients With 
CD20 Positive Diffuse Large B Cell Lymphoma 
NCT Number: NCT04660799  
Document Date: Protocol Version 1.0: 20-April-2020 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Rituximab—F. Hoffmann-La Roche Ltd
Protocol YO42207, Version 1.0
PROTOCOL
TITLE:
A PHASE II COMPARATIVE, OPEN LABEL, 
RANDOMIZED, MULTICENTER, CHINA-ONLY 
STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, EFFICACY AND SAFETY 
OF SUBCUTANEOUS RITUXIMAB VERSUS 
INTRAVENOUS RITUXIMAB, BOTH IN 
COMBINATION WITH CHOP IN PREVIOUSLY 
UNTREATED PATIENTS WITH CD20 POSITIVE 
DIFFUSE LARGE B CELL LYMPHOMA
PROTOCOL NUMBER:
YO42207
VERSION NUMBER:
1.0
NCT NUMBER:
To be determined
TEST PRODUCT:
Rituximab (RO0452294) (MabThera)
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below
 
20-Apr-2020 09:30:00
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Rituximab—F. Hoffmann-La Roche Ltd
2/Protocol YO42207, Version 1.0
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 8
PROTOCOL SYNOPSIS ...................................................................................... 9
1.
BACKGROUND .......................................................................................... 17
1.1
Background on Non-Hodgkin’s Lymphoma:  
Diffuse Large B-Cell Lymphoma and Current 
Standard of Care ................................................................... 17
1.2
Background on Rituximab Subcutaneous.............................. 19
1.3
Study Rationale and Benefit-Risk Assessment...................... 21
2.
OBJECTIVES AND ENDPOINTS ............................................................... 22
2.1
Primary Objective .................................................................. 22
2.2
Secondary Objectives............................................................ 23
3.
STUDY DESIGN......................................................................................... 23
3.1
Description of the Study......................................................... 23
3.1.1
Overview of Study Design and Dosing Regimen................... 23
3.1.2
Independent Review Committee............................................ 25
3.2
End of Study and Length of Study......................................... 26
3.3
Rationale for Study Design.................................................... 26
3.3.1
Rationale for Rituximab Subcutaneous Dose and 
Schedule................................................................................ 26
3.3.2
Rationale for Study Design.................................................... 27
4.
MATERIALS AND METHODS .................................................................... 28
4.1
Patients.................................................................................. 28
4.1.1
Inclusion Criteria.................................................................... 28
4.1.2
Exclusion Criteria................................................................... 29
4.2
Method of Treatment Assignment.......................................... 30
4.2.1
Treatment Assignment........................................................... 30
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 31
4.3.1
Investigational Medicinal Product .......................................... 31
4.3.1.1
Rituximab IV (Comparator Investigational 
Medicinal Product)................................................................. 31


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4.3.1.2
Rituximab SC (Experimental Investigational 
Medicinal Product)................................................................. 32
4.3.1.3
Storage, Packaging, and Labeling of Rituximab 
IV and SC Formulations......................................................... 33
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 34
4.3.2.1
RIV-CHOP .............................................................................. 34
4.3.2.2
RSC-CHOP ............................................................................. 35
4.3.3
Investigational Medicinal Product Accountability ................... 36
4.4
Concomitant Therapy ............................................................ 37
4.4.1
Permitted Therapy................................................................. 37
4.4.1.1
Prophylaxis of Administration-Related Reactions.................. 37
4.4.1.2
Prophylaxis of Nausea and Vomiting..................................... 37
4.4.1.3
Antimicrobial and Antiviral Prophylaxis.................................. 37
4.4.1.4
Prophylaxis for Hemorrhagic Cystitis..................................... 37
4.4.1.5
Tumor-Lysis Syndrome Prophylaxis ...................................... 38
4.4.1.6
Central Nervous System Prophylaxis .................................... 38
4.4.1.7
Hepatitis B Reactivation Prophylaxis ..................................... 38
4.4.1.8
Pre-planned Consolidation Radiotherapy .............................. 38
4.4.2
Prohibited Therapy ................................................................ 39
4.5
Study Assessments ............................................................... 39
4.5.1
Informed Consent Forms and Screening Log........................ 39
4.5.2
Medical History, Demographic Data, IPI, Ann 
Arbor Staging, and ECOG Performance Status..................... 39
4.5.3
Physical Examinations........................................................... 40
4.5.4
Vital Signs.............................................................................. 40
4.5.5
Tumor and Response Evaluations......................................... 40
4.5.6
Laboratory Assessments ....................................................... 41
4.5.7
Pharmacokinetic Assessments.............................................. 43
4.5.7.1
PK Sampling for Patients Randomized to the RIV-
CHOP Arm............................................................................. 43
4.5.7.2
PK Sampling for Patients Randomized to RSC-
CHOP Arm............................................................................. 44
4.5.8
Immunogenicity Assessments ............................................... 44
4.5.9
Electrocardiograms................................................................ 45


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4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 46
4.6.1
Study Treatment Discontinuation........................................... 46
4.6.2
Patient Discontinuation from the Study.................................. 46
4.6.3
Study Discontinuation............................................................ 47
4.6.4
Site Discontinuation............................................................... 47
4.7
Follow-up............................................................................... 48
5.
ASSESSMENT OF SAFETY....................................................................... 48
5.1
Safety Plan ............................................................................ 48
5.1.1
Management of Patients Who Experience 
Adverse Events ..................................................................... 48
5.1.2
Dose modifications of Rituximab IV, Rituximab 
SC and CHOP Chemotherapy for Toxicity............................. 49
5.1.2.1
Administration-Related Reactions ......................................... 53
5.2
Safety Parameters and Definitions ........................................ 54
5.2.1
Adverse Events ..................................................................... 55
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 55
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 56
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 57
5.3.1
Adverse Event Reporting Period ........................................... 57
5.3.2
Eliciting Adverse Event Information....................................... 57
5.3.3
Assessment of Severity of Adverse Events ........................... 57
5.3.4
Assessment of Causality of Adverse Events ......................... 58
5.3.5
Procedures for Recording Adverse Events............................ 59
5.3.5.1
Administration-Related Reactions ......................................... 59
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 59
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 60
5.3.5.4
Persistent or Recurrent Adverse Events................................ 60
5.3.5.5
Abnormal Laboratory Values ................................................. 61
5.3.5.6
Abnormal Vital Sign Values ................................................... 61
5.3.5.7
Abnormal Liver Function Tests.............................................. 62


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5.3.5.8
Deaths ................................................................................... 62
5.3.5.9
Preexisting Medical Conditions.............................................. 63
5.3.5.10
Lack of Efficacy or Worsening of DLBCL............................... 63
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 63
5.3.5.12
Cases of Accidental Overdose or Medication 
Error....................................................................................... 64
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 65
5.4.1
Emergency Medical Contacts................................................ 65
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 66
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 66
5.4.2.2
Events That Occur after Study Drug Initiation........................ 66
5.4.3
Reporting Requirements for Pregnancies.............................. 66
5.4.3.1
Pregnancies in Female Patients............................................ 66
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 67
5.4.3.3
Abortions ............................................................................... 67
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 68
5.5
Follow-Up of Patients after Adverse Events .......................... 68
5.5.1
Investigator Follow-Up........................................................... 68
5.5.2
Sponsor Follow-Up ................................................................ 68
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 68
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, 
and Ethics Committees.......................................................... 69
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 69
6.1
Determination of Sample Size ............................................... 69
6.2
Summaries of Conduct of Study............................................ 70
6.3
Summaries of Treatment Group Comparability ..................... 70
6.4
Pharmacokinetic Analyses..................................................... 70
6.4.1
Pharmacokinetic Analysis Population.................................... 70
6.4.2
Pharmacokinetic Endpoints ................................................... 70
6.4.2.1
Pharmacokinetic Primary Endpoint........................................ 70


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6.4.2.2
Pharmacokinetic Secondary Endpoint................................... 71
6.4.3
Other Pharmacokinetic Parameters....................................... 71
6.4.4
Analysis of Pharmacokinetic Parameters .............................. 71
6.5
Efficacy Analyses .................................................................. 71
6.5.1
Efficacy Endpoints................................................................. 71
6.5.2
Analysis of Efficacy Endpoints............................................... 72
6.6
Safety Analyses..................................................................... 72
6.7
Immunogenicity Analyses...................................................... 73
7.
DATA COLLECTION AND MANAGEMENT ............................................... 73
7.1
Data Quality Assurance......................................................... 73
7.2
Electronic Case Report Forms............................................... 74
7.3
Source Data Documentation.................................................. 74
7.4
Use of Computerized Systems .............................................. 74
7.5
Retention of Records............................................................. 75
8.
ETHICAL CONSIDERATIONS.................................................................... 75
8.1
Compliance with Laws and Regulations ................................ 75
8.2
Informed Consent.................................................................. 75
8.3
Institutional Review Board or Ethics Committee.................... 76
8.4
Confidentiality........................................................................ 77
8.5
Financial Disclosure .............................................................. 77
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 78
9.1
Study Documentation ............................................................ 78
9.2
Protocol Deviations................................................................ 78
9.3
Management of Study Quality ............................................... 78
9.4
Site Inspections ..................................................................... 78
9.5
Administrative Structure......................................................... 78
9.6
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 79
9.7
Protocol Amendments ........................................................... 80
10. REFERENCES ........................................................................................... 81


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LIST OF TABLES
Table 1
Administration and Dose Modification of First and 
Subsequent Infusions of Rituximab IV ........................................ 32
Table 2
Schedule of RIV-CHOP for Cycles 1 to 8..................................... 35
Table 3
Schedule of RSC-CHOP in Cycle 1.............................................. 35
Table 4
Schedule of RSC-CHOP in Cycles 2 to 8 ..................................... 36
Table 5
Guidelines for Dose Delay or Modification of Rituximab IV, 
Rituximab SC and CHOP Chemotherapy (Cycle 2 to Cycle 6 
[or 8], Day 1) ............................................................................... 50
Table 6
Recommended Steps of Dose reduction for R-CHOP ................ 53
Table 7
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE 5.0 ......................................... 58
Table 8
Causal Attribution Guidance ....................................................... 59
Table 9
Reference Safety Information ..................................................... 69
Table 10
Sample Size for Primary Endpoint (i.e., Non-inferiority in 
Ctrough) ......................................................................................... 70
LIST OF FIGURE
Figure 1
Dosing Schema........................................................................... 24
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................. 83
Appendix 2
Schedule of Pharmacokinetic Samples (Treatment Period 
and Follow-Up Period) ................................................................ 88
Appendix 3
Anaphylaxis Precautions............................................................ 90
Appendix 4
Lugano Response Criteria for Malignant Lymphoma  
(Cheson et al. 2014) ................................................................... 91
Appendix 5
International Prognostic Index and Ann Arbor Staging 
Classification............................................................................... 97
Appendix 6
Eastern Cooperative Oncology Group Performance Status 
Scale........................................................................................... 98


Rituximab—F. Hoffmann-La Roche Ltd
8/Protocol YO42207, Version 1.0
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE II COMPARATIVE, OPEN LABEL, 
RANDOMIZED, MULTICENTER, CHINA-ONLY
STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, EFFICACY AND SAFETY 
OF SUBCUTANEOUS RITUXIMAB VERSUS 
INTRAVENOUS RITUXIMAB, BOTH IN 
COMBINATION WITH CHOP IN PREVIOUSLY 
UNTREATED PATIENTS WITH CD20 POSITIVE 
DIFFUSE LARGE B CELL LYMPHOMA
PROTOCOL NUMBER:
YO42207
VERSION NUMBER:
1.0
NCT NUMBER:
To be determined
TEST PRODUCT:
Rituximab (RO0452294) (MabThera)
MEDICAL MONITOR:
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of the 
signed form as instructed by your local study monitor.


Rituximab—F. Hoffmann-La Roche Ltd
9/Protocol YO42207, Version 1.0
PROTOCOL SYNOPSIS
TITLE:
A PHASE II COMPARATIVE, OPEN LABEL, RANDOMIZED, 
MULTICENTER, CHINA-ONLY STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, EFFICACY AND SAFETY OF
SUBCUTANEOUS RITUXIMAB VERSUS INTRAVENOUS 
RITUXIMAB, BOTH IN COMBINATION WITH CHOP IN 
PREVIOUSLY UNTREATED PATIENTS WITH CD20 POSITIVE 
DIFFUSE LARGE B CELL LYMPHOMA
PROTOCOL NUMBER:
YO42207
VERSION NUMBER:
1.0
IND NUMBER:
To be determined
TEST PRODUCT:
Rituximab (RO0452294) (MabThera)
PHASE:
II
INDICATION:
Previously untreated CD20 positive Diffuse Large B Cell Lymphoma
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of subcutaneous (SC)
rituximab compared with intravenous (IV) rituximab, both in combination with cyclophosphamide, 
doxorubicin, vincristine, prednisone (CHOP), in previously untreated patients with CD20 positive 
diffuse large B cell lymphoma (DLBCL).  Specific objectives and corresponding endpoints for 
the study are outlined below.
Primary Objectives
The primary objective of this study is to demonstrate the non-inferiority of rituximab serum Ctrough
obtained at Cycle 7, 21 days after SC administration, with that obtained at Cycle 7, 21 days 
after IV administration on the basis of the following endpoint:

Ratio of Ctrough,SC/Ctrough,IV during Cycle 7
Secondary Objectives
The secondary objectives of this study are to compare and assess other PK parameters, 
efficacy and safety profiles (including immunogenicity) of rituximab SC and rituximab IV, both in 
combination with CHOP, on the basis of the following endpoints and outcome measures:

Ratio of AUCSC/AUCIV during Cycle 7

Other PK parameters, such as AUC and Ctrough at other treatment cycles, maximum 
serum concentration (Cmax), total clearance, volume of distribution at steady state, and 
terminal half-life (t1/2) (if feasible or appropriate) as appropriate

Complete response rate (CRR) at the end of the study treatment, as determined by the 
Independent Review Committee (IRC) using Lugano Response Criteria for Malignant 
Lymphoma as key efficacy endpoint

Objective response rate (ORR), defined as complete response (CR) or partial response 
(PR) at the end of the study treatment, as determined by investigator and IRC using 
Lugano Response Criteria for Malignant Lymphoma

CRR (CR, complete response unconfirmed [CRu]) at the end of study treatment, as 
determined by IRC using International Working Group (IWG) Response Criteria for 
Non-Hodgkin’s lymphoma (NHL) 1999 Guidelines


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
CRR at the end of the study treatment, as determined by the investigator using Lugano 
Response Criteria for Malignant Lymphoma

Safety outcomes as assessed by adverse events, including rituximab administration-
related reactions (ARRs), laboratory assessments, and vital signs; and immunogenicity 
as assessed by anti-rituximab antibodies and anti-rHuPH20 antibodies
Study Design
Description of Study
This is a Phase II, multicenter, randomized, controlled, open-label, China-only study to 
investigate the PK, efficacy, and safety of rituximab SC in combination with CHOP versus 
rituximab IV in combination with CHOP in previously untreated patients with CD20 positive 
DLBCL. This study will be conducted at approximately 8 sites in China.  Approximately 
50 patients will receive eight cycles of rituximab SC or rituximab IV combined with six or eight
cycles of standard CHOP chemotherapy. Centers must choose whether they plan to administer 
six or eight cycles of CHOP chemotherapy prior to study start.  Previous results have 
demonstrated that a fixed rituximab SC dose at 1400 mg is expected to achieve non-inferior 
Ctrough values to the rituximab IV regimen (375 mg/m2) prior to Cycle 8 (Study BO22334). In this 
study, a sample size of 50 patients (approximately 18 evaluable patients per arm) who have 
completed Cycle 7 will be adequate for testing non-inferiority for the estimated ratio 
Ctrough,SC/Ctrough,IV. Previously untreated patients with CD20 positive DLBCL will be randomized 
into the following two treatment groups at a 1:1 ratio (crossover to the experimental arm is not 
permitted):

RSC-CHOP:  Cycle 1 rituximab IV plus seven cycles of rituximab SC in combination with 
six or eight cycles of CHOP chemotherapy administered every 3 weeks; rituximab IV
will be used at the standard dose of 375 mg/m2 and rituximab SC will be given at a 
dose of 1400 mg as confirmed in the Phase III Study BO22334.

RIV-CHOP:  eight cycles of rituximab IV in combination with six or eight cycles of CHOP 
chemotherapy administered every 3 weeks; rituximab IV will be used at the standard 
dose of 375 mg/m2.
Eligible patients will be stratified during randomization according to International Prognostic 
Index (IPI) scores (IPI 0-2 versus IPI 35).  
Patients will be assessed for disease response by the investigator and IRC, on the basis of 
regular clinical and laboratory examinations, physical examinations, computed tomography (CT) 
scans, positron emission tomography (PET)-CT scans, and bone marrow examinations,
according to the Lugano Response Criteria for Malignant Lymphoma.  PET-CT and dedicated 
CT scans will be obtained at screening and 6-8 weeks after completion of study treatment, or 
sooner in the event that a patient discontinues early.  An interim assessment will be obtained 
after Cycle 4 and should include PET-CT and dedicated CT.  If local practice prohibits obtaining 
both assessments after Cycle 4, PET-CT alone (preferred) or CT alone may be obtained at this 
time point.  During the follow-up period, imaging (may be CT only) will be performed every 3 
months, i.e., Week 12 and 24 after last treatment, in accordance with study visits and will 
include the neck (if involved at baseline), chest, abdomen, and pelvis.
After the end of study treatment, patients will be followed-up every 3 months for 6 months (i.e., 
12 and 24 weeks after the last dose of study treatment).  Assessments will include clinical
evaluation of tumor response/progression, PK and immunogenicity (blood sampling), physical 
examination, standard hematologic and biochemistry assessments, vital signs and weight
measurements, liver and spleen size and B-symptoms assessments.
Safety will be evaluated by monitoring all adverse events, and abnormalities identified through 
physical examination, vital signs, and laboratory assessments.  Such events will be graded 
using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5
(NCI CTCAE v5.0).  Laboratory safety assessments will include the routine monitoring of 
hematology and blood chemistries.
Number of Patients
Approximately 50 patients with previously untreated CD20 positive DLBCL will be enrolled in 
this study.


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Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent and to comply with the study protocol

Age 18 and 80 years at time of signing Informed Consent Form

Previously untreated CD20 positive DLBCL histologically documented

Patients with an IPI score of 1 to 5 or IPI score of 0 with bulky disease, defined as one 
lesion 7.5 cm

At least one bi-dimensionally measurable lesion defined as 1.5 cm in its largest dimension 
on CT scan 

Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Left ventricular ejection fraction (LVEF) 50% on cardiac multiple-gated acquisition (MUGA) 
scan or cardiac echocardiogram

A negative serum pregnancy test or a negative urine pregnancy test within 7 days prior to 
study treatment must be available both for pre-menopausal women (including those who 
have had a tubal ligation) and for women who are less than 2 years after the onset of 
menopause; if negative serum pregnancy test is within 14 days of study treatment start, a 
confirmatory urine pregnancy test must be available within 7 days prior to study treatment 
start

For men who are not surgically sterile, agreement to use a barrier method of contraception 
during the treatment period and until 12 months after the last dose of rituximab SC or 
rituximab IV or according to institutional guidelines for CHOP chemotherapy, whichever is 
longer, and agreement to request that their partners use an additional method of 
contraception, such as oral contraceptives, intrauterine device, barrier method, or 
spermicidal jelly

For women of reproductive potential who are not surgically sterile, agreement to use 
adequate methods of contraception, such as oral contraceptives, intrauterine device, or 
barrier method of contraception in conjunction with spermicidal jelly during the treatment 
period and until 12 months after the last dose of rituximab SC or rituximab IV or according 
to institutional guidelines for CHOP chemotherapy, whichever is longer

Adequate hematologic function confirmed within 14 days prior to randomization which is 
independent to stimulating factors and transfusion (unless related to lymphoma infiltration of 
the bone marrow)

Hemoglobin 9.0 g/dL

Absolute neutrophil count (ANC) 1.5 109/L

Platelet count 75 109/L
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Transformed NHL or types of NHL other than DLBCL and its subtypes according to World 
Health Organization classification

History of severe allergic or anaphylactic reactions to humanized or murine monoclonal 
antibodies or known sensitivity or allergy to murine products 

Contraindication to any of the individual components of CHOP, including prior receipt of 
anthracyclines

Prior therapy for DLBCL, with the exception of nodal biopsy or local irradiation or surgery for 
diagnosis

Prior treatment with cytotoxic drugs or rituximab for another condition (e.g., rheumatoid 
arthritis) or prior use of an anti-CD20 antibody

Current or recent (within the 30 days prior to starting study treatment) treatment with 
another investigational drug or participation in another investigational therapeutic study


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
Ongoing corticosteroid use, 30 mg/day of prednisone or equivalent

Patients receiving corticosteroid treatment with 30 mg/day of prednisone or 
equivalent must be documented to be on a stable dose for duration of at least 4 
weeks prior to randomization.

Primary central nervous system (CNS) lymphoma, blastic variant of mantle cell lymphoma, 
or histologic evidence of transformation to a Burkitt lymphoma, primary mediastinal DLBCL, 
primary effusion lymphoma, and primary cutaneous DLBCL

History of other malignancy that could affect compliance with the protocol or interpretation 
of results

Patients with a history of curatively treated basal or squamous cell carcinoma or 
melanoma of the skin or in situ carcinoma of the cervix are eligible.

Patients with a malignancy that has been treated but not with curative intent will also 
be excluded unless the malignancy has been in remission without treatment for 
5 years prior to enrollment.

Evidence of significant, uncontrolled concomitant diseases that could affect compliance with 
the protocol or interpretation of results, including but not limited to significant cardiovascular 
disease (such as New York Heart Association Class III or IV cardiac disease, myocardial 
infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary 
disease (including obstructive pulmonary disease and history of bronchospasm)

Any of the following abnormal laboratory values:

Creatinine 1.5 upper limit of normal (ULN) (unless creatinine clearance normal) or 
calculated creatinine clearance 40 mL/min (using the Cockcroft-Gault formula)

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 2.5 ULN

Total bilirubin 1.5 ULN; patients with documented Gilbert disease may be enrolled 
if total bilirubin is 3.0 ULN

International normalized ratio (INR) 1.5 ULN in the absence of therapeutic 
anticoagulation

Partial thromboplastin time (PTT) or activated Partial thromboplastin time (aPTT)
1.5 ULN in the absence of a lupus anticoagulant

Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 

Patients with occult or prior HBV infection (defined as negative HBsAg and positive 
total hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable, 
provided that they are willing to undergo monthly DNA testing during the treatment 
period and the follow-up period. 

Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)

Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR)
is negative for HCV RNA.

Known history of human immunodeficiency virus (HIV) seropositive status or infection

Signs or symptoms of other active and/or severe infection

Evidence of any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates use of an investigational drug or patient at high risk from treatment 
complications

Any co-existing medical or psychological condition that would compromise ability to give 
informed consent
End of Study and Length of Study
The end of study is defined as the date when the last patient last visit (LPLV) occurs. LPLV is 
expected to occur approximately 6 months after the last patient enrolled has received the last
study treatment, or sooner, if all patients have progressed, died, or withdrawn from the study. 
The Sponsor has the right to terminate the study at any time.


Rituximab—F. Hoffmann-La Roche Ltd
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Investigational Medicinal Products
Test Product (Investigational Drug)
The experimental investigational medicinal product of the study is rituximab SC supplied as a 
ready-to-use liquid formulation with a nominal content of 120 mg/mL rituximab.  The drug 
product contains 2000 U/mL rHuPH20 acting as a permeation enhancer, histidine/histidine-HCl 
(buffer), α,α-trehalose (bulking agent), methionine (stabilizer), and polysorbate 80 (surfactant) in 
Water for Injection (WFI) at a pH of 5.5.  Rituximab SC will be administered by SC injection on 
Day 1 of Cycles 2 to 8 to patients randomized to the RSC-CHOP treatment arm.
Comparator
The comparator investigational medicinal product of the study is rituximab IV provided as 
500 mg/50 mL liquid-filled vials with a nominal content of 10 mg/mL rituximab. The drug 
product contains sodium acetate (buffer), sodium chloride (tonicity adjustment), and polysorbate 
80 (surfactant) in WFI at a pH of 6.5.  Rituximab IV will be administered by IV infusion on Day 1 
of Cycles 1 to 8 to patients randomized to the RIV-CHOP treatment arm and on Day 1 of Cycle 1 
to patients randomized to RSC-CHOP treatment arm.
Non-Investigational Medicinal Products
The CHOP chemotherapy will be prepared according to the standard practice at the institution.
Statistical Methods
Primary Analysis
All PK analyses will be based on all patients for whom PK assessments were made.  PK 
analyses will be analyzed as treated.  Patients will be excluded from the PK analysis population 
if they significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete, where the PK analysis might be influenced.  
Excluded cases will be documented, including the reason for exclusion. All decisions on 
exclusions from the analysis will be made prior to database closure.
The primary PK endpoint is the ratio of Ctrough,SC/Ctrough,IV during Cycle 7.  The serum rituximab 
Ctrough at Cycle 7 will be measured at pre-dose of Cycle 8. The lower limit of the two-sided 90% 
confidence interval (CI) should be above 0.80 in order to show non-inferiority of Ctrough,SC versus 
Ctrough,IV.
Determination of Sample Size  
Under the assumption of a coefficient of variation equal to 0.5 and assuming that the true Ctrough
of rituximab SC formulation is 20% above the rituximab IV formulation (i.e., mean Ctrough,SC to be 
20% above Ctrough,IV), 20 patients in each treatment arm are needed in order to achieve 80% 
power with one-sided alpha of 0.05 (i.e., 2-sided 90% confidence interval [CI]).  Assuming that 
20% of patients would not have valid PK data at Cycle 8 pre-dose, a total of approximately 
50 patients will be enrolled into the study.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ADA
anti-drug antibody
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase 
ANC
absolute neutrophil count 
aPTT
activated Partial thromboplastin time
ARR
administration-related reaction
AST
aspartate aminotransferase
AUC
area under the concentration–time curve
BSA
Body Surface Area 
BUN
blood urea nitrogen
CHOP
cyclophosphamide, doxorubicin, vincristine, prednisone
CI
confidence interval
CL
clearance
CLL
chronic lymphocytic leukemia
CNS
central nervous system 
CR
complete response 
CRu
complete response unconfirmed 
CRR
complete response rate 
CT
computed tomography 
CTCAE
Common Terminology Criteria for Adverse Event
Ctrough
trough serum concentration
CV
coefficient of variation
CVP
cyclophosphamide, vincristine, prednisone
DLBCL
diffuse large B cell lymphoma
EC
Ethics Committee
ECG
electrocardiogram
ECLIA
electrochemiluminescence immunoassay 
ECOG
Eastern Cooperative Oncology Group 
eCRF
electronic csase report form
EDC
electronic data capture 
EFS
event-free survival 
ELISA
enzyme-linked immunosorbent assay 
FDA
U.S. Food and Drug Administration
FDG
fluorodeoxyglucose 
FL
follicular lymphoma 


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Abbreviation
Definition
G-CSF
granulocyte colony-stimulating factor
HBcAb
hepatitis B core antibody 
HBV
hepatitis B virus 
HBsAg
hepatitis B surface antigen 
HCV
hepatitis C virus
HIV
human immunodeficiency virus 
HR
hazard ratio
IB
Investigator’s Brochure 
ICH
International Council for Harmonization 
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio 
IPI
International Prognostic Index 
IRB
Institutional Review Board
IRC
Independent Review Committee 
IRR
infusion-related reaction
IV
intravenous 
IVRS
Interactive Voice Response System 
IWG
International Working Group 
IWRS
Interactive Web-based response system
IxRS
Interactive Voice or Web-based response system
LDH
lactate dehydrogenase 
LPLV
last patient last visit 
LVEF
left ventricular ejection fraction
LVSD
left ventricular systolic dysfunction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging 
MUGA
multiple-gated acquisition
NCI
National Cancer Institute
NHL
Non-Hodgkin’s lymphoma
NONMEM
non-linear mixed effects modeling
ORR
objective response rate 
OS
overall survival 
PCR
polymerase chain reaction
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetics 


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Abbreviation
Definition
PO
oral
PR
partial response 
PT
prothrombin time
PTT
partial thromboplastin time 
RBC
red blood cell
RIV
rituximab IV 
RSC
rituximab SC
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous 
SD
standard deviation 
SOC
standard-of-care 
TLS
tumor-lysis syndrome 
ULN
upper limit of normal 
WBC
white blood cell
WFI
Water for Injection
WHO
World Health Organization 


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1.
BACKGROUND
1.1
BACKGROUND ON NON-HODGKIN’S LYMPHOMA: DIFFUSE 
LARGE B-CELL LYMPHOMA AND CURRENT STANDARD OF 
CARE
Non-Hodgkin’s lymphoma (NHL) ranked as the 5th to 9th most common cancer in most 
countries worldwide, with almost 510,000 new cases estimated in 2018. In China, 
88,090 new cases of NHL are expected every year (Globocan 2018).  The majority of 
NHLs are of B-cell origin and are characterized by the expression of a membrane 
antigen, CD20, which is important in cell cycle initiation and differentiation (Anderson et 
al. 1984).
Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of NHL 
in China, accounting for approximately 54% of B-NHL cases (Chen 2011).  DLBCL 
arises from mature B cells, the majority of which express a CD20 positive cell surface 
protein.  Patients with DLBCL present with rapidly enlarging masses, often with 
symptoms both local and systemic, fever, recurrent night sweats, or weight loss (B 
symptoms).  Forty-five percent to 60% of patients present with advanced-stage disease 
(Ann Arbor Stage III or IV).  The incidence of DLBCL increases with age, with a median 
age of 64 at presentation (Flowers et al. 2010).
The International Prognostic Index (IPI) for aggressive NHL (e.g., DLBCL) identifies five 
risk factors prognostic of overall survival (OS):

Age (60 vs. 60 years)

Serum lactate dehydrogenase level (normal vs. elevated)

Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs. 2–4)

Stage (I or II vs. III or IV)

Extranodal site involvement (0 or 1 vs. 2–4)
Patients with two or more risk factors have a 50% chance of relapse after 5 years. 
Study LNH98-5 (GELA) identified patients at high risk of relapse on the basis of specific 
sites of involvement, including bone marrow, central nervous system (CNS), liver, lung, 
and spleen.  Molecular profiles of gene expression created by using DNA microarrays 
may be used to help stratify patients for new therapies that are targeted to better predict 
survival after standard chemotherapy (Shipp et al. 1993; Rosenwald et al. 2002; Lossos 
et al. 2004; Abramson et al. 2005; Feugier et al. 2005; de Jong et al. 2007; Fu et al. 
2008).
The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, prednisone
(CHOP)-based chemotherapy improves patient outcomes, as demonstrated in three 
randomized prospective studies consisting of approximately 2000 (60 or 60 years of 
age, depending on the study) previously untreated patients with advanced DLBCL.


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Study LNH98-5 (GELA) randomized 399 patients 60 years of age who had DLBCL in a 
1:1 ratio to receive CHOP alone or rituximab in combination with CHOP (R-CHOP) 
(Coiffier et al. 2002).  All patients received up to eight 3-week cycles of CHOP induction 
therapy.  Patients in the R-CHOP arm received 375 mg/m2 rituximab on Day 1 of each 
cycle.  The median event-free survival was 1.1 years in the CHOP arm and 2.9 years in 
the R-CHOP arm, with OS rates of 58% and 69%, respectively, at 2 years.  The 10-year 
follow-up of patients in Study LNH98-5 (GELA) showed OS rates of 44% in the R-CHOP 
arm and 28% in the CHOP arm (Coiffier et al. 2010).
Study E4494 randomized 632 patients 60 years of age who had DLBCL in a 1:1 ratio to 
receive treatment with CHOP alone or with R-CHOP.  Patients received six or eight 
cycles of CHOP, with each cycle lasting 21 days.  Patients in the R-CHOP arm received 
four doses of 375 mg/m2 rituximab on Days −7 and −3 (prior to Cycle 1) and 48−72 
hours prior to Cycle 3 and 5.  Patients who received eight cycles of CHOP also received 
rituximab prior to Cycle 7.  The median progression-free survival (PFS) was 3.1 years in 
the R-CHOP arm and 1.6 years in the CHOP arm, with OS rates of 74% and 63%, 
respectively, at 2 years (Habermann et al. 2006).
The MabThera International Trial (MInT) evaluated a total of 823 patients 18−60 years of 
age who had DLBCL (Pfreundschuh et al. 2006).  Patients were randomized in a 1:1 
ratio to receive an anthracycline-containing chemotherapy regimen given alone or in 
combination with rituximab.  The survival rate at 2 years was 86% in the chemotherapy 
arm and 95% in the chemotherapy rituximab arm (Pfreundschuh et al. 2006).
These three studies led to the approval of rituximab for the treatment of DLBCL in the 
United States, the European Union, China and other countries.
According to the 2009 European Society for Medical Oncology DLBCL clinical practice 
guidelines, for young, low- and low-intermediaterisk patients (age-adapted IPI 1), six 
or eight cycles of CHOP combined with six or eight doses of rituximab is the current 
standard treatment; for high- and high-intermediaterisk patients, six or eight cycles of 
CHOP combined with eight doses of rituximab is most frequently administered (Tilly et al. 
2015).  Among patients with advanced-stage disease, 50% are cured with doxorubicin-
based combination chemotherapy and rituximab (Coiffier et al. 2002; Coiffier 2005; 
Habermann et al. 2006).
On the basis of the three studies, eight cycles of rituximab administered intravenously 
combined with six or eight cycles of CHOP is considered standard of care for patients 
with advanced DLBCL (National Comprehensive Cancer Network 2019; National 
Comprehensive Cancer Network 2017 [Chinese]) and will serve as the control arm for 
this study.


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1.2
BACKGROUND ON RITUXIMAB SUBCUTANEOUS
In contrast to the intravenous (IV) infusion, rituximab subcutaneous (SC) injection takes 
only a few minutes. In previous studies, predominantly conducted in Caucasian patients 
leading to approval of rituximab SC in Europe, the USA and the rest of the world, the 
subcutaneous administration of rituximab was demonstrated to result in non-inferior 
rituximab levels compared with the IV rituximab admiration and comparable efficacy and 
safety while markedly reducing the treatment burden for patients and improving the 
resource utilization at the treatment facilities (de Cock E, et al. 2016; Rummel M, et al. 
2017 ). The simplicity of the SC injection is therefore expected to significantly reduce 
the time a patient spends in the hospital and eliminate hospital burden associated with 
IV administration. In this context it is envisaged that a SC formulation of rituximab would 
bring significant and clinically meaningful benefits to patients as well as an improved 
resource utilization to treatment facilities also in China.
The active ingredient of the rituximab SC injection, the study drug, is rituximab.  In order 
to reduce the volume needed for therapeutic doses, the rituximab SC formulation 
contains a 12-fold increased rituximab concentration (120 mg/mL) compared with the 
rituximab IV formulation (10 mg/mL).
In addition, rituximab SC contains human recombinant hyaluronidase, rHuPH20, 
developed by Halozyme Therapeutics, as an excipient at a concentration of 2000 U/mL 
for injection in order to allow the installation of the relatively large volume of 11.7 mL into 
the SC tissue.  Halozyme Therapeutics received approval from the U.S. Food and Drug 
Administration (FDA) in 2005 for an injectable formulation of rHuPH20 (Hylenex), which 
has been shown to increase the dispersion and absorption of co-administered drugs 
when given subcutaneously.
The rituximab SC formulation contains 2000 U/mL rHuPH20 excipient acting as a 
permeation enhancer. By reversible hydrolysis of hyaluron in the hypodermis, rHuPH20 
temporarily opens the interstitial space in the SC tissue to allow the infusion of large 
volumes of rituximab with an improved delivery into systemic circulation.
The dose of rituximab SC that will be used in this trial was established in the Phase Ib 
Study BP22333 and further confirmed in the Phase III Study BO22334.
Study BP22333 was a two-stage, randomized, open-label, multicenter Phase Ib trial 
investigating the pharmacokinetics (PK), safety, and tolerability of rituximab SC in 
patients with follicular lymphoma (FL) as part of maintenance treatment.  BP22333 was 
designed to determine and confirm the SC rituximab dose that yielded non-inferior
steady-state concentration at the end of a dosing interval (Ctrough) compared to the 
standard IV dose (375 mg/m2) in the maintenance setting. Results from Stage 1 have 
been reported (Salar et al. 2010). Based on modeling and simulation of PK data from 
Stage 1, a fixed dose of 1400 mg (used in Stage 2) was established and considered to 
be non-inferior to the rituximab IV dose of 375 mg/m2.  The results of Stage 2 of the 


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BP22333 trial examining the rituximab levels after SC injection compared to IV infusion
(SC/IV ratio) confirm that the selected SC dose of 1400 mg produces non-inferior 
rituximab levels. This has been assessed by non-inferiority testing with a lower 
boundary above 0.8 for the 90% confidence interval (CI). The estimated Ctrough SC/IV 
ratio was 1.24 (90% CI: 1.02, 1.51) for the 2-monthly regimen and 1.12 (90% CI: 0.86, 
1.45) for the 3-monthly treatment interval in patients with CD20 positive indolent NHL 
during maintenance. Additionally, the estimated area under the concentration–time curve 
(AUC) SC/IV ratio was 1.35 (90% CI: 1.23, 14.9) and 1.35 (90% CI: 1.23, 1.48) for the 2-
and 3-monthly regimens, respectively. For Stage 1, the most informative safety data 
were derived following the single cycle of randomized rituximab IV/SC treatment. Aside 
from administration-related reactions (ARRs), the incidence and types of adverse events 
(AEs) were similar across treatment cohorts. There were no clear trends related to 
event incidence or intensity/seriousness and dose of study drug.  Forty-three patients 
included in the SC extension had a longer exposure to rituximab SC than the other 
patients in Stage 1 (who received only a single dose of rituximab SC) and they received 
a cycle of rituximab SC, followed by cycles of rituximab IV, and then 1–5 further cycles of 
rituximab SC at the final selected dose of 1400 mg. Twenty-three of forty-three patients 
(53%) experienced at least one AE during the SC extension, the most commonly 
reported AE by preferred term being ARRs. Four patients (9%) each reported a Grade 3 
AE, three of which were also considered serious. Four patients (9%) in total 
experienced serious adverse events (SAEs) during the SC extension. In Stage 2, the 
proportion of patients who experienced one or more AEs was similar following treatment 
with either rituximab SC 1400 mg or rituximab IV 375 mg/m2. The incidence of severe 
(Grade 3) AEs, SAEs, and AEs leading to withdrawal was also balanced following SC 
and IV treatment. There was one fatal AE in each treatment group; both events were 
considered by the investigator to be unrelated to study drug. The incidence of ARRs
was higher in the rituximab SC cohort than in the rituximab IV cohort; however, no ARRs 
across either cohort were reported to be serious or severe. The imbalance regarding 
ARRs reflects the expected change in ARR profile as a result of the SC route of 
administration and is assessed to be a change that is not medically relevant to the 
overall safety profile of rituximab.
Study BO22334 was a randomized, open-label, multicenter, two-stage, two-arm 
comparative Phase III study of rituximab SC with CHOP or cyclophosphamide, 
vincristine, prednisone (CVP) induction treatment followed by rituximab SC maintenance 
treatment versus rituximab IV with CHOP or CVP induction treatment followed by 
rituximab IV maintenance treatment.  A total of 410 patients were randomized: 205 
patients to rituximab IV and 205 patients to rituximab SC. The eligible patient population 
was adult patients with previously untreated, CD20 positive FL of Grade 1, 2, or 3a 
requiring therapy. The primary endpoint for Stage 1 of the study (noninferiority of 
trough serum concentrations [Ctrough] at Cycle 7) was met.  Non-inferior Ctrough with the 
fixed rituximab SC dose of 1400 mg was demonstrated compared with rituximab IV 
375 mg/m2 given every 3 weeks. The ratio Ctrough,SC/Ctrough,IV at Cycle 7 was 1.62 (90% CI:


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1.36,1.94). The coefficients of variation (CVs) for Ctrough at Cycle 7 were 43.2% in the 
rituximab SC arm and 36.7% in the rituximab IV arm, demonstrating comparable 
variability in the two treatment arms. The geometric mean AUC was also higher in the 
rituximab SC arm, with observed rituximab serum AUC(SC)/AUC(IV) ratio during Cycle 7 of 
1.38 (90% CI: 1.24,1.53) and comparable variability between the two arms (coefficient of 
variation [CV] 33.7% in the rituximab SC arm and CV 28.0% in the rituximab IV arm).
Data on B-cell levels (CD19+ counts) showed similar trends in both treatment arms, with 
significant depletion of peripheral B-cells following Cycle 1 (rituximab IV) and continued 
depletion with additional cycles in the induction and maintenance phases. Based on the 
investigator assessments, objective response rate (ORR) results at the end of induction 
were comparable between the arms: 84.9% (95% CI: 79.2%, 89.5%) in the rituximab IV 
arm versus 84.4% (95% CI: (78.7%, 89.1%) in the rituximab SC arm. Point estimates 
and 95% CIs for complete response (complete response [CR] or complete response 
unconfirmed [CRu]) at the end of induction were identical between the treatment arms: 
32.2% (95% CI: 25.9%, 39.1%). Based on the unstratified analyses, the time-to-event 
endpoints of PFS (hazard ratio [HR] = 0.84; 95% CI: 0.57, 1.23), event-free survival 
(EFS) (HR = 0.91; 95% CI: 0.64, 1.31), OS (HR = 0.81; 95% CI: 0.42, 1.57), showed no 
evidence of difference in efficacy of SC formulation compared with the IV formulation 
and provided further evidence that the SC route of administration of rituximab had no 
impact on long-term efficacy, based on the median duration of observation of 
approximately of 37 months. The safety profile of rituximab SC was comparable to that 
of rituximab IV, with the exception of mainly mild to moderate ARRs and local cutaneous 
reactions reflecting the safety profile when switching to the SC route of administration.
See the rituximab SC Investigator’s Brochure (IB) for details on nonclinical and clinical 
studies.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Rituximab IV is administered as an infusion over several hours (4 to 6 hours).  
Frequently observed infusion-related reactions (IRRs) may require prolonging the 
infusion time further.  These long infusion times and the side effects related to the 
infusion were cited by some patients as uncomfortable consequences of the current 
therapeutic treatment (Coates et al. 1983). Furthermore, the required procedure to 
establish IV access is considered invasive and can be painful, particularly in patients 
with malignant diseases who are treated repeatedly.  Rituximab for SC administration 
has been developed to address these limitations (e.g., IRRs, long administration times, 
hospital facilities requirements, difficulty in treating patients with poor venous vascular 
conditions).  SC administration of rituximab takes significantly less time (several minutes) 
compared with IV infusion and this is expected to improve treatment convenience, 
patient satisfaction and compliance.  Hence, the development of a rituximab SC 
formulation addresses an unmet medical need. The previously performed global clinical 
trial program consisted of several studies conducted with rituximab SC in different


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settings of indolent NHL: maintenance (BP22333), induction and maintenance
(BO22334), and chronic lymphocytic leukemia (CLL) (BO25341).
Previously, SC administration of rituximab has been hindered by the relatively large 
volume required. These hurdles have now been overcome by concentrating the IV 
rituximab formulation 12-fold and by adding rHuPH20 as a novel excipient and a 
permeation enhancer. As a recombinant human hyaluronidase, rHuPH20 hydrolyses 
hyaluronic acid fibers and reversibly opens the interstitial space in the subcutaneous
tissue, allowing injection volumes larger than 2 to 3 mL. The approved indication for 
rHuPH20 includes “hypodermoclysis” (i.e., SC injection/infusion of fluid in large volume).
This study will explore the efficacy of rituximab SC and rituximab IV, respectively, in 
previously untreated DLBCL patients, based on the complete response rate (CRR)
observed with each formulation.
Rituximab IV and SC have a well-established benefit-risk profile and are approved in 
more than 90 countries or regions.  The SC formulation is expected to bring significant 
and clinically meaningful benefits to Chinese patients in terms of improved tolerability 
with potentially fewer and less severe ARRs.  This expectation is based on rituximab 
peak serum concentrations after SC administration, which are attained more slowly than 
after IV, as well as an improved treatment convenience due to the faster and more 
convenient SC administration. Safety data collected for patients exposed to rituximab 
SC during study BP22334 and BO22334 revealed no safety signals other than those 
expected with exposure to rituximab IV.  Therefore, the overall benefit-risk assessment 
of the current study is considered to be positive.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the pharmacokinetics, efficacy, and safety of rituximab SC 
compared with rituximab IV, both in combination with CHOP, in previously untreated 
patients with CD20 positive DLBCL.  Specific objectives and corresponding endpoints for 
the study are outlined below.
In this protocol, "study treatment" refers to the treatment of rituximab SC + CHOP 
chemotherapy (RSC-CHOP) and the treatment of rituximab IV + CHOP chemotherapy 
(RIV-CHOP).
2.1
PRIMARY OBJECTIVE
The primary objective of this study is to demonstrate the non-inferiority of rituximab 
serum Ctrough obtained at Cycle 7, 21 days after SC administration, with that obtained at 
Cycle 7, 21 days after IV administration on the basis of the following endpoint:

Ratio of Ctrough,SC/Ctrough,IV during Cycle 7


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2.2
SECONDARY OBJECTIVES
The secondary objectives of this study are to compare and assess other PK parameters, 
efficacy and safety profiles (including immunogenicity) of rituximab SC and rituximab IV, 
both in combination with CHOP, on the basis of the following endpoints and outcome 
measures:

Ratio of AUCSC/AUCIV during Cycle 7

Other PK parameters, such as AUC and Ctrough at other treatment cycles, maximum 
serum concentration (Cmax), total clearance, volume of distribution at steady state, 
and terminal half-life (t1/2) (if feasible or appropriate) as appropriate

Complete response rate (CRR) at the end of the study treatment, as determined by 
the Independent Review Committee (IRC) using Lugano Response Criteria for 
Malignant Lymphoma (Cheson et al. 2014) as key efficacy endpoint

Objective response rate (ORR), defined as CR or partial response (PR) at the end 
of the study treatment, as determined by investigator and IRC using Lugano 
Response Criteria for Malignant Lymphoma (Cheson et al. 2014)

CRR (CR, CRu) at the end of study treatment, as determined by IRC using 
International Working Group (IWG) Response Criteria for NHL 1999 Guidelines

CRR at the end of the study treatment, as determined by the investigator using 
Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) 

Safety outcomes as assessed by adverse events, including rituximab 
administration-related reactions (ARRs), laboratory assessments, and vital signs; 
and immunogenicity as assessed by anti-rituximab antibodies and anti-rHuPH20 
antibodies
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design and Dosing Regimen
This is a Phase II, multicenter, randomized, controlled, open-label, China-only study to 
investigate the PK, efficacy, and safety of rituximab SC in combination with CHOP 
versus rituximab IV in combination with CHOP in previously untreated patients with 
CD20 positive DLBCL. This study will be conducted at approximately 8 sites in China.  
Approximately 50 patients will receive eight cycles of rituximab SC or rituximab IV 
combined with six or eight cycles of standard CHOP chemotherapy. Centers must 
choose whether they plan to administer six or eight cycles of CHOP chemotherapy prior 
to study start.  Previous results have demonstrated that a fixed rituximab SC dose at 
1400 mg is expected to achieve non-inferior Ctrough values to the rituximab IV regimen 
(375 mg/m2) prior to Cycle 8 (Study BO22334). In this study, a sample size of 50
patients (approximately 18 evaluable patients per arm) who have completed Cycle 7 will
be adequate for testing non-inferiority for the estimated ratio Ctrough,SC/Ctrough,IV. The 
overall study design is illustrated in Figure 1. Previously untreated patients with CD20


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positive DLBCL will be randomized into the following two treatment groups at a 1:1 ratio
(crossover to the experimental arm is not permitted):

RSC-CHOP:  Cycle 1 rituximab IV plus seven cycles of rituximab SC in combination 
with six or eight cycles of CHOP chemotherapy administered every 3 weeks;
rituximab IV will be used at the standard dose of 375 mg/m2 and rituximab SC will 
be given at a dose of 1400 mg as confirmed in the Phase III Study BO22334.

RIV-CHOP:  eight cycles of rituximab IV in combination with six or eight cycles of 
CHOP chemotherapy administered every 3 weeks; rituximab IV will be used at the 
standard dose of 375 mg/m2.
Figure 1
Dosing Schema
CHOPcyclophosphamide, doxorubicin, vincristine, and prednisone; DLBCLdiffuse large B-cell 
lymphoma; IVintravenous; SCsubcutaneous.
Fifty patients will be randomized into the study with intensive PK sampling to confirm the 
non-inferiority of the 1400 mg SC dose to IV 375 mg/m2 dose.
Eligible patients will be stratified during randomization according to IPI scores (IPI 0-2 
versus IPI 35).  
IPI score is widely accepted as the prognostic index, which predicts the risk of disease 
recurrence and overall treatment outcome in this patient population through five adverse 
prognostic risk factors: disease stage, age, ECOG performance status, serum lactate 
dehydrogenase (LDH) levels, and the presence or absence of multiple extranodal sites 
of lymphoma (Appendix 5).  Stratification during randomization will group patients with 
highest-risk disease (IPI 4-5) and high-intermediate risk disease (IPI 3), as these 
patients have been found across studies to have the poorest outcomes from R-CHOP 
treatment (Sehn et al. 2007; Zhou et al. 2014).  The IPI 3-5 group will be stratified 
against IPI 0-2, a population with low and low-intermediate risks, who typically have 
better prognosis but continue to have unmet medical need.
Please refer to Section 4.3 for additional information on RIV-CHOP and RSC-CHOP 
administrations.


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Patients will be assessed for disease response by the investigator and IRC, on the basis 
of regular clinical and laboratory examinations, physical examinations, computed 
tomography (CT) scans, positron emission tomography (PET)-CT scans, and bone 
marrow examinations, according to the Lugano Response Criteria for Malignant 
Lymphoma (Cheson et al. 2014; see Appendix 3). PET-CT and dedicated CT scans will 
be obtained at screening and 6-8 weeks after completion of study treatment, or sooner in 
the event that a patient discontinues early.  An interim assessment will be obtained after 
Cycle 4 and should include PET-CT and dedicated CT.  If local practice prohibits 
obtaining both assessments after Cycle 4, PET-CT alone (preferred) or CT alone may be 
obtained at this time point.  During the follow-up period, imaging (may be CT only) will be 
performed every 3 months, i.e., Week 12 and 24 after last treatment, in accordance with 
study visits and will include the neck (if involved at baseline), chest, abdomen, and pelvis.
Diagnostic contrast enhanced CT scans obtained as part of a PET-CT scan may be 
used in lieu of dedicated CT scans. Contrast-enhanced CT scan should include the 
chest, abdomen, pelvis (including inguinal/femoral regions), and, if clinically indicated, 
the neck or other anatomic locations.  In case of any suspected disease progression by 
the investigator, a full tumor assessment including anatomic scans must be performed.  
At all times during the course of the study, disease progression diagnosed based on 
clinical examination must be confirmed by imaging (e.g., CT, PET-CT) as soon as 
feasible (maximum, within 30 days) and prior to initiation of non-protocol specified anti-
lymphoma therapy.  See Section 4.5.5 and Appendix 1 for details on the tumor 
evaluation and response.
After the end of study treatment, patients will be followed-up every 3 months for 
6 months (i.e., 12 and 24 weeks after the last dose of study treatment).  Assessments 
will include clinical evaluation of tumor response/progression, PK and immunogenicity 
(blood sampling), physical examination, standard hematologic and biochemistry 
assessments, vital signs and weight measurements, liver and spleen size and 
B-symptoms assessments.
Safety will be evaluated by monitoring all adverse events, and abnormalities identified 
through physical examination, vital signs, and laboratory assessments.  Such events will 
be graded using the National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5 (NCI CTCAE v5.0).  Laboratory safety assessments will include the 
routine monitoring of hematology and blood chemistries.
In addition, PK samples (see Section 4.5.7) and samples for assessing immunogenicity 
(see Sections 4.5.6 and 4.5.8) will be taken.
The schedules of assessments are provided in Appendix 1 and Appendix 2.
3.1.2
Independent Review Committee
An IRC composed of certified radiologists and a hematologist or oncologist with 
experience in malignant lymphoma will assess all patients for response according to 


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Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (see 
Appendix 3) and IWG Response Criteria for NHL 1999 Guidelines, respectively, on the 
basis of imaging results and biopsy results that are performed related to efficacy 
evaluation.  Decisions will be guided by a Charter specific to the independent review.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of study is defined as the date when the last patient last visit (LPLV) occurs. 
LPLV is expected to occur approximately 6 months after the last patient enrolled has 
received the last study treatment, or sooner, if all patients have progressed, died, or 
withdrawn from the study. The Sponsor has the right to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Rituximab Subcutaneous Dose and Schedule
The dose of 1400 mg rituximab SC that will be used in this trial was established in the 
Phase Ib study BP22333 and further confirmed in the pivotal Phase III study BO22334.
The results of these 2 studies are summarized in Section 1.2 and details on study design, 
dose rationale, and results can be found in the respective clinical study reports (the 
reports will be available on request).
The efficacy, safety and PK results of the pivotal Phase III study BO22334 (a two-stage, 
randomized, controlled, open-label study to investigate the PK, efficacy and safety of 
rituximab SC in combination with CHOP or CVP versus rituximab IV in combination with 
CHOP or CVP in 410 patients with previously untreated FL) confirmed that the fixed SC 
dose of 1400 mg was efficacious and safe:
The primary endpoint of the study was met: non-inferior Ctrough with the fixed rituximab 
SC dose of 1400 mg was demonstrated compared with rituximab IV 375 mg/m2 given 
every 3 weeks in combination with CHOP or CVP chemotherapy as induction treatment.  
The ratio of Ctrough,SC/Ctrough,IV at Cycle 7 was 1.62 (90% CI: 1.36,1.94). The CVs for 
Ctrough at Cycle 7 were 43.2% in the rituximab SC arm and 36.7% in the rituximab IV arm, 
respectively, demonstrating comparable variability in the two treatment arms.
The efficacy data for ORR and CRR as well as PFS and OS data for rituximab SC were 
comparable to those of rituximab IV and indicated that the anti-lymphoma activity of 
rituximab was not impaired when given subcutaneously.
The safety profile of rituximab SC was comparable to that of rituximab IV with the 
exception of ARRs and local cutaneous reactions, which were manageable and 
expected. With the exception of the anticipated administration reactions, SC formulation 
did not cause any additional safety burden compared with the IV formulation during the 
induction and maintenance phases, hence demonstrating a positive benefit-risk profile of 
the SC formulation without compromising the safety of rituximab.


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The PK, efficacy and safety following rituximab IV or SC are expected to be comparable 
between Asian and non-Asian patients, and therefore the fixed SC dose of 1400 mg 
rituximab will be used also in this trial, which is conducted in Chinese patients.
For a dose of 1400 mg, a patient will receive a subcutaneous dosing volume of 11.7 mL 
(see Section 4.3.1.2).
3.3.2
Rationale for Study Design
This is a Phase II, prospective, multicenter, randomized, controlled, open-label, China-
only study to estimate the PK parameters, meanwhile collecting data of efficacy and 
safety for rituximab SC and rituximab IV, both in combination with CHOP chemotherapy, 
in approximately 50 adult patients with previously untreated CD20 positive DLBCL.
Screening and pre-treatment (baseline) evaluations will also include Ann Arbor staging, 
ECOG performance status, and IPI score.  The IPI has been the primary clinical tool 
used to predict outcome for patients with aggressive NHL.  Based on the number of 
negative prognostic factors present at the time of diagnosis (age 60 years, stage III/IV 
disease, elevated LDH level, ECOG performance status 2, more than one extranodal 
site of disease), 4 discrete outcome groups were identified (high risk, highintermediate
risk, lowintermediate risk and low risk) with a 5-year overall survival ranging from 26% 
to 73%.
Randomization will be stratified according to IPI score (IPI 0-2 versus IPI 35).
The key efficacy endpoint is the CRR at the end of study treatment determined by IRC 
using the Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014), i.e.,
68 weeks after the last dose of study treatment or 48 weeks after last dose of study 
treatment for early discontinuation.  The response will be assessed on the basis of
radiographic (PET-CT scans, diagnostic CT scans [or magnetic resonance imaging (MRI)
scans]) and clinical evidence of disease including bone marrow examinations, through 
use of the Lugano Response Criteria for Malignant Lymphoma (Appendix 4). The widely 
used Lugano criteria are based predominantly on PET-CT scan and include CT scan as 
part of the response assessment.  PET using [18F]fluorodeoxyglucose (FDG) has since 
emerged as a powerful functional imaging tool for staging, restaging, and response 
assessment of lymphomas.  PET-CT and dedicated CT scans will be obtained at 
screening and 6-8 weeks after completion of study treatment, or sooner in the event that 
a patient discontinues early. An interim assessment will be obtained after Cycle 4 and 
should include PET-CT and dedicated CT. If local practice prohibits obtaining both 
assessments after Cycle 4, PET-CT alone (preferred) or CT alone may be obtained at 
this time point. During the follow-up period, imaging (may be CT only) will be performed 
every 3 months, i.e., Week 12 and 24 after last treatment, in accordance with study visits 
and will include the neck (if involved at baseline), chest, abdomen, and pelvis.  Magnetic 
resonance imaging (MRI) may be used instead of CT scans with contrast in patients for 
whom CT scans with contrast are contraindicated.


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The study treatment regimen selected for both treatment groups is consistent with the 
approved dosing for rituximab IV and standard treatment practices.  Due to the inherent 
differences between the two rituximab formulations, treatment assignment will not be 
blinded in this study.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients with previously untreated, CD20 positive advanced DLBCL who meet below 
eligibility criteria as defined in Sections 4.1.1 and 4.1.2 will be enrolled in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able and willing to provide written informed consent and to comply with the study 
protocol

Age 18 and 80 years at time of signing Informed Consent Form

Previously untreated CD20 positive DLBCL histologically documented

Patients with an IPI score of 1 to 5 or IPI score of 0 with bulky disease, defined as 
one lesion 7.5 cm (see Appendix 5) 

At least one bi-dimensionally measurable lesion defined as 1.5 cm in its largest 
dimension on CT scan 

ECOG performance status of 0, 1, or 2 (see Appendix 6)

Left ventricular ejection fraction (LVEF) 50% on cardiac multiple-gated acquisition 
(MUGA) scan or cardiac echocardiogram

A negative serum pregnancy test or a negative urine pregnancy test within 7 days 
prior to study treatment must be available both for pre-menopausal women 
(including those who have had a tubal ligation) and for women who are less than 
2 years after the onset of menopause; if negative serum pregnancy test is within 
14 days of study treatment start, a confirmatory urine pregnancy test must be
available within 7 days prior to study treatment start

For men who are not surgically sterile, agreement to use a barrier method of 
contraception during the treatment period and until 12 months after the last dose of 
rituximab SC or rituximab IV or according to institutional guidelines for CHOP 
chemotherapy, whichever is longer, and agreement to request that their partners 
use an additional method of contraception, such as oral contraceptives, intrauterine 
device, barrier method, or spermicidal jelly

For women of reproductive potential who are not surgically sterile, agreement to use 
adequate methods of contraception, such as oral contraceptives, intrauterine device, 
or barrier method of contraception in conjunction with spermicidal jelly during the 
treatment period and until 12 months after the last dose of rituximab SC or 
rituximab IV or according to institutional guidelines for CHOP chemotherapy, 
whichever is longer


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
Adequate hematologic function confirmed within 14 days prior to randomization 
which is independent to stimulating factors and transfusion (unless related to 
lymphoma infiltration of the bone marrow)

Hemoglobin 9.0 g/dL

Absolute neutrophil count (ANC) 1.5 109/L

Platelet count 75 109/L
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Transformed NHL or types of NHL other than DLBCL and its subtypes according to 
World Health Organization classification

History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies or known sensitivity or allergy to murine products 

Contraindication to any of the individual components of CHOP, including prior 
receipt of anthracyclines

Prior therapy for DLBCL, with the exception of nodal biopsy or local irradiation or 
surgery for diagnosis

Prior treatment with cytotoxic drugs or rituximab for another condition (e.g., 
rheumatoid arthritis) or prior use of an anti-CD20 antibody

Current or recent (within the 30 days prior to starting study treatment) treatment with 
another investigational drug or participation in another investigational therapeutic 
study

Ongoing corticosteroid use, 30 mg/day of prednisone or equivalent

Patients receiving corticosteroid treatment with 30 mg/day of prednisone 
or equivalent must be documented to be on a stable dose for duration of at 
least 4 weeks prior to randomization.

Primary CNS lymphoma, blastic variant of mantle cell lymphoma, or histologic 
evidence of transformation to a Burkitt lymphoma, primary mediastinal DLBCL, 
primary effusion lymphoma, and primary cutaneous DLBCL

History of other malignancy that could affect compliance with the protocol or 
interpretation of results

Patients with a history of curatively treated basal or squamous cell 
carcinoma or melanoma of the skin or in situ carcinoma of the cervix are 
eligible.

Patients with a malignancy that has been treated but not with curative 
intent will also be excluded unless the malignancy has been in remission 
without treatment for 5 years prior to enrollment.

Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including but not limited to 
significant cardiovascular disease (such as New York Heart Association Class III or 


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IV cardiac disease, myocardial infarction within the last 6 months, unstable 
arrhythmias, or unstable angina) or pulmonary disease (including obstructive 
pulmonary disease and history of bronchospasm)

Any of the following abnormal laboratory values:

Creatinine 1.5 upper limit of normal (ULN) (unless creatinine clearance 
normal) or calculated creatinine clearance 40 mL/min (using the 
Cockcroft-Gault formula)

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
2.5 ULN

Total bilirubin 1.5 ULN; patients with documented Gilbert disease may 
be enrolled if total bilirubin is 3.0 ULN

International normalized ratio (INR) 1.5 ULN in the absence of 
therapeutic anticoagulation

Partial thromboplastin time (PTT) or activated Partial thromboplastin time 
(aPTT) 1.5 ULN in the absence of a lupus anticoagulant

Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive 
hepatitis B surface antigen [HBsAg] serology) 

Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive total hepatitis B core antibody [HBcAb]) may be included if HBV 
DNA is undetectable, provided that they are willing to undergo monthly 
DNA testing during the treatment period and the follow-up period. 

Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)

Patients positive for HCV antibody are eligible only if polymerase chain 
reaction (PCR) is negative for HCV RNA.

Known history of human immunodeficiency virus (HIV) seropositive status or 
infection

Signs or symptoms of other active and/or severe infection

Evidence of any other disease, metabolic dysfunction, physical examination finding, 
or clinical laboratory finding giving reasonable suspicion of a disease or condition 
that contraindicates use of an investigational drug or patient at high risk from 
treatment complications

Any co-existing medical or psychological condition that would compromise ability to 
give informed consent
4.2
METHOD OF TREATMENT ASSIGNMENT
4.2.1
Treatment Assignment
This is a randomized open-label study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS).


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Patients will be randomly assigned to one of two treatment arms of RIV-CHOP or RSC-
CHOP.  Randomization will occur in a 1:1 ratio through use of a permuted-block 
randomization method to ensure a balanced assignment to each treatment arm.  
Randomization will be stratified according to IPI scores (IPI 0-2 versus IPI 3-5).
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are rituximab IV
(comparator), and rituximab SC (experimental).  Both rituximab IV and rituximab SC will 
be used in combination with CHOP.  Both IMPs will be supplied by the Sponsor.  For 
further information on the formulation, packaging and handling of rituximab IV and 
rituximab SC, see the rituximab Oncology IV IB and rituximab SC IB, respectively; for 
that of CHOP chemotherapy, see the local prescribing information.
4.3.1
Investigational Medicinal Product
4.3.1.1
Rituximab IV (Comparator Investigational Medicinal Product)
Rituximab IV will be provided as 500 mg/50 mL (RO0452294/V02) liquid-filled vials with 
a nominal content of 10 mg/mL rituximab. The drug product contains sodium acetate 
(buffer), sodium chloride (tonicity adjustment), and polysorbate 80 (surfactant) in Water 
for Injection (WFI) at a pH of 6.5. The drug product is a sterile, colorless to pale yellow 
liquid.
Preparation and Administration of Rituximab IV Formulation
The qualified individual responsible for dispensing the study drug will prepare the correct 
dose.  This individual will write the date dispensed and patient number on the study drug 
vial label and on the Drug Accountability Record.  This individual will also record the 
study drug batch or lot number received by each patient during the study.
Patients receiving rituximab IV will be administered a dose of 375 mg/m2.  The 
appropriate amount of solution should be withdrawn from the vial using the following 
calculation:
Volume (mL)Body Surface Area (BSA) (m2)dose (375 mg/m2)/concentration of 
reconstituted solution mg/mL (500 mg/50 mL)
The recommended initial rate for infusion is 50 mg/hour.  After the first 30 minutes, it can 
be escalated in 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour. 
Subsequent doses of rituximab IV can be infused at an initial rate of 100 mg/hour and 
increased by 100 mg/hour increments at 30-minute intervals, to a maximum of 
400 mg/hour.
The prepared rituximab IV solution should be administered as an intravenous infusion 
through a dedicated line.  It should not be administered as an intravenous push or bolus.  


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Patients should be closely monitored for the onset of cytokine release syndrome. In 
patients who develop evidence of severe reactions, especially severe dyspnea, 
bronchospasm, or hypoxia, the infusion should be interrupted immediately.  Patients 
should then be evaluated for evidence of tumor lysis syndrome, including appropriate 
laboratory tests and, for pulmonary infiltration, with a chest X-ray.  In all patients, the 
infusion should not be restarted until the complete resolution of all symptoms and the 
normalization of laboratory values and chest X-ray findings.  At this time, the infusion 
can be initially resumed at not more than one-half the previous rate.  If the same severe 
adverse reactions occur for a second time, the decision to stop the treatment should be 
evaluated on a case-by-case basis.  Mild or moderate ARRs usually respond to a 
reduction in the rate of infusion.  The infusion rate may be increased upon improvement 
of symptoms.  See Table 1 for further details on the administration of rituximab IV in the 
first and subsequent infusions.
Table 1
Administration and Dose Modification of First and Subsequent 
Infusions of Rituximab IV
First Infusion (Day 1)
Subsequent Infusions
Begin infusion at an initial rate of 
50 mg/hour.
If no infusion-associated or 
hypersensitivity reaction occurs, 
increase the infusion rate in 
50 mg/hour increments every 
30 minutes, to a maximum of 
400 mg/hour.
If an infusion reaction develops, stop 
or slow the infusion. Administer 
infusion-reaction medications and 
supportive care in accordance with 
institutional guidelines.  If the reaction 
resolves, resume the infusion at a 
50% reduction in rate (i.e., 50% of rate 
being used at the time that the 
reaction occurred).
If patients experienced an infusion-associated or a 
hypersensitivity reaction during the prior infusion, 
begin infusion at an initial rate of 50 mg/hour and 
follow instructions for the first infusion.
If the patient tolerated the prior infusion well 
(defined as an absence of Grade 2 reactions 
during a final infusion rate of 100 mg/hour), begin 
the infusion at a rate of 100 mg/hour.
If no infusion reaction occurs, increase the infusion 
rate in 100 mg/hour increments every 30 minutes,
to a maximum of 400 mg/hour.
If an infusion reaction develops, stop or slow the 
infusion.  Administer infusion-reaction medications 
and supportive care in accordance with institutional 
guidelines.  If the reaction resolves, resume the 
infusion at a 50% reduction in rate (i.e., 50% of 
rate being used at the time that the reaction 
occurred).
IV = intravenous.
Note: A fast infusion is not allowed.
4.3.1.2
Rituximab SC (Experimental Investigational Medicinal Product)
Rituximab SC (MabThera SC; RO0452294/F02-01) will be supplied as a ready-to-use 
liquid formulation with a nominal content of 120 mg/mL rituximab and must not be diluted 
prior to administration.  The drug product contains 2000 U/mL rHuPH20 acting as a 
permeation enhancer, histidine/histidine-HCl (buffer), α,α-trehalose (bulking agent), 
methionine (stabilizer), and polysorbate 80 (surfactant) in WFI at a pH of 5.5.  The drug 
product is a sterile, colorless to yellowish, clear to opalescent liquid in colorless 15-mL 


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vials (extractable volume: 11.7 mL).  Vials contain no preservative and are for single 
use only. The same formulation was used in a Good Laboratory Practice toxicity study 
described in the rituximab SC IB.
Preparation and Administration of Rituximab SC Formulation
Patients receiving rituximab SC will be administered the study drug at a dose of 1400 mg, 
and 11.7 mL of solution should be withdrawn from the vial.
The SC injection needle will be inserted using sterile technique in the SC tissue of the 
abdomen. The needle should be fully inserted, being careful that the tip of the needle is 
deeper than the dermis but not as deep as the underlying muscle. The goal of the 
placement angle and needle depth is to achieve uniform placement into subcutaneous 
tissue.  The study drug should not be injected into moles, scars, or bruises. The skin 
should be pinched and the needle inserted before the skin is released and the pressure 
on the syringe applied.
The injection should be manually pushed at a flow rate of approximately 2 mL/min,
therefore an administration volume of 11.7 mL should take approximately 5 to 6 minutes.
If there is a request by the patient to interrupt the injection, the pressure on the syringe 
should initially be eased to alleviate pain. If pain is not alleviated, the injection should be 
stopped and the patient should indicate when he/she is comfortable to resume the 
injection.
4.3.1.3
Storage, Packaging, and Labeling of Rituximab IV and SC 
Formulations
The recommended storage condition for rituximab SC is at 2°C–8°C, protected from light.  
The product should be used immediately after the first opening.  Batch-specific details 
and information on shelf-life are given on the packaging label.  Please refer to the IB of 
rituximab SC for further formulation, storage, and handling instructions for rituximab SC.
The recommended storage condition for rituximab IV is 2°C–8°C, protected from light.  
Prepared infusion solutions of rituximab are biologically and chemically stable at 
2°C8°C for 24 hours and at room temperature for an additional 12 hours. The product 
should not be used beyond the expiration date stamped on the carton.  Rituximab IV 
vials should be protected from direct sunlight.  No incompatibilities between rituximab 
and polyvinylchloride or polyethylene bags have been observed.  Please refer to the 
rituximab Oncology IV IB for further formulation, storage, and handling instructions for 
rituximab IV.
Packaging of the study drug will be monitored by the Roche Clinical Trial Supplies 
department and will bear a label with the protocol number, drug identification, dosage 
and identification as required by local law.  The packaging and labeling of the study drug 
will be in accordance with Roche standards and local regulations.


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Rituximab SC is supplied as a ready-to-use liquid formulation with a nominal content of 
120 mg/mL rituximab in 15-mL vials (12.25 mL fill).  Rituximab IV drug product will be 
provided in 500 mg/50 mL vials.
Upon arrival of the investigational products at the site, site personnel should check them 
for damage and verify proper identity, quantity, integrity of vials, and temperature 
conditions, and report any deviations or product complaints to the study monitor.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1.  Refer to the pharmacy 
manual for detailed instructions on drug preparation, storage, and administration.
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated adverse events, should be 
reported as described in Section 5.3.5.12.
Guidelines for dosage delay and modifications for patients who experience adverse 
events are provided in Section 5.1.
4.3.2.1
RIV-CHOP
Patients scheduled to be treated with RIV-CHOP will receive six or eight cycles of 
standard CHOP chemotherapy given in 21-day treatment intervals (see Table 2).  The 
sites will elect prior to study start whether they will be administering six or eight cycles of 
CHOP chemotherapy for all patients.
Institutions should follow their standard administration regimens for RIV-CHOP, including 
anti-emetics and hydration. All patients are required to receive the following oral 
premedication 30 to 60 minutes prior to starting each infusion of rituximab:

1000 mg paracetamol (acetaminophen)

50 mg to 100 mg diphenhydramine hydrochloride or alternative antihistamine
Rituximab IV will be prepared per the manufacturer’s instructions and CHOP will be 
prepared according to the standard practice at the institution.


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Table 2
Schedule of RIV-CHOP for Cycles 1 to 8
Medication
Dose
Mode
D1
D2
D3
D4
D5
Rituximab IV
375 mg/m2
IV
x a
Cyclophosphamide
750 mg/m2
IV
x
Doxorubicin
50 mg/m2
IV
x
Vincristine
1.4 mg/m2 (2 mg max)
IV
x
Prednisone
100 mg/d
PO
x b
x
x
x
x
CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone; D = day; IV intravenous; 
PO oral.
a
The first cycle of rituximab IV can be given on Day 1 or Day 2, depending on institutional 
practice.
b
Rituximab should be administered after administration of the glucocorticoid component of 
the chemotherapy if applicable.
4.3.2.2
RSC-CHOP
4.3.2.2.1
Cycle 1
Patients randomized to the RSC-CHOP arm will receive rituximab IV + CHOP in Cycle 1 
as shown in Table 3.
Table 3
Schedule of RSC-CHOP in Cycle 1
Medication
Dose
Mode
D1
D2
D3
D4
D5
Rituximab IV
375 mg/m2
IV
x a
Cyclophosphamide
750 mg/m2
IV
x
Doxorubicin
50 mg/m2
IV
x
Vincristine
1.4 mg/m2 (2 mg max)
IV
x
Prednisone
100 mg/d
PO
x b
x
x
x
X
CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone; D = day; IV intravenous; 
PO oral.
a The first cycle of rituximab IV can be given on Day 1 or Day 2, depending on institutional 
practice.
b Rituximab should be administered after administration of the glucocorticoid component of the
chemotherapy if applicable.
4.3.2.2.2
Cycles 2 to 8
Patients randomized to the RSC-CHOP arm will receive rituximab SC + CHOP from 
Cycles 2 to 8.  The second cycle of RSC-CHOP will be the first subcutaneous 
administration of rituximab.  Please see Table 4 for details.
All patients are required to receive the following oral premedication 30 to 60 minutes 
prior to starting each injection of rituximab SC:


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
1000 mg paracetamol (acetaminophen)

50 mg to 100 mg diphenhydramine hydrochloride or alternative antihistamine
Rituximab SC will be prepared and administered according to Section 4.3.1.2 and CHOP 
will be prepared according to the standard practice at the institution.
Table 4
Schedule of RSC-CHOP in Cycles 2 to 8
Medication
Dose
Mode
D1
D2
D3
D4
D5
Rituximab SC
1400 mg
SC
x
Cyclophosphamide
750 mg/m2
IV
x
Doxorubicin
50 mg/m2
IV
x
Vincristine
1.4 mg/m2 (2 mg max)
IV
x
Prednisone
100 mg/d
PO
x a
x
x
x
x
CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone; D = day; IV intravenous; 
PO oral; SCsubcutaneous.
a
Rituximab should be administered after administration of the glucocorticoid component of the
chemotherapy if applicable.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study will be provided by the Sponsor.  The study 
site will acknowledge receipt of IMPs supplied by the Sponsor, using the Interactive 
Voice Response System (IVRS)/Interactive Web-based response system (IWRS) to 
confirm the shipment condition and content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
The standard-of-care (SOC) therapy for DLBCL involves chemotherapy with 
complementary mechanisms of action combined with immunotherapy. Up to eight 
cycles of rituximab plus CHOP given in 21-day intervals (R-CHOP-21) is considered to 
be the SOC therapy for patients with previously untreated DLBCL. The Sponsor does 
not have any plans to provide the Roche study drug (rituximab SC or rituximab IV) or 
any other study treatment to the patients after they complete the study considering the 
patient will have received SOC in the study duration. 


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4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, over-the-
counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used 
by a patient in addition to protocol-mandated treatment from 28 days prior to initiation of 
study drug to study termination.  All such medications should be reported to the 
investigator and recorded on the Concomitant Medications eCRF.
Patients should receive full supportive care including granulocyte colony-stimulating 
factor (G-CSF) support, transfusions of blood and blood products, antibiotics, anti-
emetics etc., where applicable.
4.4.1
Permitted Therapy
4.4.1.1
Prophylaxis of Administration-Related Reactions
Premedication with oral acetaminophen and diphenhydramine approximately 30 minutes 
prior to rituximab administration is required as per institutional practice.  If given, they 
must be documented on the Concomitant Medications eCRF.
Rituximab SC or IV should be administered on Day 1 of each cycle, after administration 
of the glucocorticoid component of CHOP chemotherapy (the interval between 
prednisone and rituximab depending on institutional practice). For patients who do not 
experience ARRs with their previous infusion or injection, premedication at subsequent 
infusions/injections may be omitted at the investigator’s discretion.
4.4.1.2
Prophylaxis of Nausea and Vomiting
Premedication to prevent nausea and vomiting is allowed, as per institutional practice. 
This does include glucocorticosteroids (e.g., dexamethasone).  If glucocorticosteroids 
are as part of the anti-emetic regimen, they should be administered prior to the rituximab 
administration and should be documented on the Concomitant Medications eCRF 
accordingly.
Please note that additional administrations of high-dose glucocorticosteroids in 
lymphoma-therapeutic doses given outside of the CHOP regimen are not permitted.
4.4.1.3
Antimicrobial and Antiviral Prophylaxis
Antimicrobial and antiviral prophylaxis may be used as per institutional practice. If given, 
they must be documented on the Concomitant Medications eCRF.
4.4.1.4
Prophylaxis for Hemorrhagic Cystitis
Patients should be adequately hydrated prior to and after cyclophosphamide 
administration and should be instructed to void the bladders frequently.  Mesna 
(2-mercapto ethane sulfonate sodium) may be used as prophylaxis according to 
institutional practice and should be documented on the Concomitant Medications eCRF.


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4.4.1.5
Tumor-Lysis Syndrome Prophylaxis
Patients with high tumor burden and who are considered by the investigator to be at risk 
for tumor lysis should also receive tumor-lysis prophylaxis prior to the initiation of 
treatment.  Patients should be well hydrated.  Starting one or two days before the first 
dose of rituximab, it is desirable to maintain a fluid intake of approximately 3 L/day. In 
addition, all patients with high tumor burden and who are considered by the investigator 
to be at risk for tumor lysis should be treated with 300 mg/day allopurinol PO or a 
suitable alternative treatment starting 48–72 hours prior to Cycle 1, Day 1 of treatment 
and hydration.  Patients should continue to receive repeated prophylaxis with allopurinol 
and adequate hydration prior to each subsequent infusion/injection, if deemed 
appropriate by the investigator. Prophylaxis against tumor-lysis syndrome (TLS), may 
be given as per institutional practice and should be documented on the Concomitant 
Medications eCRF.
4.4.1.6
Central Nervous System Prophylaxis
CNS prophylaxis with intrathecal chemotherapy may be given as per institutional 
practice and should be documented on the Concomitant Medications eCRF.
4.4.1.7
Hepatitis B Reactivation Prophylaxis
Hepatitis B virus reactivation is a potential risk for R-CHOP. Patients who are both 
HBsAg negative and anti-hepatitis B core positive may be included into this study. 
Prophylactic antiviral therapy should be considered, lamivudine or entecavir, or as per 
institutional practice and should be documented on the Concomitant Medication eCRF. 
These patients should have HBV DNA levels obtained monthly during treatment and 
follow-up periods, as follows:

If the HBV DNA assay becomes positive and is above the World Health 
Organization (WHO) cutoff of 100 IU/mL, study treatment chemotherapy will be held 
and the patient should be treated (for at least 6 months after the last dose of 
rituximab) with an appropriate nucleoside analog and immediately referred to a 
gastroenterologist or hepatologist for management as needed. Patients may 
resume study treatment once HBV DNA levels have decreased to undetectable 
levels.

If a patient’s HBV DNA level exceeds 100 IU/mL while the patient is receiving 
antiviral medication, study treatment will be discontinued.
4.4.1.8
Pre-planned Consolidation Radiotherapy
Radiotherapy may be applied to initial sites of bulky or extranodal disease at a dose of 
30–40 Gy (according to institutional practice).  If indicated, pre-planned radiotherapy 
should be initiated within 8 weeks after the last study drug treatment and should start 
after all End of Treatment assessments, including PET-CT scans for disease response 
assessment, are completed. Any radiotherapy should be pre-planned by the center and 
documented prior to randomization and then entered in the eCRF once the patient is 


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randomized. All unplanned radiotherapy administered to patients will be considered as a 
new anti-lymphoma treatment.
4.4.2
Prohibited Therapy
The following concomitant medications or treatments will result in withdrawal of patients 
from study treatment:

Other concomitant anti-tumor agents not defined in this protocol as study treatment, 
including lymphoma-therapeutic doses of glucocorticosteroids

Unplanned radiotherapy or other concurrent investigational agents of any type
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed during the study is provided in Appendix 1, 
and Appendix 2.  All activities should be performed and documented for each patient.
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained from the patient 
or the patient’s legally authorized representative before performing any study-related 
procedures (including screening evaluations) or any prohibited medications being 
withheld for purposes of study participation.  Informed Consent Forms for enrolled 
patients and for patients who are not subsequently enrolled will be maintained at the 
study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Tests that are performed as standard of care prior to obtaining informed consent may be 
used for screening and baseline assessments provided that they have been performed 
within the allowable timeframe as described in the schedule of assessments (see
Appendix 1).  Not all study assessments need to be obtained at every study visit; please 
refer to Appendix 1 and Appendix 2 for details on frequency.
4.5.2
Medical History, Demographic Data, IPI, Ann Arbor Staging, 
and ECOG Performance Status
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
demographic data (including age, sex, and self-reported race/ethnicity), IPI score, and 
Ann Arbor staging will be collected and recorded at screening.  ECOG performance


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status and B symptoms will be assessed at screening, Day 1 of Cycles 1 to 8, at each 
visit during the follow-up period, and at the end of study.
Please see Appendix 5 for the description of the IPI and Ann Arbor staging and 
Appendix 6 for the ECOG performance status scale.
4.5.3
Physical Examinations
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, and neurological systems.  New or worsened abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.  As part of the tumor 
assessment, physical examinations should also include the evaluation of the presence 
and degree of enlarged lymph nodes, hepatomegaly, and splenomegaly.  These will be 
recorded as non-target lesions on the Tumor Assessment eCRF.  Targeted physical 
examinations should be limited to systems of primary relevance, including 
cardiovascular, respiratory, those associated with symptoms, and those associated with 
tumor assessment (lymph nodes, liver, and spleen).
4.5.4
Vital Signs
Vital signs will include measurements of systolic and diastolic blood pressure while the 
patient is in a supine position, pulse rate, respiratory rate, body temperature, height, 
weight, and determination of BSA at baseline. During rituximab IV or SC administration 
visits, vital signs will include the measurement of weight, systolic and diastolic blood 
pressure, respiratory rate, and pulse rate.
4.5.5
Tumor and Response Evaluations
All evaluable or measurable disease must be documented at screening and re-assessed 
at each subsequent tumor evaluation until disease progression or end of follow-up (6 
months after the last dose of the study treatment).  Response assessments will be 
assessed by the investigator and IRC, on the basis of physical examinations, diagnostic 
CT scans (or MRI scans), PET-CT scans, and bone marrow examinations, using Lugano 
Response Criteria for Malignant Lymphoma (Cheson et al. 2014; see Appendix 4).
Diagnostic contrast enhanced CT scans are currently the best available and most 
reproducible methods for measuring target lesions selected for response assessment; 
conventional CT scans (or MRI scans, if CT is contraindicated) should be performed with 
contiguous cuts of 8 mm in slice thickness and contrast enhanced if not medically 
contraindicated. CT scans should include the chest, abdomen, and pelvis; CT scans of 
the neck or other anatomic locations should be included if clinically indicated.
In patients for whom contrast is contraindicated (e.g., patients with contrast allergy or 
impaired renal clearance), CT or combined PET-CT scans without contrast or MRI scans 
are permitted as long as they permit consistent and precise measurement of target 
lesions during the study treatment period.  The same radiographic assessment modality 


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should be used for all response evaluations, in order to ensure consistency across 
different time points.
PET-CT scans in conjunction with diagnostic contrast enhanced CT scans will be 
obtained in this study. CT and PET-CT scans are required at screening (within 35 days 
prior to the initiation of study treatment unless otherwise approved by the Medical 
Monitor), during Cycle 4 (i.e., Day 19 [3 days] of Cycle 4), and at the end of study 
treatment (i.e., 68 weeks after the last dose of Cycle 8 treatment or 4-8 weeks after the 
last dose of study treatment in the event that a patient discontinues early). Diagnostic 
contrast enhanced CT scans obtained as part of a PET-CT scan may be used in lieu of 
dedicated CT scans. An interim assessment will be obtained after Cycle 4 and should 
include PET-CT and dedicated CT.  If local practice prohibits obtaining both 
assessments after Cycle 4, PET-CT alone (preferred) or CT alone may be obtained at 
this time point.  During the follow-up period, imaging (may be CT only) will be performed 
every 3 months.  Contrast-enhanced CT scan should include the chest, abdomen, pelvis 
(including inguinal/femoral regions), and, if clinically indicated, the neck and other 
anatomic locations should be imaged.
In case of any suspected disease progression by the investigator, a full tumor 
assessment including anatomic scans must be performed.  At all times during the study, 
diagnosis of disease progression based on clinical examination must be confirmed by 
imaging (e.g., CT, PET-CT) as soon as feasible (maximum, within 30 days) and prior to 
initiation of non-protocol specified anti-lymphoma therapy.
Bone marrow examinations are required at screening and should include biopsy for 
morphology.  Repeat bone marrow examinations are required if the bone marrow was 
involved with tumor at screening and the repeat bone marrow examination is required to 
confirm a radiological assessment of CR at the end of therapy.
4.5.6
Laboratory Assessments
Central laboratory assessments will include the following:

Anti-rituximab antibodies will be assessed for both treatment groups (i.e., RIV-CHOP 
and RSC-CHOP) (see Section 4.5.8).

Anti-rHuPH20 antibodies will be assessed only in patients randomized to the RSC-
CHOP treatment group (see Section 4.5.8).

For the subset of patients who are HBsAg negative and HBcAb positive and have 
undetectable HBV DNA levels at screening, monitoring of HBV DNA levels is 
mandatory for the patients. For instructions on the management of these patients, 
see Section 4.4.1.7.

Rituximab PK Samples (see Section 4.5.7).


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Samples for hematology, serum chemistry, pregnancy test, coagulation, hepatitis B and 
C serologies, quantitative immunoglobulin assessments, and cerebrospinal fluid 
assessment will be analyzed at the study site’s local laboratory:

Hematology:  hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, 
white blood cell (WBC) count, percent or absolute differential count.

Serum chemistry:  At screening, serum chemistry will include sodium, potassium, 
chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, calcium, phosphorus, 
total bilirubin, total protein, albumin, AST, ALT, LDH, alkaline phosphatase, uric acid, 
and calculated creatinine clearance.  During Cycles 1–8 and the follow-up period, 
serum chemistry will include sodium, potassium, creatinine, calcium, total bilirubin, 
total protein, albumin, AST, ALT, LDH, alkaline phosphatase, and uric acid.

Pregnancy test: A negative serum pregnancy test or a negative urine pregnancy 
test within 7 days prior to study treatment must be available both for pre-
menopausal women (including those who have had a tubal ligation) and for women 
who are less than 2 years after the onset of menopause; if a negative serum 
pregnancy test within 14 days prior to study treatment, there must be a confirmatory 
urine pregnancy test within 7 days prior to study treatment start.  Another test will be
performed at the end of study.

Coagulation:  aPTT or PTT, prothrombin time (PT), and INR

Viral serology and detection: 
o
Hepatitis B (HbsAg and total HBcAb)
o
Hepatitis C virus antibody

Quantitative immunoglobulins (Igs):  IgG, IgA, and IgM

Cerebrospinal fluid assessment:  Lumbar puncture is indicated for patients with 
high-risk disease or with one or more of the following sites of involvement: 
paranasal sinuses, testicular, paramenigeal, peri-orbital, CNS, paravertebral, or 
bone marrow.
The procedures for the collection, handling, and shipping of laboratory samples are 
specified in the laboratory manual.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
The biological samples (blood samples for PK and immunogenicity analysis) will be 
destroyed no later than 6 months after the completion of the final Clinical Study Report.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.


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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.7
Pharmacokinetic Assessments
The PK parameter, observed Ctrough levels of rituximab, serves as the primary endpoint in 
the study; therefore, it is of utmost importance to adhere to the visiting schedule and to 
take the PK samples on the exact day scheduled (see Appendix 1 and Appendix 2).
PK samples on the day of IV administration of rituximab must not be taken from the 
same arm as IV drug administration. In the case of a patient being unable to provide 
venous access on the opposite arm from the infusion arm, the leg may be used for PK 
blood sampling.
Rituximab serum concentrations will be measured by a specific and validated method.  
Details on sampling procedures, sample storage, and shipment will be provided in the 
Sample Collection, Handling, and Logistics Manual.
The total volume of blood that will be obtained for PK assessments over a period of 
48 weeks will be approximately 77 mL (22 samples) for patients randomized to the 
rituximab IV arm and 70 mL (20 samples) for patients randomized to the rituximab SC 
arm.
4.5.7.1
PK Sampling for Patients Randomized to the RIV-CHOP Arm
For patients randomized to the rituximab IV arm, PK sampling of rituximab will be 
performed at the following time points:

Cycle 1:  within 2 hours pre-dose and at end of infusion (15 minutes)

Cycle 2:  within 2 hours pre-dose, at end of infusion (+ 15 minutes), 24 hours 
post-dose (4 hours), Day 3 (4 hours), Day 7 (24 hours), Day 15 (48 hours)

Cycles 3 and 4:  within 2 hours pre-dose

Cycle 5:  within 2 hours pre-dose and at end of infusion (15 minutes)

Cycle 6:  within 2 hours pre-dose

Cycle 7:  within 2 hours pre-dose, at end of infusion (15 minutes), 24 hours post-
dose (4 hours), Day 3 (± 4 hours), Day 7 (24 hours), and Day 15 (48 hours)

Cycle 8:  within 2 hours pre-dose and Day 29 (24 hours)

Follow-up phase: 24 weeks (7 days) after the last rituximab dose
If patients discontinue the study treatment prematurely, blood samples for PK will be 
taken when the patients return to the clinic for an early termination visit.
Please note that all PK samples obtained at the end of infusion must be taken from the 
side of the body opposite to the rituximab IV administration.


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For more detailed PK sampling information, see Appendix 1 and Appendix 2.
4.5.7.2
PK Sampling for Patients Randomized to RSC-CHOP Arm
For patients randomized to the RSC-CHOP arm, PK sampling will be performed at the 
following time points:

Cycle 1 (rituximab IV):  within 2 hours pre-dose and at end of infusion (15 minutes)

Cycle 2:  within 2 hours pre-dose, 24 hours post-dose (4 hours), Day 3 (4 hours), 
Day 7 (24 hours), Day 15 (48 hours)

Cycles 3 and 4:  within 2 hours pre-dose

Cycle 5:  within 2 hours pre-dose and Day 7 (24 hours)

Cycle 6:  within 2 hours pre-dose

Cycle 7:  within 2 hours pre-dose, 24 hours post-dose (4 hours), Day 3 (4 hours), 
Day 7 (24 hours), and Day 15 (48 hours)

Cycle 8:  within 2 hours pre-dose and Day 29 (24 hours)

Follow-up phase: 24 weeks (7 days) after last rituximab dose
If patients discontinue the study treatment prematurely, blood samples for PK will be 
taken when the patients return to the clinic for an early termination visit.
For Cycle 1 please note that the PK sample obtained at the end of infusion must be 
taken from the side of the body opposite to the rituximab IV administration.
For more detailed PK sampling information, see Appendix 1 and Appendix 2.
4.5.8
Immunogenicity Assessments
Blood samples will be taken for the assessment of immunogenicity (i.e., anti-rituximab
antibody samples [in all patients] and anti-rHuPH20 antibody samples [only in patients 
randomized to the SC arm]). These samples will be drawn prior to rituximab 
administration at each cycle and then at 12 weeks and 24 weeks after the last dose of 
rituximab during the follow-up period (Appendix 1).  If patients discontinue the study 
treatment prematurely, blood samples for immunogenicity will be taken when the 
patients return to the clinic for an early termination visit.
In any patient who experiences a severe AE or SAE that is considered immunogenic and 
possibly related to study medication, a blood sample should be collected within 7 days of 
the event becoming known to the Investigator. These samples will be analyzed for 
immunogenicity and rituximab PK as appropriate.
Patients with anti-rituximab antibody titers may develop allergic or hypersensitivity 
reactions when treated with other diagnostic or therapeutic monoclonal antibodies.


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A validated enzyme-linked immunosorbent assay (ELISA) will be used to detect and 
confirm the presence of anti-rituximab antibodies in serum.
A validated bridging electrochemiluminescence immunoassay (ECLIA) will be used to 
detect and confirm the presence of anti-rHuPH20 antibodies in plasma samples.
A three-tiered approach for immunogenicity sample analysis will be used for the analysis 
of anti-rituximab antibodies and anti-rHuPH20 antibodies. A panel of assays to detect, 
confirm, and characterize the antibody responses are outlined below:

Screening assays to detect anti-rituximab antibodies or anti-rHuPH20 antibodies in 
samples (screen-positives)

Confirmatory assays to assess the specificity of the screen-positive results by 
competition with excess rituximab or rHuPH20 (confirmed positives)

Titration assays to determine the anti-rituximab or anti-rHuPH20 antibody titers for 
confirmed positive samples

A neutralizing antibody assay to characterize the confirmed antibodies to rHuPH20.
The total volume of blood that will be obtained for anti-rituximab antibody assessments 
over a period of 48 weeks will be approximately 30 mL (10 samples) per patient.
The total volume of blood that will be obtained for anti-rHuPH20 antibody assessments 
over a period of 48 weeks will be approximately 30 mL (10 samples) per patient.
4.5.9
Electrocardiograms
A 12-lead electrocardiogram (ECG) is required at screening, at the end of study 
treatment, at the end of the study, and as clinically indicated (See Appendix 1).  ECGs 
for each patient should be obtained using the same machine wherever possible.
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and should not be obtained within 3 hours 
after any meal.  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  
If at a particular postdose timepoint the mean QTcF is 500 ms and/or 60 ms
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on two 


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successive ECGs.  The Medical Monitor should be notified.  Standard-of-care treatment 
may be instituted per the discretion of the investigator.  If a PK sample is not scheduled 
for that time point, an unscheduled PK sample should be obtained.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia).
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy

Use of an anti-cancer therapy not required per protocol

Symptomatic deterioration attributed to disease progression

Confirmed disease progression per investigator assessment according to Lugano 
Response Criteria for Malignant Lymphoma (Cheson et al. 2014)

Any event that meets stopping criteria defined in Section 5.1

Patient/investigator decision
Patient who discontinue study treatment prematurely are required to return to the clinic 
for an early termination visit within 48 weeks after the last dose of study treatment.  The 
primary reasons for early discontinuation of treatment must be documented on the 
appropriate eCRF.
If a patient discontinues study treatment early because of toxicity, every effort should be 
made to continue study assessments until progression and standard follow-up
(Appendix 1).  In cases of study treatment discontinuation for reasons other than disease 
progression and withdrawal of consent, patients will enter the follow-up period.  Once 
progression occurs, only the applicable follow-up of adverse event reporting will be 
assessed.
Patients who discontinue study treatment prematurely will not be replaced.
4.6.2
Patient Discontinuation from the Study
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time.  
See Appendix 1 for the list of assessments to be performed for patients who prematurely 
withdraw from the study during the treatment period. Patients who are withdrawn or 


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discontinued from study participation (and not just study treatment) will not be followed 
for any reason after consent has been withdrawn.
Reasons for patient discontinuation from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent

Study termination or site closure

Adverse event

Loss to follow-up

Pregnancy

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor

Any medical condition that the investigator determines may jeopardize the patient’s 
safety if he or she continues in the study

In the best interest of the patient as determined by the investigator
Every effort should be made to obtain a reason for patient discontinuation from the study.  
The primary reason for discontinuation from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.

Data recording is inaccurate or incomplete.
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonization (ICH) guideline for 
Good Clinical Practice


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
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
4.7
FOLLOW-UP
After the last administration of study treatment, patients will be followed up for 6 months 
(every 3 months).  During the follow-up period, patients who continue the study and who 
have not progressed will be followed according to the protocol-specified follow-up 
schedule.  All patients will be followed as specified unless the patient requests to be 
withdrawn from study follow-up; this request must be documented in the patient’s 
medical record and signed by the investigator.
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Rituximab IV has been approved in both China and other countries.  Rituximab SC is
approved in more than 90 countries across the world, but not yet approved in China.  
The safety plan for patients in this study is based on clinical experience with rituximab in 
completed and ongoing studies and post-marketing experience.  The anticipated 
important safety risks for rituximab are outlined below.  Please refer to local prescribing 
information for the detailed safety information on CHOP chemotherapy.  Please refer to 
the rituximab SC IB and rituximab Oncology IV IB for a complete summary of safety 
information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dose, are provided below.
5.1.1
Management of Patients Who Experience Adverse Events
Patients will be evaluated clinically and with standard laboratory tests before and at 
regular intervals during their participation in this study.  Safety evaluations will consist of 
medical interviews, recording of adverse events, physical examinations, and laboratory 
measurements.
All adverse events occurring after the initiation of study treatment will be reported until 
28 days after administration of the last dose of study treatment.  Patients who have an 
ongoing adverse events resulting in treatment discontinuation will be followed until the 
event resolution, the investigator assesses the event as stable, the patient is lost to 
follow-up, or the patient initiates a new anti-lymphoma treatment (whichever occurs 
earlier).
The NCI CTCAE v 5.0 will be used to grade toxicity.  Rituximab IV or SC in combination 
with CHOP will be given as specified in Section 4.3.2.  Before starting a new treatment 


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cycle, toxicity must have resolved (Section 5.1.2). See Section 5.1.2 for the details on 
the dose modifications for rituximab IV, rituximab SC and CHOP chemotherapy for 
toxicity.
5.1.2
Dose modifications of Rituximab IV, Rituximab SC and CHOP 
Chemotherapy for Toxicity
Dose reductions (CHOP chemotherapy) are based on all laboratory values obtained 
within 72 hours prior to a study treatment infusion or injection (i.e., RIV-CHOP or RSC-
CHOP).

There should be no dose modification for rituximab IV or rituximab SC.  If 
chemotherapy is delayed, rituximab administration must also be delayed (so that 
they are given on Day 1 of the same cycles).

Patients who experience a delay exceeding 14 days in the initiation of the next 
planned treatment cycle will be removed from receiving study treatment.

For large changes in body weight compared with baseline (10%), the dose of
chemotherapy may be adjusted according to institutional practice.
Chemotherapy doses can be re-escalated (even to the full dose) at the discretion of the 
investigator and per the site standards in subsequent cycles according to patient 
tolerance.  In addition, resumption of dosing without complete resolution of toxicity may 
only be considered after careful weighing of the risks and benefits with the patient and 
agreement between the investigator and the Sponsor.
Patients who discontinue all study treatment for adverse events should remain on the 
study and continue to have disease assessments until progression and standard follow-
up.
See the details for dose delay and modification for selected events described in Table 5.
Guideline for dose delays and modifications of R-CHOP are shown in Table 6.


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Table 5
Guidelines for Dose Delay or Modification of Rituximab IV, 
Rituximab SC and CHOP Chemotherapy (Cycle 2 to Cycle 6 [or 8], 
Day 1)
Event(s)
Dose Delay or Modification
Hematologic toxicity
Grade 1 or 2 neutropenia 
and/or thrombocytopenia
No dose reduction or delay
Grade 3 or 4 neutropenia, with 
or without infection or fever, 
first episode

Delay doses of RIV-CHOP or RSC-CHOP for a maximum of 
2 weeks.  

Growth factors, e.g., G-CSF for neutropenia are permitted.  

If ANC counts recover to 1.0 109/L Day 7 after the 
scheduled date of the next cycle administer current dose of 
cyclophosphamide and/or doxorubicin.  

If ANC recovers to 1.0 109/L 8 days after the 
scheduled date for the next cycle, consider reducing the 
dose of cyclophosphamide and/or doxorubicin to a lower 
dose level (Table 6). 

Rituximab and prednisone should not be modified for this 
reason.
Recurrent Grade 3 or 4 
neutropenia with/without fever 
and infection

Delay all study treatment for a maximum of 2 weeks. 

Growth factors, e.g., G-CSF for neutropenia are permitted.

If ANC counts recover to 1.0 109/L Day 7 after the 
scheduled date of the next cycle, administer current dose of 
cyclophosphamide and/or doxorubicin.

If ANC recovers to 1.0 109/L 8 days after the scheduled 
date for the next cycle, consider reducing the dose of 
cyclophosphamide and/or doxorubicin to the next dose level 
(Table 6). 

Rituximab and prednisone should not be modified for this 
reason.

If Grade 3 or 4 neutropenia persists despite growth factor 
support and following cyclophosphamide and doxorubicin 
dose reductions, in the absence of fever, patient may 
continue study treatment at the investigator’s discretion with 
consultation of the Medical Monitor.


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Table 5
Guidelines for Dose Delay or Modification of Rituximab IV, 
Rituximab SC and CHOP Chemotherapy (Cycle 2 to Cycle 6 [or 8], 
Day 1) (cont.)
Event(s)
Dose Delay or Modification
Grade 3 or 4 
thrombocytopenia, first 
episode

Delay all study treatment for a maximum of 2 weeks

If platelet count recovers to 75 109/L Day 7 after the 
scheduled date of the next cycle, administer full dose of all 
study drugs.

If platelet count recovers to 75 109/L Day 8 after the 
scheduled date of the next cycle, consider reducing the 
dose of cyclophosphamide and/or doxorubicin to a lower 
dose level (Table 6). Full dose/current dose of all other 
study drugs may be given.

If the primary cause of thrombocytopenia is thought to be 
lymphoma infiltration into the bone marrow, the investigator 
may elect not to reduce the dose of cyclophosphamide 
and/or doxorubicin.
Recurrent Grade 3 or 4 
thrombocytopenia 

If patient develops recurrent Grade 3-4 thrombocytopenia 
following cyclophosphamide and/or doxorubicin dose 
reductions, consider reducing the dose of 
cyclophosphamide and doxorubicin to the next dose level 
(Table 6).
Non-hematologic toxicity
Grade 1
No dose reduction or delay
Grade 2

Delay RIV-CHOP or RSC-CHOP for a maximum of 2 weeks.  

If improvement to Grade 1 or baseline, then administer the 
previous dose of CHOP with the full dose of rituximab IV or 
SC for subsequent cycles.
Grade 2 (excluding alopecia, 
nausea, and vomiting)
Delay treatment with RIV-CHOP or RSC-CHOP until 
resolution to Grade 1 (or baseline status for all except 
hemorrhagic cystitis) for a maximum of 14 days. 
Grade 3 or 4 non-hematologic 
toxicity not specifically 
described above

Delay RIV-CHOP or RSC-CHOP for a maximum of 2 weeks.  
First episode:  If improvement to Grade 1 or baseline, 
decrease cyclophosphamide dose to 500 mg/m2 and 
doxorubicin to 35 mg/m2 for subsequent cycles with full 
dose of rituximab or at the discretion of the investigator per 
site’s standard.

Second episode:  If improvement to Grade 1 or baseline, 
decrease cyclophosphamide dose to 375 mg/m2 and 
doxorubicin dose to 25 mg/m2 for subsequent cycles. 

Third episode:  Discontinue CHOP.  If improvement to 
Grade 1 or baseline, continue full dose of rituximab.

Fourth episode:  Discontinue all study treatment.


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Table 5
Guidelines for Dose Delay or Modification of Rituximab IV, 
Rituximab SC and CHOP Chemotherapy (Cycle 2 to Cycle 6 [or 8], 
Day 1) (cont.)
Event(s)
Dose Delay or Modification
Hemorrhagic cystitis

Patients should be adequately hydrated prior to and after 
cyclophosphamide administration and should be instructed 
to void frequently.  

Mesna may be used as prophylaxis according to 
institutional practice.  

If gross hematuria develops, cyclophosphamide should be 
withheld until resolution of cystitis.  

A dose reduction of 50% for cyclophosphamide may be 
considered at the next cycle.  

Re-escalation of cyclophosphamide to the initial full dose is 
recommended if symptoms do not recur.
Hepatotoxicity
Bilirubin 3.0 mg/dL

Dose reduction should be avoided if hyperbilirubinemia is 
not related to hepatic injury (i.e., hemolysis or Gilbert’s
disease).  In these cases, dose reduction considerations 
should be guided by direct bilirubin levels. 

Withhold doxorubicin and vincristine until resolution to 
Grade 1 within 14 days.  Evaluate for causality.  Dosing of 
rituximab, cyclophosphamide, and prednisone may 
continue.
Bilirubin between 1.5 and 
3.0 mg/dL

Dose reduction should be avoided if hyperbilirubinemia is 
not related to hepatic injury (i.e., hemolysis or Gilbert’s 
disease).  In these cases, dose reduction considerations 
should be guided by direct bilirubin levels.

Reduce doxorubicin dose by 25% of baseline and 
vinctistine should be reduced to the next level (Table 6).  
With subsequent courses of treatment if bilirubin has 
returned to Grade 1, full doses may be given.  Give full 
dose of rituximab, and continue current dose of 
cyclophosphamide and prednisone.
Cardiotoxicity
Grade 2–4 heart failure or 
Grade 3 or 4 LVSD
Discontinue RIV-CHOP or RSC-CHOP
chemotherapy permanently.
Neurotoxicity
Grade 1 (peripheral 
neuropathy)
Continue treatment at full dose; vincristine may be decreased 
at the discretion of the investigator.
Grade 2 or 3
Hold RIV-CHOP or RSC-CHOP.  If recovered to Grade 1 
value within 14 days, administer full dose rituximab and 
continue current dose of cyclophosphamide and prednisone.  
Reduce vincristine dose by 50% for current cycle and all 
subsequent cycles.
Grade 4 

Discontinue RIV-CHOP or RSC-CHOP chemotherapy
permanently.

Patients should be evaluated regarding the continuation of 
R-CHOP on the basis of their risk/benefit.


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Table 5
Guidelines for Dose Delay or Modification of Rituximab IV, 
Rituximab SC and CHOP Chemotherapy (Cycle 2 to Cycle 6 [or 8], 
Day 1) (cont.)
Event(s)
Dose Delay or Modification
Administration-related reactions
Grade 3, second episode
Discontinue rituximab IV or SC permanently.  CHOP alone 
may be continued when recovered if not attributable to CHOP. 
Grade 4 
Discontinue rituximab IV or SC permanently.  CHOP alone 
may be continued when recovered if not attributable to CHOP.  
Mucositis (Grade 2)
Delay the next cycle of RIV-CHOP or RSC-CHOP delayed in 
1-week increments for up to a maximum of 14 days until the 
event resolves to Grade 1.
Tumor lysis syndrome (Grade 
3 or 4)
Hold all study treatment (RIV-CHOP or RSC-CHOP).  The
patient’s next dose may be delayed for up to 14 days.  
Following complete resolution tumor lysis syndrome, rituximab 
may be re-administered at the full dose during next scheduled 
infusion or injection, in conjunction with prophylactic therapy 
and CHOP chemotherapy.  
Anaphylaxis
Discontinue rituximab IV or SC permanently.  CHOP alone 
may be continued when recovered if not attributable to CHOP. 
ANC absolute neutrophil count; CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone; 
GCSF granulocyte colonystimulating factor; HBV hepatitis B virus; LVSD left ventricular systolic 
dysfunction; R rituximab.
Table 6
Recommended Steps of Dose reduction for R-CHOP
Dose Level
Rituximab IV/SC Cyclophosphamide
Doxorubicin
Vincristine
Starting dose
100% of starting 
dose per cycle
100% of starting 
dose per cycle
100% of starting 
dose per cycle
100% of starting 
dose per cycle
First dose 
reduction a
No modification 
allowed
75% of starting dose 
per cycle
75% of starting 
dose per cycle
75% of starting 
dose per cycle
Maximum dose 
reduction a
No modification 
allowed
50% of starting dose 
per cycle or 
discontinue drug
50% of starting 
dose per cycle or 
discontinue drug
50% of starting 
dose per cycle or 
discontinue drug
Subsequent 
dose reduction 
No modification 
allowed
Discontinue drug
Discontinue drug
Discontinue drug
CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; IV = intravenous; R = rituximab; 
SC = subcutaneous.
a
Steps of dose reduction listed are suggested dose changes. Investigators may opt for alternative 
levels of dose reduction as clinically indicated.
5.1.2.1
Administration-Related Reactions
Rituximab IV can be associated with ARRs that may be related to the release of 
cytokines and/or other chemical mediators and which might be clinically 


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indistinguishable from hypersensitivity reactions.  Severe ARRs (such as bronchospasm 
and hypotension) may occur in about 10% of the cases.  The incidence of ARRs
decreases substantially with subsequent infusions and occurs in less than 1% of patients 
by the eighth cycle of rituximab-containing treatments.  Patients with a high tumor 
burden may be at a higher risk of developing severe ARRs.  Severe ARRs usually 
manifest within 1 to 2 hours after starting the first rituximab infusion.  Reactions are 
characterized by pulmonary events, and in some cases, include features of tumor lysis 
syndrome, fever, chills, rigors, hypotension, urticaria, angioedema, and other symptoms.  
These symptoms are usually reversible with the interruption of the infusion and should 
be treated with diphenhydramine and paracetamol (acetaminophen).  Additional 
treatment with bronchodilators or IV saline may be indicated.  In most cases, the infusion 
can be resumed at a 50% reduction in infusion rate (e.g., from 100 mg/hour to 50 
mg/hour) when symptoms have completely resolved.  Most patients who have 
experienced ARRs that are not life-threatening have been able to complete the full 
course of rituximab therapy.  In order to reduce the incidence and severity of ARRs, all 
patients should receive premedication consisting of antipyretics and antihistaminics (e.g., 
paracetamol and diphenhydramine) before every infusion of rituximab.
After administration, rituximab SC is absorbed slowly from the interstitial tissue (time to 
Cmax [Tmax] of approximately 2 to 7 days), and the mean Cmax will be approximately 50% 
decreased as compared with the IV administration.  Therefore, the risk of experiencing a 
Grade 3 or 4 ARR after rituximab SC administration is expected to be minimal.
Patients randomized to the rituximab SC arm who experience a Grade 3 or 4 ARRs after 
the first rituximab infusion but who are able to receive the full dose of rituximab at 
Cycle 1 can receive the second dose of rituximab subcutaneously (Cycle 2, Day 1).
Patients randomized to the rituximab SC arm who are unable to receive the full dose of 
rituximab at Cycle 1 as a result of an ARR should receive the second rituximab 
administration intravenously.  If the patients subsequently do not experience Grade 3 or 
4 ARRs, they will receive the third rituximab administration subcutaneously (Cycle 3, 
Day 1).
Patients with Grade 3 or 4 ARRs after the second rituximab infusion will be withdrawn 
from study treatment.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.


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Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9
and 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)


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The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.3.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.

ARRs: Grade 3 and 4 ARRs will need to be reported to the Sponsor expeditiously. 
Unless otherwise stated by investigators, adverse events occurring within 24 hours 
after administration of rituximab (rituximab IV or rituximab SC) and considered 
related to the study drug, will be considered as ‘administration-related reactions’, 
based upon NCI CTCAE v 5.0. ARRs can present with one or more of the following 
symptoms: allergic reaction, arthralgia, bronchospasm, chills, cough, dizziness,
dyspnoea, headache, hypertension, hypotension, myalgia, nausea, pruritus, pyrexia,
rash, tachycardia, urticaria, vomiting.  ARRs must be recorded on the Adverse 
Event eCRF.  In order to capture potential differences in terms of clinical relevance 
of these events, it is important to report and assess the intensity of all symptoms of 
the ARRs.


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5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after 
administration of the final dose of study treatment.
Patients who have an ongoing adverse events resulting in treatment discontinuation will 
be followed until the event resolution, the investigator assesses the event as stable, the 
patient is lost to follow-up, or the patient initiates a new anti-lymphoma treatment 
(whichever occurs earlier).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 7 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 7
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 5.0
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event”, it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 8:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event


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Table 8
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Administration-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion/injection should be captured as a 
diagnosis (e.g., "infusion-related reaction", "injection-site reaction" or "anaphylactic 
reaction") on the Adverse Event eCRF.  If possible, avoid ambiguous terms such as 
"systemic reaction."  Associated signs and symptoms should be recorded on the 
dedicated Infusion Related Reaction or Injection Reaction eCRF.  If a patient 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion Related Reaction or 
Injection Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 


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eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.


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5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator's judgment 
Note:  For oncology trials, certain abnormal values may not qualify as adverse events.
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator's judgment 


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It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.5) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.8
Deaths
Deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1) that are attributed by the investigator solely to progression of DLBCL
should be recorded on the Death Attributed to Progressive Disease eCRF.  All other 
deaths that occur during the adverse event reporting period, regardless of relationship to 
study drug, must be recorded on the Adverse Event eCRF and immediately reported to 
the Sponsor (see Section 5.4.2).
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").


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Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of DLBCL
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014).  In rare cases, the determination of clinical progression will be 
based on symptomatic deterioration.  However, every effort should be made to 
document progression through use of objective criteria.  If there is any uncertainty as to 
whether an event is due to disease progression, it should be reported as an adverse 
event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event

Hospitalization due solely to progression of the underlying cancer


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An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Cases of Accidental Overdose or Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For rituximab
IV or SC, adverse events associated with special situations should be recorded as 
described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with rituximab IV or SC, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.


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
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for China
Medical Monitor:
Mobile Telephone No.:


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To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 6 months after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.
Instructions for reporting serious adverse events that occur 6 months after the final
dose of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 12 months after the final
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 


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24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
12 months after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.


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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event and adverse event of special interest that occurs after the end of the 
adverse event reporting period (defined as 28 days after the final dose of study drug), if 
the event is believed to be related to prior study drug treatment.  These events should be 
reported through use of the Adverse Event eCRF.  However, if the EDC system is not 
available, the investigator should report these events directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the paper Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number 
or email address provided to investigators.


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5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, Institutional Review Boards
(IRBs), Ethics Committees (ECs), and applicable health authorities based on applicable 
legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed in Table 9:
Table 9
Reference Safety Information
Drug
Document
Rituximab IV
Rituximab IV Summary of Product Characteristics 
Rituximab SC
Rituximab SC Investigator's Brochure
CHOP
Prescribing information on cyclophosphamide, doxorubicin, 
vincristine, and prednisone, respectively
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
A detailed Statistical Analysis Plan (SAP) will specify in more detail all analyses that are 
outlined in this section of the protocol.
6.1
DETERMINATION OF SAMPLE SIZE
Under the assumption of a coefficient of variation equal to 0.5 and assuming that the 
true Ctrough of rituximab SC formulation is 20% above the rituximab IV formulation (i.e., 
mean Ctrough,SC to be 20% above Ctrough,IV), 20 patients in each treatment arm are needed 
in order to achieve 80% power with one-sided alpha of 0.05 (i.e., 2-sided 90% CI).  
Assuming that 20% of patients would not have valid PK data at Cycle 8 pre-dose, a total 
of approximately 50 patients will be enrolled into the study (see Table 10).


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Table 10 Sample Size for Primary Endpoint (i.e., Non-inferiority in Ctrough)
Parameter
Value
Test significance levels, (one-sided)
0.050
Lower equivalence limit for T/S, L
0.800
Expected ratio, T/S
1.200
Coefficient of variation, S/S
0.500
Power (%)
80
Number of patients per group
18 (rounded to 20)
Number of patients (total)
36 (rounded to 40)
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation will be listed and 
summarized.  Enrollment and major protocol deviations will be listed and evaluated for 
their potential effects on the interpretation of study results.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (such as age, sex, and weight) will be 
summarized using means, standard deviations, medians, and ranges for continuous 
variables and proportions for categorical variables, as appropriate.  Summaries will be 
presented overall and by treatment group.
6.4
PHARMACOKINETIC ANALYSES
6.4.1
Pharmacokinetic Analysis Population
All PK analyses will be based on all patients for whom PK assessments were made.  PK 
analyses will be analyzed as treated. Patients will be excluded from the PK analysis 
population if they significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or if data are unavailable or incomplete, where the PK 
analysis might be influenced. Excluded cases will be documented, including the reason 
for exclusion. All decisions on exclusions from the analysis will be made prior to 
database closure.
6.4.2
Pharmacokinetic Endpoints
6.4.2.1
Pharmacokinetic Primary Endpoint
The primary PK endpoint is the ratio of Ctrough,SC/Ctrough,IV during Cycle 7.  The serum 
rituximab Ctrough at Cycle 7 will be measured at pre-dose of Cycle 8. The lower limit of 
the two-sided 90% CI should be above 0.80 in order to show non-inferiority of Ctrough,SC
versus Ctrough,IV.


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6.4.2.2
Pharmacokinetic Secondary Endpoint
The secondary PK endpoint is the ratio of observed rituximab area under the serum 
concentration curve of Cycle 7 (AUCSC/AUCIV). A two-sided 90% CI will be constructed.
6.4.3
Other Pharmacokinetic Parameters
Following rituximab PK parameters for both of the treatment groups of RSC-CHOP and 
RIV-CHOP will be analyzed:

Area under the serum concentration-time curve (AUC) over the rituximab dosing 
interval of Cycle 2

Trough serum concentration (Ctrough), i.e., serum concentration at the end of dosing 
interval before the next dose administration at other treatment cycles

Maximum observed serum concentration (Cmax)

Total clearance (serum) (CLss)

Volume of distribution at steady state (Vss)

Terminal half-life (t1/2) (if feasible or appropriate)
6.4.4
Analysis of Pharmacokinetic Parameters
PK parameters of rituximab will be estimated using standard non-compartmental 
analysis.  The data may also be analyzed as appropriate by a population approach using 
a PK model previously developed in non-linear mixed effects modeling (NONMEM)
(Gibiansky E 2016).  The influence of covariates (e.g., body weight, age, gender, and 
concomitant medications) on PK parameters may be investigated.
Individual and mean serum rituximab concentration versus time data will be tabulated 
and plotted by treatment arms.  The serum pharmacokinetics of rituximab will be 
summarized by estimating AUC, Ctrough, Cmax, total clearance, volume of distribution at 
steady state, and terminal half-life (as appropriate for data collected).  Estimates for 
these PK parameters will be tabulated and summarized by treatment group (arithmetic 
mean, standard deviation (SD), percent arithmetic mean CV%, geometric mean, percent 
geometric mean coefficient of variation (CV% geo mean), median, minimum, and 
maximum).  Inter-patient variability will be also evaluated.
Additional PK analyses may be conducted as appropriate.
6.5
EFFICACY ANALYSES
The analysis population for the efficacy analyses will consist of all randomized patients, 
with patients grouped according to their assigned treatment.
6.5.1
Efficacy Endpoints
The efficacy endpoints include CRR at the end of the study treatment as determined by 
the IRC using Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) 
and IWG for NHL 1999 Guidelines; ORR (CR+PR) at the end of the study treatment as 


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determined by the investigator and IRC using Lugano Response Criteria for Malignant 
Lymphoma (Cheson et al. 2014); and CRR at the end of the study treatment as 
determined by the investigator using Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014). 
CRR at the end of treatment assessment as determined by the IRC using Lugano 
Response Criteria for Malignant Lymphoma (Cheson et al. 2014), will be used as the key 
efficacy endpoint.
6.5.2
Analysis of Efficacy Endpoints
CRR at the end of treatment will be analyzed in frequency tables, including 95% 
two-sided CIs (Pearson-Clopper) by treatment group.  For the difference in response 
rates, 95% two-sided CIs (Hauck-Andersen) will be calculated.
ORR (CR+PR) at the end of treatment will be analyzed in frequency tables including 95% 
two-sided CIs (Pearson-Clopper) by treatment group.  For the difference in response 
rates, 95% two-sided CIs (Hauck-Andersen) will be calculated.
6.6
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received. 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs.
Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics.
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0.  All adverse events, serious adverse events, adverse 
events leading to death, adverse events of special interest, and adverse events leading 
to study treatment discontinuation that occur on or after the first dose of study treatment 
(i.e., treatment emergent adverse events) will be summarized by mapped term, 
appropriate thesaurus level, and severity grade.  For events of varying severity, the 
highest grade will be used in the summaries.  Deaths and cause of death will be 
summarized.
Relevant laboratory, vital sign (pulse rate, respiratory rate, blood pressure, pulse 
oximetry, and temperature), and ECG data will be displayed by time, with grades 
identified where appropriate.  Additionally, a shift table of selected laboratory tests will be 
used to summarize the baseline and maximum post-baseline severity grade.  Changes 
in vital signs and ECGs will be summarized.


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6.7
IMMUNOGENICITY ANALYSES
The immunogenicity analysis population will consist of all patients with at least one anti-
drug antibody (ADA) assessment.  The ADAs include anti-rituximab antibodies and anti-
rHuPH20 antibodies.  Patients will be grouped according to treatment received or, if no 
treatment is received prior to study discontinuation, according to treatment assigned.
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected).
The relationship between ADA status and safety, efficacy, and PK endpoints may be 
analyzed and reported via descriptive statistics.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
externally generated electronic study data will be sent directly to the Sponsor, using the
Sponsor's standard procedures to handle and process the electronic transfer of these 
data.
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures.


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7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC)
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 


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submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
If the Consent Forms are revised (through an amendment or an addendum) while a 
patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient's
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).


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In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted Clinical Study Reports and other summary reports will be provided 
upon request (see Section 9.5).
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor will manage the quality of the study, focusing on processes and data that 
are essential to ensuring patient safety and data integrity. The Sponsor will identify 
potential risks associated with critical trial processes and data and will implement plans 
for evaluating and controlling these risks.  Risk evaluation and control will include the 
selection of risk-based parameters (e.g., adverse event rate, protocol deviation rate) and 
the establishment of quality tolerance limits for these parameters.  Detection of 
deviations from quality tolerance limits will trigger an evaluation to determine if action is 
needed. Details on the establishment and monitoring of quality tolerance limits will be 
provided in a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.5
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.


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Approximately 10 sites in China will participate to enroll approximately 50 patients.  
Enrollment will occur through an Interactive Voice or Web-based response system 
(IxRS).
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, immunogenicity analyses and PK analyses), as 
specified in Section 4.5.  Accredited local laboratories will be used for routine monitoring; 
local laboratory ranges will be collected.
Tumor response and progression will be evaluated by the investigator and the IRC.
9.6
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 


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monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.7
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Chen XQ. The primary report of 20112 cases of malignant lymphoma classification of 
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Fu K, Weisenburger DD, Choi WW, et al. Addition of rituximab to standard 
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free survival for rituximab IV and SC in patients with follicular lymphoma (study 
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Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or 
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(NCCN Guidelines), Non-Hodgkin’s lymphoma. Version 4, 2019. Available 
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Appendix 1
Schedule of Activities
Assessment/Procedure
Screening
Treatment Period
End of Treatment
FollowUp 
(6 months)
C13
C4
C58
TCV
ETTV a
Days
28 to 1
Days
14 to 1
D1
D1
Interim 
Assessment
D19 (3)
D1
68 weeks 
after last 
treatment
48 weeks 
after last 
treatment
12 weeks and 
24 weeks after last 
treatment
Written informed consent b
x
Inclusion/exclusion criteria
x
Demographic information and 
medical history
x
Height
x
BSA
x
Weight
x
x
x
x
x
x
x
Vital Signs
x
x
x
x
x
x
x
Complete physical exam c
x
Targeted physical exam d
x
x
x
x
x
x
x
ECOG performance status e
x
x
x
x
x
DLBCL diagnosis, staging, 
and IPI score f
x
B symptoms
x
x
x
x
x
x
x
Tumor assessment g
x
x
x
x
x
12-lead-ECG and LVEF
x
x
x
x


Appendix 1: Schedule of Activities (cont.)
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Assessment/Procedure
Screening
Treatment Period
End of Treatment
FollowUp 
(6 months)
C13
C4
C58
TCV
ETTV a
Days
28 to 1
Days
14 to 1
D1
D1
Interim 
Assessment
D19 (3)
D1
68 weeks 
after last 
treatment
48 weeks 
after last 
treatment
12 weeks and 
24 weeks after last 
treatment
Hematology and serum 
chemistry h
x
x
x
x
x
x
x
x
Coagulation (aPTT or PTT, 
PT, and INR)
x
Pregnancy test (if applicable) i
x
x
Serology testing for HCV, 
HBV j
x
Hepatitis B DNA on PCR (as 
indicated) k
x
x
x
x
x
x
x
Lumbar puncture for CSF (as 
indicated) l
x
Bone marrow 
aspiratebiopsy (as 
indicated) m
x
x
x
Study treatment n
x
x
x
Rituximab PK sample o
x
x
x
x
x p
Anti-rHuPH20 antibody 
sample q
xr
xr
xr
x
x s
Anti-rituximab antibody 
sample 
xr
xr
xr
x
x s


Appendix 1: Schedule of Activities (cont.)
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Assessment/Procedure
Screening
Treatment Period
End of Treatment
FollowUp 
(6 months)
C13
C4
C58
TCV
ETTV a
Days
28 to 1
Days
14 to 1
D1
D1
Interim 
Assessment
D19 (3)
D1
68 weeks 
after last 
treatment
48 weeks 
after last 
treatment
12 weeks and 
24 weeks after last 
treatment
Sample for quantitative 
immunoglobulins (lgA, lgG, 
and lgM)
x
x
x
Adverse events t
x
x
x
x
x
x
x
x
x 
Concomitant medications u
x
x
x
x
x
x
x
x
x
BSAbody surface area; C = cycle; CHOPcyclophosphamide, doxorubicin, vincristine, and prednisone; CSF cerebrospinal fluid; D = day; 
DLBCLdiffuse large B-cell lymphoma; ECOGEastern Cooperative Oncology Group; ETTV = early treatment termination visit, 
FACSfluorescence-activated cell sorting; HBVhepatitis B virus; HCVhepatitis C virus; IPIInternational Prognostic Index; IVintravenous; 
LVEF = left ventricular ejection fraction; TCV = treatment completion visit, SCsubcutaneous.
Note:  After the end of the study treatment period, all patients will be followed until the end of the study according to local practice for resolution of 
adverse events related to rituximab therapy, survival, disease status, and whether a new lymphoma treatment has been started.  The visit window 
during each cycle of study treatment is ±3 days. The window for the treatment discontinuation/early treatment termination and post-treatment study 
visits is ± 1 week (unless otherwise specified).
a Patients who discontinue the study treatment prematurely are required to return to the clinic for an early termination visit within 48 weeks after 
the last dose of study treatment.
b Written informed consent must be obtained prior to any study-specific procedures (including screening evaluations) performed or any prohibited 
medications being withheld for purposes of study participation.  Please see Section 4.5.1 for more details.
c Includes evaluation of the head, eyes, ears, nose, and throat, and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems.  See Section 4.5.3 for more details.
d A targeted physical examination should be limited to systems of primary relevance, including cardiovascular, respiratory, those associated with
symptoms, and those with tumor assessment (lymph nodes, liver, and spleen).
e ECOG performance status must be 2 for inclusion of the patient into the study.
f
Diagnosis of DLBCL before treatment must have included histological diagnosis and initial CD20 expression confirmation.  See Section 4.1.1 for 
more details.


Appendix 1: Schedule of Activities (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
86/Protocol YO42207, Version 1.0
Assessment/Procedure
Screening
Treatment Period
End of Treatment
FollowUp 
(6 months)
C13
C4
C58
TCV
ETTV a
Days
28 to 1
Days
14 to 1
D1
D1
Interim 
Assessment
D19 (3)
D1
68 weeks 
after last 
treatment
48 weeks 
after last 
treatment
12 weeks and 
24 weeks after last 
treatment
g Tumor assessments will be based on PET-CT scans (or MRI scans, if CT scans are contraindicated) of the neck (if clinically indicated), chest, 
abdomen, and pelvis where applicable.  PET-CT scans will be obtained at screening, interim response assessment (i.e., Day 19 [±3 days] of 
Cycle 4) and End of Treatment assessment (68 weeks after the last dose of study treatment or 48 weeks after last dose of study treatment for 
early discontinuation). All other imaging may be CT only (i.e., follow-up period [12 and 24 weeks after the last dose of study treatment]).
h Hematology will include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent or absolute differential count.  At screening, 
serum chemistry will include sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, phosphorus, total bilirubin, total protein, albumin, 
AST, ALT, LDH, alkaline phosphatase, uric acid, and calculated creatinine clearance.  During Cycles 1–8 and the follow-up period, serum 
chemistry will include sodium, potassium, creatinine, calcium, total bilirubin, total protein, albumin, AST, ALT, LDH, alkaline phosphatase, and uric 
acid.
i
A negative serum pregnancy test or a negative urine pregnancy test within 7 days prior to study treatment must be available both for pre-
menopausal women (including those who have had a tubal ligation) and for women who are less than 2 years after the onset of menopause; if a 
negative serum test within 14 days prior to study treatment, a confirmatory urine pregnancy test must be within 1 week prior to study treatment 
start. 
j
Patients known to have HIV, hepatitis C, active hepatitis B, or signs or symptoms of other active and/or severe infection must not be included in 
the study.  Serology should be performed according to clinical judgment before and during treatment with rituximab.  Patients found to have HIV, 
hepatitis C, or active hepatitis B must either not start or must stop rituximab therapy and enter active follow-up.  Local guidelines for patient 
consent to viral testing must be adhered to.
k Patients with occult or prior HBV infection may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA 
testing.
l
Lumbar puncture is indicated for patients with high-risk disease or with one or more of the following sites of involvement: paranasal sinuses, 
testicular, paramenigeal, peri-orbital, CNS, paravertebral, or bone marrow.
m Bone marrow examinations are required at screening and should include biopsy for morphology.  Repeat bone marrow examinations are required 
if the bone marrow was involved with tumor at screening and the repeat bone marrow examination is required to confirm a radiological 
assessment of complete response at the end of therapy.
n See details on administration schedule of the study treatment in Section 4.3.2.


Appendix 1: Schedule of Activities (cont.)
Rituximab—F. Hoffmann-La Roche Ltd
87/Protocol YO42207, Version 1.0
Assessment/Procedure
Screening
Treatment Period
End of Treatment
FollowUp 
(6 months)
C13
C4
C58
TCV
ETTV a
Days
28 to 1
Days
14 to 1
D1
D1
Interim 
Assessment
D19 (3)
D1
68 weeks 
after last 
treatment
48 weeks 
after last 
treatment
12 weeks and 
24 weeks after last 
treatment
o See details on rituximab PK sample in Appendix 2.
p Samples for rituximab PK will be collected 24 weeks after last rituximab administration.
q Only patients who are randomized to rituximab SC will be assessed for anti-rHuPH20 antibodies.
r
Samples are drawn within 2 hours pre-dose.
s Samples for anti-rituximab antibodies and anti-rHuPH20 antibodies will be collected 12 weeks and 24 weeks after last rituximab dose.
t
After informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  
After this period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to 
prior study drug treatment (see Section 5.6).
u Any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 28 days prior to initiation of study drug to study termination.  Any new lymphoma 
treatment initiated after the baseline visit will be recorded as concomitant treatments.


Rituximab—F. Hoffmann-La Roche Ltd
88/Protocol YO42207, Version 1.0
Appendix 2
Schedule of Pharmacokinetic Samples (Treatment Period and 
Follow-Up Period)
For patients randomized to the rituximab IV arm:
Treatment Period
Follow-Up
Period
C1 a
C2 b
C3 b
C4 b
C5 b
C6 b
C7 b
C8 b
Within 2 hr pre-dose
x
x
x
x
x
x
x
x
Within 15 min of end of 
infusion
x
x
x
x
24 hr post-dose 
(4 hr) c
x
x
Day 3 (4 hr)
x
x
Day 7 (24 hr)
x
x
Day 15 (48 hr)
x
x
Day 29 (24 hr)
x
24 wks (7 days) after 
the last rituximab dose
x
a Rituximab at Cycle 1 can be given on either Day 1 or Day 2, depending on institutional 
practice.
b Rituximab at Cycles 2 to 8 is to be given on Day 1.
c Defined as 24 hours (4 hr) after start of the previous dosing.


Appendix 2: Schedule of Pharmacokinetic Samples
Rituximab—F. Hoffmann-La Roche Ltd
89/Protocol YO42207, Version 1.0
For patients randomized to the rituximab SC arm:
Treatment Period
Follow-Up
Period
C1 a
C2 b
C3 b
C4 b
C5 b
C6 b
C7 b
C8 b
Within 2 hr pre-dose
x
x
x
x
x
x
x
x
Within 15 min of end of 
infusion
x
24 hr post-dose 
(4 hrs) c
x
x
Day 3 (4 hr) d
x
x
Day 7 (24 hr)
x
x
x
Day 15 (48 hr)
x
x
Day 29 (24 hr)
x
24 wks (7 days) after 
the last rituximab dose
x
a Rituximab at Cycle 1 can be given on either Day 1 or Day 2, depending on institutional 
practice.
b Rituximab at Cycles 2 to 8 is to be given on Day 1.
c Defined as 24 hours (4 hr) after start of the previous dosing.
d Defined as 48 hours (4 hr) after start of the previous dosing.


Rituximab—F. Hoffmann-La Roche Ltd
90/Protocol YO42207, Version 1.0
Appendix 3
Anaphylaxis Precautions
These guidelines are intended as a reference and should not supersede pertinent local
or institutional standard operating procedures.
REQUIRED EQUIPMENT AND MEDICATION
The following equipment and medication are needed in the event of a suspected 
anaphylactic reaction during study treatment infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for subcutaneous, intramuscular, intravenous, and/or endotracheal 
administration in accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
PROCEDURES
In the event of a suspected anaphylactic reaction during study treatment infusion, 
the following procedures should be performed:
1.
Stop the study treatment infusion.
2.
Call for additional medical assistance.
3.
Maintain an adequate airway.
4.
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring if possible.
5.
Administer antihistamines, epinephrine, or other medications and IV fluids as 
required by patient status and as directed by the physician in charge.
6.
Continue to observe the patient and document observations.
7.
Collect blood samples for immunogenicity testing (i.e., anti-rituximab antibody 
samples [in all patients] and anti rHuPH20 antibody samples [only in patients 
randomized to the SC arm])
8.
Ask the patient to return for immunogenicity sample collection at the time of washout, 
if appropriate.


Rituximab—F. Hoffmann-La Roche Ltd
91/Protocol YO42207, Version 1.0
Appendix 4
Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014)
Response should be determined on the basis of radiographic and clinical evidence of 
disease.  For the end of treatment assessment, an FDG-PET (18F fluorodeoxyglucose 
positron emission tomography)/CT (computed tomography) scan will be performed 68 
weeks after Cycle 6, Day 1 or the final dose of study treatment, as assessed by an 
Independent Review Committee and the investigator.  Assessment of the PET-CT scan 
should follow the criteria presented below (Cheson et al. 2014).
Target and Non-Target Lesions
Up to six of the largest target nodes, nodal masses, or other lymphomatous lesions that 
are measurable in two diameters should be identified from different body regions 
representative of the patient’s overall disease burden and include mediastinal and 
retroperitoneal disease, if involved.  At baseline, a measurable node must be greater 
than 15 mm in longest diameter (LDi).  Measurable extranodal disease may be included 
in the six representative, measured lesions.  At baseline, measurable extranodal lesions 
should be greater than 10 mm LDi. 
All other lesions (including nodal, extranodal, and assessable disease) should be 
followed as non-measured disease as non-target lesions (e.g., cutaneous, 
gastrointestinal, bone, spleen, liver, kidneys, pleural or pericardial effusions, ascites, 
bone, bone marrow). 
Split Lesions and Confluent Lesions
Lesions may split or may become confluent over time. In the case of split lesions, the 
individual product of the perpendicular diameters (PPDs) of the nodes should be 
summed together to represent the PPD of the split lesion; this PPD is added to the sum 
of the PPDs of the remaining lesions to measure response.  If subsequent growth of any 
or all of these discrete nodes occurs, the nadir of each individual node is used to 
determine progression.  In the case of confluent lesions, the PPD of the confluent mass 
should be compared with the sum of the PPDs of the individual nodes, with more than 
50% increase in PPD of the confluent mass compared with the sum of individual nodes 
necessary to indicate progressive disease.  The LDi and smallest diameter (SDi) are no 
longer needed to determine progression.


Appendix 4 Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014)
Rituximab—F. Hoffmann-La Roche Ltd
92/Protocol YO42207, Version 1.0
Response and Site
PET-CT–Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all of 
the following)
Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3 a with or without a 
residual mass on 5PS b
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic 
uptake or with activation within spleen 
or marrow (e.g., with chemotherapy or 
myeloid colony-stimulating factors), 
uptake may be greater than normal 
mediastinum and/or liver.  In this 
circumstance, complete metabolic 
response may be inferred if uptake at 
sites of initial involvement is no greater 
than surrounding normal tissue even if 
the tissue has high physiologic uptake.
Target nodes/nodal masses must 
regress to 1.5 cm in LDi
No extralymphatic sites of 
disease
Non-measured lesion
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
indeterminate, IHC negative


Appendix 4 Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014)
Rituximab—F. Hoffmann-La Roche Ltd
93/Protocol YO42207, Version 1.0
Response and Site
PET-CT–Based Response
CT-Based Response
Partial
Partial metabolic response
Partial remission (all of the following)
Lymph nodes and 
extralymphatic sites
Score 4 or 5 b with reduced uptake 
compared with baseline and residual 
mass(es) of any size
50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites
At interim, these findings suggest 
responding disease
When a lesion is too small to 
measure on CT, assign 5 mm5 
mm as the default value
At end of treatment, these findings 
indicate residual disease
When no longer visible, 00 mm
For a node 5 mm5 mm, but 
smaller than normal, use actual 
measurement for calculation
Non-measured lesion
Not applicable
Absent/normal, regressed, but no 
increase
Organ enlargement
Not applicable
Spleen must have regressed by 
50% in length beyond normal
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline (diffuse uptake compatible 
with reactive changes from 
chemotherapy allowed).  If there are 
persistent focal changes in the marrow in 
the context of a nodal response, 
consideration should be given to further 
evaluation with MRI or biopsy or an 
interval scan.
Not applicable


Appendix 4 Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014)
Rituximab—F. Hoffmann-La Roche Ltd
94/Protocol YO42207, Version 1.0
Response and Site
PET-CT–Based Response
CT-Based Response
No response or stable 
disease 
No metabolic response
Stable disease
Target nodes/nodal 
masses, extranodal 
lesions
Score 4 or 5 b with no significant change 
in FDG uptake from baseline at interim 
or end of treatment
50% decrease from baseline in 
SPD of up to 6 dominant, measurable 
nodes and extranodal sites; no 
criteria for progressive disease are 
met
Non-measured lesion
Not applicable
No increase consistent with 
progression
Organ enlargement
Not applicable
No increase consistent with 
progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable


Appendix 4 Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014)
Rituximab—F. Hoffmann-La Roche Ltd
95/Protocol YO42207, Version 1.0
Response and Site
PET-CT–Based Response
CT-Based Response
Progressive disease
Progressive metabolic disease
Progressive disease requires at least 
1 of the following 
Individual target 
nodes/nodal masses
Score 4 or 5 b with an increase in 
intensity of uptake from baseline and/or
PPD progression:
Extranodal lesions
New FDG-avid foci consistent with 
lymphoma at interim or end-of-treatment 
assessment
An individual node/lesion must be 
abnormal with:
LDi 1.5 cm and
Increase by 50% from PPD nadir 
and
An increase in LDi or SDi from nadir
0.5 cm for lesions 2 cm
1.0 cm for lesions 2 cm
In the setting of splenomegaly (13 
cm), the splenic length must increase 
by 50% of the extent of its prior 
increase beyond baseline (e.g., a 15-
cm spleen must increase to 16 cm).  
If no prior splenomegaly, must 
increase by at least 2 cm from 
baseline.
New or recurrent splenomegaly 
Non-measured lesions
None
New or clear progression of 
preexisting non-measured lesions
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology 
(e.g., infection, inflammation); if 
uncertain regarding etiology of new 
lesions, biopsy or interval scan may be 
considered
Regrowth of previously resolved 
lesions
A new node 1.5 cm in any axis
A new extranodal site 1.0 cm in any 
axis; if 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement


Appendix 4 Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014)
Rituximab—F. Hoffmann-La Roche Ltd
96/Protocol YO42207, Version 1.0
5PS 5-point scale; CT computed tomography; FDG fluorodeoxyglucose; IHC immunohistochemistry; 
LDi longest transverse diameter of a lesion; MRI magnetic resonance imaging; PET positron emission 
tomography (scan); PPD cross product of the LDi and perpendicular diameter; SDi shortest axis 
perpendicular to the LDi; SPD sum of the product of the perpendicular diameters for multiple lesions.
a
A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time 
of an interim scan.  However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid undertreatment).  Measured 
dominant lesions:  Up to six of the largest dominant nodes, nodal masses, and extranodal lesions 
selected to be clearly measurable in two diameters.  Nodes should preferably be from disparate regions 
of the body and should include, where applicable, mediastinal and retroperitoneal areas.   Non-nodal 
lesions include those in solid organs (e.g., liver, spleen, kidneys, lungs), gastrointestinal involvement, 
cutaneous lesions, or those noted on palpation.  Non-measured lesions:  Any disease not selected as 
measured; dominant disease and truly assessable disease should be considered not measured.  These 
sites include any nodes, nodal masses, and extranodal sites not selected as dominant or measurable or 
that do not meet the requirements for measurability but are still considered abnormal, as well as truly 
assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively 
with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging.  In Waldeyer’s ring or in 
extranodal sites (e.g., GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum 
with complete metabolic response, but should be no higher than surrounding normal physiologic uptake 
(e.g., with marrow activation as a result of chemotherapy or myeloid growth factors).
b
PET 5PS:  1 no uptake above background; 2 uptake mediastinum; 3 uptake mediastinum but 
liver; 4 uptake moderately liver; 5 uptake markedly higher than liver and/or new lesions; X new 
areas of uptake unlikely to be related to lymphoma. 


Rituximab—F. Hoffmann-La Roche Ltd
97/Protocol YO42207, Version 1.0
Appendix 5
International Prognostic Index and Ann Arbor Staging 
Classification
International Prognostic Index
Risk factors
    Ann Arbor Stage III or IV
    Age 60 years
    Elevated lactate dehydrogenase
    ECOG performance status 2
    Extranodal involvement 2
IPI risk group
Number of IPI risk factors
  Low
0 or 1
  Low-intermediate
2
  High-intermediate
3
  High
4 or 5
ECOGEastern Cooperative Oncology Group; IPIInternational Prognostic Index.
Ann Arbor Staging Classification for Hodgkin and Non-Hodgkin’s Lymphoma a
Stage I
Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE) b
Stage II
Involvement of two or more lymph node regions or lymphatic structures on the same side of 
the diaphragm alone (II) or with involvement of limited, contiguous extralymphatic organ or 
tissue (IIE)
Stage III
Involvement of lymph node regions on both sides of the diaphragm (III), which may include 
the spleen (IIIS) or limited, contiguous extralymphatic organ or site (IIIE) or both (IIIES)
Stage IV
Diffuse or disseminated foci of involvement of one or more extralymphatic organs or tissues, 
with or without associated lymphatic involvement
a All cases are subclassified to indicate the absence (A) or presence (B) of the systemic (“B”) symptoms of 
significant unexplained fever (38°C), night sweats, or unexplained weight loss exceeding 10% of body 
weight during the 6 months prior to diagnosis. Clinical stage refers to the extent of disease determined by 
diagnostic tests following a single diagnostic biopsy.  If a second biopsy of any kind is obtained, even if 
negative, the term pathologic stage is used.
b
The designation “E” generally refers to extranodal contiguous extension (i.e., proximal or contiguous 
extranodal disease) that can be encompassed within an irradiation field appropriate for nodal disease of 
the same anatomic extent.  A single extralymphatic site as the only site of disease should be classified as 
IE rather than Stage IV.
Adapted from:
1.
Carbone PP, Kaplan HS, Musshoff K, et al. Report of the committee on Hodgkin’s disease staging 
classification. Cancer Res 1971;31:1860–1.
2.
Lister TA, Crowther D, Sutcliffe SB, et al. Report of a committee convened to discuss the evaluation 
and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 1989;7:1630–6.


Rituximab—F. Hoffmann-La Roche Ltd
98/Protocol YO42207, Version 1.0
Appendix 6
Eastern Cooperative Oncology Group Performance Status Scale
Grade
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature, e.g., light housework or office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up 
and about 50% of waking hours
3
Capable of only limited self-care, confined to a bed or chair > 50% of waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead

SAP_001.pdf: 
 
Official Title: A Phase II Comparative, Open Label, Randomized, Multicenter, 
China-Only Study to Investigate the Pharmacokinetics, Efficacy and 
Safety of Subcutaneous Rituximab Versus Intravenous Rituximab, 
Both in Combination With CHOP in Previously Untreated Patients With 
CD20 Positive Diffuse Large B Cell Lymphoma 
NCT Number: NCT04660799   
Document Date: SAP Version 1.0: 20-May-2022 
 
 
 


 
CONFIDENTIAL 
 
This is F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Rituximab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan YO42207 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE II COMPARATIVE, OPEN LABEL, RANDOMIZED, 
MULTICENTER, CHINA-ONLY STUDY TO INVESTIGATE 
THE PHARMACOKINETICS, EFFICACY AND SAFETY OF 
SUBCUTANEOUS RITUXIMAB VERSUS INTRAVENOUS 
RITUXIMAB, BOTH IN COMBINATION WITH CHOP IN 
PREVIOUSLY UNTREATED PATIENTS WITH CD20 
POSITIVE DIFFUSE LARGE B CELL LYMPHOMA 
PROTOCOL NUMBER: 
YO42207 
STUDY DRUG: 
Rituximab (RO0452294) (MabTheraⓇ) 
VERSION NUMBER: 
1.0 
IND NUMBER: 
Not applicable  
EUDRACT NUMBER: 
Not applicable 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
 
DATE FINAL: 
See electronic date stamp on the last page of this 
document 
 
 


Rituximab—F. Hoffmann-La Roche Ltd 
2/Statistical Analysis Plan YO42207 
                                        TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 4 
2. 
STUDY DESIGN ........................................................................................... 4 
2.1 
PROTOCOL SYNOPSIS ......................................................... 5 
2.2 
ENDPOINTS ............................................................................ 5 
2.2.1 
Primary Pharmacokinetic Endpoints ........................................ 5 
2.2.2 
Secondary Pharmacokinetic Endpoints ................................... 5 
2.2.3 
Key Efficacy Endpoints ............................................................ 6 
2.2.4 
Secondary Efficacy Endpoints ................................................. 6 
2.2.5 
Safety Endpoints ..................................................................... 6 
2.3 
DETERMINATION OF SAMPLE SIZE..................................... 6 
2.4 
ANALYSIS TIMING ................................................................. 6 
3. 
STUDY CONDUCT ....................................................................................... 7 
3.1 
RANDOMIZATION .................................................................. 7 
3.2 
INDEPENDENT REVIEW FACILITY ....................................... 7 
4. 
STATISTICAL METHODS ............................................................................ 7 
4.1 
ANALYSIS POPULATIONS ..................................................... 7 
4.1.1 
Intent-to-Treat Population ........................................................ 7 
4.1.2 
Pharmacokinetic-Evaluable Population ................................... 7 
4.1.3 
Per Protocol PK Population ..................................................... 7 
4.1.4 
Safety Population .................................................................... 8 
4.1.5 
Immunogenicity Population ...................................................... 8 
4.2 
ANALYSIS OF STUDY CONDUCT ......................................... 8 
4.3 
ANALYSIS OF TREATMENT GROUP 
COMPARABILITY ................................................................... 8 
4.4 
PHARMACOKINETIC ANALYSES .......................................... 8 
4.4.1 
Pharmacokinetic Primary Endpoint .......................................... 9 
4.4.2 
Pharmacokinetic Secondary Endpoint ................................... 10 
4.5 
EFFICACY ANALYSIS .......................................................... 11 
4.5.1 
Key Efficacy Endpoint ............................................................ 11 
4.5.2 
Secondary Efficacy Endpoints ............................................... 11 
4.5.3 
Sensitivity Analyses ............................................................... 11 


Rituximab—F. Hoffmann-La Roche Ltd 
3/Statistical Analysis Plan YO42207 
4.5.4 
Subgroup Analyses ............................................................... 12 
4.6 
SAFETY ANALYSES ............................................................. 12 
4.6.1 
Exposure of Study Medication ............................................... 12 
4.6.2 
Adverse Events ..................................................................... 12 
4.6.3 
Laboratory Data ..................................................................... 13 
4.6.4 
Vital Signs .............................................................................. 13 
4.6.5 
ECG Evaluations ................................................................... 13 
4.6.6 
Immunogenicity Analyses ...................................................... 13 
4.7 
MISSING DATA ..................................................................... 13 
4.8 
INTERIM ANALYSES ............................................................ 13 
5. 
REFERENCES ........................................................................................... 13 
 
 
                                     LIST OF FIGURES 
 
Figure 1             Dose schema .............................................................................. 5 
 
 
                                     LIST OF APPENDICES 
 
Appendix 1         Protocol Synopsis .................................................................... 15 
Appendix 2         Schedule of Activities ............................................................... 21 
 
 
 


Rituximab—F. Hoffmann-La Roche Ltd 
4/Statistical Analysis Plan YO42207 
1. 
BACKGROUND 
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for Study YO42207 “a Phase II comparative, open label, randomized, 
multicenter, China-only study to investigate the pharmacokinetics, efficacy and safety of 
subcutaneous rituximab versus intravenous rituximab, both in combination with CHOP in 
previously untreated patients with CD20 positive diffuse large B cell lymphoma”. 
Study BO22334, a global two-stage Phase III trial, has demonstrated non−inferiority of 
trough serum concentrations [Ctrough] at Cycle 7 (Stage 1 primary endpoint).  Non-inferior 
Ctrough with the fixed rituximab SC dose of 1400 mg was demonstrated compared with 
rituximab IV 375 mg/m2 given every 3 weeks.  The ratio Ctrough,SC/Ctrough,IV at Cycle 7 was 
1.62 (90% CI: 1.36,1.94)) with comparable variability (coefficient of variation [CV] 43.2% 
in the rituximab SC arm and CV 36.7% in the rituximab IV arm).  The geometric mean 
AUC was also higher in the rituximab SC arm, with observed rituximab serum 
AUC(SC)/AUC(IV) ratio during Cycle 7 of 1.38 (90% CI: 1.24,1.53) and comparable 
variability between the two arms (coefficient of variation [CV] 33.7% in the rituximab SC 
arm and CV 28.0% in the rituximab IV arm).  Study BO22334 has also shows 
comparable Objective response rate (ORR) based on the investigator assessments 
(84.9% (95% CI: 79.2%, 89.5%) in the rituximab IV arm versus 84.4% (95% CI: (78.7%, 
89.1%) in the rituximab SC arm. 
Rituximab IV and SC have a well-established benefit-risk profile and are approved in 
more than 90 countries or regions.  The SC formulation is expected to bring significant 
and clinically meaningful benefits to Chinese patients in terms of improved tolerability 
with potentially fewer and less severe administration-related reactions (ARRs). 
The purpose of Study YO42207 is to evaluate pharmacokinetics, efficacy and safety of 
subcutaneous rituximab in a randomized, controlled, and comparative setting for 
Chinese patients with CD20 positive diffuse large B cell lymphoma.  This study will 
explore the efficacy of rituximab SC and rituximab IV, respectively, in previously 
untreated DLBCL patients, based on the complete response rate (CRR) observed with 
each formulation. 
2. 
STUDY DESIGN 
This is a Phase II, multicenter, randomized, controlled, open-label, China-only study to 
investigate the PK, efficacy, and safety of rituximab SC in combination with CHOP 
versus rituximab IV in combination with CHOP in previously untreated patients with 
CD20 positive DLBCL. 
This study will be conducted at approximately 8 sites in China and will approximately 
enroll 50 patients.  Eligible patients will be stratified according to IPI scores (IPI 0-2 
versus IPI 3-5) and randomized at a 1:1 ratio into the following two treatment groups 
(crossover to the experimental arm is not permitted):  
● 
RSC-CHOP: Cycle 1 rituximab IV plus seven cycles of rituximab SC in combination 
with six or eight cycles of CHOP chemotherapy administered every 3 weeks; 
rituximab IV will be used at the standard dose of 375 mg/m2 and rituximab SC will 
be given at a dose of 1400 mg as confirmed in the Phase III Study BO22334. 


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● 
RIV-CHOP: Eight cycles of rituximab IV in combination with six or eight cycles of 
CHOP chemotherapy administered every 3 weeks; rituximab IV will be used at the 
standard dose of 375 mg/m2. 
Figure 1             Dose schema 
.   
 
After the end of study treatment, patients will be followed-up every 3 months for 
6 months (i.e., 12 and 24 weeks after the last dose of study treatment). 
Patients will be assessed for disease response by the investigator and IRC according to 
the Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014).  PET-CT 
and dedicated CT scans will be obtained at screening and 6-8 weeks after completion of 
study treatment, or sooner in the event that a patient discontinues early.  An interim 
assessment will be obtained after Cycle 4 and should include PET-CT and dedicated 
CT.  If local practice prohibits obtaining both assessments after Cycle 4, PET-CT alone 
(preferred) or CT alone may be obtained at this time point.  During the follow-up period, 
imaging (may be CT only) will be performed every 3 months, i.e., Week 12 and 24 after 
last treatment, in accordance with study visits and will include the neck (if involved at 
baseline), chest, abdomen, and pelvis. 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1. For additional details, see the Schedule of 
Assessments in Appendix 2. 
2.2 
ENDPOINTS 
2.2.1 
Primary Pharmacokinetic Endpoints 
The primary objective of this study is to demonstrate the non-inferiority of rituximab 
serum Ctrough obtained at Cycle 7, 21 days after SC administration, with that obtained at 
Cycle 7, 21 days after IV administration on the basis of the following endpoint: 
● Ratio of Ctrough,SC/Ctrough,IV during Cycle 7 
2.2.2 
Secondary Pharmacokinetic Endpoints 
● 
Ratio of AUCSC/AUCIV during Cycle 7 
● 
Other PK parameters, such as AUC and Ctrough at other treatment cycles, maximum 
serum concentration (Cmax), total clearance, volume of distribution at steady state, 
and terminal half-life (t1/2) (if feasible or appropriate) as appropriate 
 
 


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2.2.3 
Key Efficacy Endpoints 
● 
Complete response rate (CRR) at the end of the study treatment, as determined by 
the Independent Review Committee (IRC) using Lugano Response Criteria for 
Malignant Lymphoma (Cheson et al. 2014) 
2.2.4 
Secondary Efficacy Endpoints 
● 
Objective response rate (ORR), defined as CR or partial response (PR) at the end 
of the study treatment, as determined by investigator and IRC using Lugano 
Response Criteria for Malignant Lymphoma (Cheson et al. 2014) 
● 
CRR (CR, CRu) at the end of study treatment, as determined by IRC using 
International Working Group (IWG) Response Criteria for NHL 1999 Guidelines 
● 
CRR at the end of the study treatment, as determined by the investigator using 
Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) 
 
2.2.5 
Safety Endpoints 
● 
Safety outcomes as assessed by adverse events, including rituximab 
administration-related reactions (ARRs), laboratory assessments, and vital signs; 
and immunogenicity as assessed by anti-rituximab antibodies and anti-rHuPH20 
antibodies 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
Under the assumption of a coefficient of variation equal to 0.5 and assuming that the 
true Ctrough of rituximab SC formulation is 20% above the rituximab IV formulation (i.e., 
mean Ctrough,SC to be 20% above Ctrough,IV), 20 patients in each treatment arm are needed 
in order to achieve 80% power with one-sided alpha of 0.05 (i.e., 2-sided 90% CI).  
Assuming that 20% of patients would not have valid PK data at Cycle 8 pre-dose, a total 
of approximately 50 patients will be enrolled into the study (see Table 1). 
Table 1 
Sample Size for Primary Endpoint (i.e., Non-inferiority in Ctrough) 
Parameter 
Value 
Test significance levels, α (one-sided) 
0.050 
Lower equivalence limit for μT/μS, ΔL 
0.800 
Expected ratio, μT/μS 
1.200 
Coefficient of variation, σS/μS 
0.500 
Power (%) 
80 
Number of patients per group 
18 (rounded to 20) 
Number of patients (total) 
36 (rounded to 40) 
 
2.4 
ANALYSIS TIMING 
Primary analysis will be conducted when all the patients have been evaluated for the tumor 
response at the end of treatment visit.  The final analysis will be performed at the end of 
study. 


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3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Patients who are eligible for study entry are randomly assigned (1:1) to either RSC-CHOP 
arm or RIV-CHOP arm via the interactive voice or Web-based response system (IxRS) 
through use of a permuted block randomization scheme. 
Randomization procedures use one stratification factor: 
● 
IPI Scores (IPI 0-2 versus IPI 3-5) 
 
3.2 
INDEPENDENT REVIEW FACILITY 
An IRC composed of certified radiologists and a hematologist or oncologist with 
experience in malignant lymphoma will assess all patients for response according to 
Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014) (see protocol 
Appendix 3) and IWG Response Criteria for NHL 1999 Guidelines, respectively, on the 
basis of imaging results and biopsy results that are performed related to efficacy 
evaluation.  Decisions will be guided by a Charter specific to the independent review. 
4. 
STATISTICAL METHODS  
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population consists of all randomized patients.  Patients are 
assigned to the treatment group to which they were randomized.  The ITT population will 
be used for the efficacy analyses. 
4.1.2 
Pharmacokinetic-Evaluable Population 
PK analyses will be based on all patients with at least one PK assessment. PK analyses 
will be analyzed as treated.  Patients will be excluded from the PK analysis population if 
they significantly violate the inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete, where the PK analysis might be 
influenced.  Excluded cases will be documented, including the reason for exclusion.  All 
decisions on exclusions from the analysis will be made prior to database closure. 
4.1.3 
Per Protocol PK Population 
 
The Per Protocol PK (PPP) analysis population will include all patients enrolled who 
adhered to the protocol.  Patients will be assigned to treatment groups as treated. 
Exclusions from the Per Protocol PK analysis populations will be made for the following 
reasons: 
● Patients are missing the Ctrough during Cycle 7 (pre-dose Cycle 8 PK) sample, 
● Patients with a Cycle 7 Ctrough sample collected with more than 3 days deviation 
from the planned date on Day 22 (i.e., before Day 19 or after Day 25), 
● Patients given a dose amount that deviates from the planned dose by >20% 
within 3 cycles (from Cycle 5), 
● Patients with a Cycle 7 dose delay of more than 7 days, 


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● Assay error impacting Cycle 7 Ctrough (pre-dose Cycle 8) measurement. 
Patients will be excluded from the PK endpoint analyses according to the exclusions 
defined above.  Excluded cases will be documented, including the reason for exclusion. 
All decisions on exclusions from the analysis will be made prior to database closure. 
The Per Protocol PK (PPP) analysis population will be used for the primary endpoint of 
ratio of Ctrough,SC/Ctrough,IV during Cycle 7 and the secondary PK endpoint of ratio of 
observed rituximab area under the serum concentration curve of Cycle 7 (AUCSC/AUCIV). 
4.1.4 
Safety Population 
The safety analysis population consists of all randomized patients who received at least 
one dose of study drug, with patients grouped according to treatment received. 
4.1.5 
Immunogenicity Population 
The immunogenicity analysis population will consist of all patients with at least one anti-
drug antibody (ADA) assessment.  The ADAs include anti-rituximab antibodies and anti-
rHuPH20 antibodies.  Patients will be grouped according to treatment received or, if no 
treatment is received prior to study discontinuation, according to treatment assigned. 
4.2 
ANALYSIS OF STUDY CONDUCT 
The number of patients who randomize, receive treatment, complete study treatment, 
discontinue from study will be summarized by treatment group.  Reasons for premature 
study treatment discontinuation will be listed and summarized by treatment group.  
Reasons for study discontinuation will be listed and summarized by treatment group. 
Enrollment and major protocol deviations will be listed and summarized by treatment 
group. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (such as age, sex, race, weight, height, BSA) 
will be summarized by treatment arm for the ITT population. 
Baseline disease characteristics (such as ECOG Performance Status, IPI Score, time 
since initial DLBCL, Ann Arbor Stage at diagnosis, Ann Arbor Stage at study entry) will 
also be summarized by treatment arm for the ITT population. 
Baseline measurements are the last available data obtained prior to patients receiving 
the first dose of study drug, unless otherwise noted. 
Continuous variables will be summarized using number of patients, means, standard 
deviations, medians and range, and categorical variables will be summarized using 
counts and proportions, as appropriate.  Summaries will be presented overall and by 
treatment arm for the ITT population. 
4.4 
PHARMACOKINETIC ANALYSES 
For all patients, Ctrough will be measured at Cycle 7 (i.e. pre-dose Cycle 8) and will be the 
basis of the primary analysis. PK parameters of rituximab will be estimated using 
standard non-compartmental analysis and reported in the CSR. 
 


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4.4.1 
Pharmacokinetic Primary Endpoint 
The primary PK endpoint is the ratio of observed Ctrough,SC/Ctrough,IV during Cycle 7.  The 
serum rituximab Ctrough at Cycle 7 will be measured at pre-dose of Cycle 8.  The lower 
limit of the two-sided 90% CI should be above 0.80 in order to show non-inferiority of 
Ctrough,SC versus Ctrough,IV. The primary analysis of Ctrough will be based on logarithmic 
values to compensate for the skewness of the distribution. According to Berinstein et al., 
a strong dependence of Ctrough levels from baseline tumor load has been noted and 
therefore, an analysis of covariance model will be used to adjust for tumor load at 
baseline and the tumor load was defined as SPD of all entered indicator lesions at 
baseline: 
𝑙𝑛 (𝐶𝑡𝑟𝑜𝑢𝑔ℎ) = 𝜇+ 𝜏+ 𝐵𝑇𝐿+ 𝜀 
Where: 
𝑙𝑛 (𝐶𝑡𝑟𝑜𝑢𝑔ℎ)  , the log-transformed Ctrough value 
𝜇, the overall mean effect 
𝜏, the treatment effects 
𝐵𝑇𝐿, the tumor load at baseline 
𝜀, a random error with normal distribution N(0,1) 
The above model will be performed using SAS procedure MIXED: 
   ods output LSMeans=lsmeans Diffs=diffs; 
proc mixed data=<data> alpha=0.1; 
class <treatment code>; 
model <logarithmic estimated Ctrough>=<treatment code> <tumor load at baseline>; 
lsmeans <treatment code>/alpha=0.1 cl diff pdiff; 
run; 
quit; 
ods output close; 
Both the LSmean of logarithmic Ctrough with its 90% CI and the treatment difference of 
LSmean with its 90% CI will be estimated. Then Geometric mean (90% CI) of Ctrough for 
each treatment and Geometric mean ratio (90% CI) of Ctrough,SC/Ctrough,IV can be 
calculated by back-transformed using the exponential function. 
For no adjusted ratio on tumor load, the two one-sided tests (TOST) equivalence test of 
Schuirmann will be used for Ctrough value on original scale with lognormal distributional 
assumption. The equivalence bounds of geometric mean Ctrough ratio is set to between 
0.8 and 1.25. Geometric mean ratio (90% CI) of Ctrough,SC/Ctrough,IV and the coefficient of 
variation will be estimated using SAS Procedure TTEST: 
ods output EquivLimits=equivlimits EqulvaTests=equlvtests; 
proc ttest data=<data> alpha=0.05 test=ratio dist=lognormal tost(0.8, 1.25); 
   class <treatment code>; 
   var <estimated Ctrough> 


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run; 
 
The following supplemental analysis will be added to support primary analysis and will 
be analyzed on Pharmacokinetic-Evaluable Population: 
 
1) Include all patients who have received at least 4 cycles of Rituximab IV/SC with at 
least one observed Ctrough from Cycle 4 to Cycle 7.  The serum rituximab Ctrough during 
each cycle will be measured at pre-dose of the next cycle.  The ratio of observed 
Ctrough,SC/Ctrough,IV during Cycle 7 will be estimated using mixed model repeated measures 
(MMRM) analysis.  The model will use restricted maximum likelihood (REML) with 
treatment, cycle and treatment-by-cycle interaction as fixed effects, tumor load at 
baseline as a covariate, and patient as random effect.  An unstructured covariance 
structure will be used to model the within-patient errors. 
 
If this analysis fails to converge, the following covariance structures will be tested in 
order: 
● toeplitz with heterogeneity 
● autoregressive with heterogeneity 
● compound symmetry with heterogeneous variances 
● toeplitz, 
● autoregressive 
● compound symmetry without heterogeneous variances 
 
The first covariance structure that converges will be used.  The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom.  Significance 
tests will be based on least-squares mean (LSMean) using Type III sum of squares. 
2) The ratio of observed Ctrough,SC/Ctrough,IV during Cycle 4 will be estimated using the 
same ANCOVA model as primary analysis. 
3) Include patients with all available observed Ctrough during cycle 7. 
4.4.2 
Pharmacokinetic Secondary Endpoint 
The secondary PK endpoint is the ratio of observed rituximab area under the serum 
concentration curve of Cycle 7 (AUCSC/AUCIV).  A two-sided 90% CI will be constructed.  
The ratio of AUC will be analyzed in a similar model as described in section 4.4.1. 
Individual and mean serum rituximab concentration versus time data will be tabulated 
and plotted by treatment arms.  The serum pharmacokinetics of rituximab will be 
characterized by estimating observed AUC, observed Ctrough, observed Cmax, total 
clearance, volume of distribution at steady state, and terminal half-life (as appropriate for 
data collected) using noncompartmental analysis (NCA).  Estimates for these PK 
parameters will be tabulated and summarized by treatment group (arithmetic mean, 
standard deviation (SD), percent arithmetic mean CV%, geometric mean, percent 
geometric mean coefficient of variation (CV% geo mean), median, minimum, and 
maximum).  Inter-patient variability will be evaluated. 


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4.5 
EFFICACY ANALYSIS 
4.5.1 
Key Efficacy Endpoint 
The key efficacy endpoint is the complete response rate (CRR) at the end of treatment 
assessment as determined by the IRC using Lugano Response Criteria for Malignant 
Lymphoma (Cheson et al. 2014). 
Complete response rate (CRR): A complete response is defined as determined by the 
IRC using Lugano Response Criteria for Malignant Lymphoma (Cheson et al. 2014).  
Patients not meeting these criteria, including patients without any post-baseline tumor 
assessments, will be considered non-responders.  And the end of treatment response is 
defined as the response after the end of treatment or at treatment discontinuation and 
before any new anti-lymphoma treatment whichever is earlier. 
CRR at the end of treatment will be analyzed in frequency tables, including 95% two-
sided CIs (Pearson-Clopper) by treatment group.  For the difference in response rates, 
95% two-sided CIs (Hauck-Andersen) will be calculated.  If applicable, the Chi- squared 
test will be used to compare the CRR between groups. Odds ratio and 95% CI (Wald) 
will also be calculated by logistic regression. 
The rates with 95% CI (Pearson-Clopper) for each response category (CR, PR, PD, SD, 
NE, Missing) will also be summarized by treatment group. 
4.5.2 
Secondary Efficacy Endpoints 
CRR (CR, CRu) at the end of study treatment, as determined by IRC using International 
Working Group (IWG) Response Criteria for NHL 1999 Guidelines and CRR at the end 
of study treatment as determined by the investigator using Lugano Response Criteria for 
Malignant Lymphoma (Cheson et al. 2014) will be performed using the same methods 
as key efficacy endpoint. 
Objective response rate (ORR): An objective response is defined as either a CR or PR, 
as determined by investigators using Lugano Response Criteria for Malignant Lymphoma 
(Cheson et al. 2014).  Patients not meeting these criteria, including patients without any 
post-baseline tumor assessments, will be considered non-responders. 
ORR at the end of treatment will be analyzed in frequency tables, including 95% two-
sided CIs (Pearson-Clopper) by treatment group.  For the difference in response rates, 
95% two-sided CIs (Hauck-Andersen) will be calculated.  If applicable, the Chi- squared 
test will be used to compare the CRR between groups.  Odds ratio and 95% CI (Wald) 
will also be calculated by logistic regression. 
The rates with 95% CI (Pearson-Clopper) for each response category (CR, PR, PD, SD, 
NE, Missing) will also be summarized by treatment group. 
Analyses on ORR assessed by IRC will also be performed using the same methods as 
ORR assessed by the investigators. 
4.5.3 
Sensitivity Analyses 
As a sensitivity analysis, the response rate will be compared between treatment arms 
using the stratified Cochran-Mantel-Haenszel test.  And the Odds ratio and 95% CI will 


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also be estimated using a logistic regression stratified by randomization stratification 
factor IPI Score according to IXRS data. 
4.5.4 
Subgroup Analyses 
To assess the consistency of treatment benefit with respect to the primary efficacy 
endpoint, CRR, across important subgroups, forest plots (including estimated Odds 
ratios) will be provided for the following variables:  
● 
Age-group (<65, >=65 years), 
● 
Sex (Male, Female), 
● 
IPI Score (0-2, 3-5), 
● 
ECOG Performance Status (0,>=1) 
● 
BSA: the cut-off will be the 33rd and 66th percentiles of BSA values at baseline: 
Low (≤ 33rd percentiles); medium (33rd percentiles< BSA ≤ 66th percentiles); high 
(> 66th percentiles) 
 
4.6 
SAFETY ANALYSES 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, changes in laboratory test results, and changes in vital signs and ECGs.  Safety 
population will be used in all safety analysis. 
4.6.1 
Exposure of Study Medication 
The numbers of patients who experience any dose modification of the study treatment 
and the reason will be summarized by treatment arm.  Descriptive statistics will be 
presented for treatment duration, total cumulative dose, percentage dose intensity, 
number of cycles, and number of patients at each treatment cycle. 
 
4.6.2 
Adverse Events 
All verbatim adverse event terms will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) thesaurus terms, and adverse event severity will be graded 
according to NCI CTCAE v5.0. 
All adverse events, serious adverse events, adverse events leading to death, adverse 
events of special interest, adverse events leading to study treatment discontinuation, 
adverse events leading to study discontinuation, adverse event leading to dose 
modification/interruption, related serious adverse event, Grade 3-5 adverse events 
(Grade 3, 4, or 5) that occur on or after the first dose of study treatment (i.e., treatment 
emergent adverse events) will be summarized by mapped term, appropriate thesaurus 
level, and severity grade.  For events of varying severity, the highest grade will be used 
in the summaries. 
Deaths and causes of death reported during the study treatment period and those 
reported during the follow-up period after treatment completion/discontinuation will be 
summarized by treatment arm. 
 


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4.6.3 
Laboratory Data 
Clinical laboratory tests will be performed at local laboratories. Laboratory test result 
data will be summarized over time with inclusion of change from baseline by treatment 
group. Values outside normal ranges will be summarized.  Additionally, a shift table of 
selected laboratory tests will be used to summarize the baseline and maximum post-
baseline severity grade. 
4.6.4 
Vital Signs 
Actual value and change from baseline in vital signs (pulse rate, respiratory rate, blood 
pressure, pulse oximetry, and temperature) will be summarized over time by the 
treatment group.  Changes in Vital signs (outside normal limits) will be summarized by 
the treatment group.  Baseline is defined as the measurement obtained on Cycle 1, 
Day 1 prior to first dose of study drug. 
4.6.5 
ECG Evaluations 
Changes in ECG (outside normal limits) will be summarized by the treatment group. 
Baseline is defined as the measurement obtained on Cycle 1, Day 1 prior to first dose of 
study drug. 
4.6.6 
Immunogenicity Analyses 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (postbaseline incidence) 
will be summarized by treatment group.  When determining postbaseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more postbaseline samples is at least 0.60 titer unit greater than the titer of the 
baseline sample (treatment-enhanced ADA response).  Patients are considered to be 
ADA negative if they are ADA negative or have missing data at baseline and all 
postbaseline samples are negative, or if they are ADA positive at baseline but do not 
have any postbaseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, and PK endpoints may be 
analyzed and reported via descriptive statistics. 
4.7 
MISSING DATA 
No values will be imputed for missing data. For CRR/ORR, patients without any post-
baseline assessment will be considered as non-responders. 
4.8 
INTERIM ANALYSES 
No efficacy interim analyses are planned. 
5. 
REFERENCES 
Final Clinical Study Report - Protocol BO22334 (SABRINA): A Two-stage Phase III, 
International, Multi-Center, Randomized, Controlled, Open-label Study to Investigate the 
Pharmacokinetics, Efficacy and Safety of Rituximab SC in Combination With CHOP or 
CVP Versus Rituximab IV in Combination with CHOP or CVP in Patients With Previously 


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Untreated Follicular Lymphoma Followed by Maintenance Treatment With Either 
Rituximab SC or Rituximab IV- Report No. 1084889-August 2018


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Appendix 1          
Protocol Synopsis 
TITLE: 
A PHASE II COMPARATIVE, OPEN LABEL, RANDOMIZED, 
MULTICENTER, CHINA-ONLY STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, EFFICACY AND SAFETY OF 
SUBCUTANEOUS RITUXIMAB VERSUS INTRAVENOUS 
RITUXIMAB, BOTH IN COMBINATION WITH CHOP IN 
PREVIOUSLY UNTREATED PATIENTS WITH CD20 POSITIVE 
DIFFUSE LARGE B CELL LYMPHOMA 
PROTOCOL NUMBER: 
YO42207 
VERSION NUMBER: 
1.0 
IND NUMBER: 
To be determined 
TEST PRODUCT: 
Rituximab (RO0452294) (MabThera→) 
PHASE: 
II 
INDICATION: 
Previously untreated CD20 positive Diffuse Large B Cell Lymphoma 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics (PK) of subcutaneous (SC) rituximab compared with intravenous (IV) rituximab, 
both in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), in previously untreated patients with CD20 positive 
diffuse large B cell lymphoma (DLBCL).  Specific objectives and corresponding endpoints for the study are outlined below. 
Primary Objectives 
The primary objective of this study is to demonstrate the non-inferiority of rituximab serum Ctrough obtained at Cycle 7, 21 days after SC 
administration, with that obtained at Cycle 7, 21 days after IV administration on the basis of the following endpoint: 
● Ratio of Ctrough,SC/Ctrough,IV during Cycle 7 


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Secondary Objectives 
The secondary objectives of this study are to compare and assess other PK parameters, efficacy and safety profiles (including immunogenicity) of 
rituximab SC and rituximab IV, both in combination with CHOP, on the basis of the following endpoints and outcome measures: 
● Ratio of AUCSC/AUCIV during Cycle 7 
● Other PK parameters, such as AUC and Ctrough at other treatment cycles, maximum serum concentration (Cmax), total clearance, volume of 
distribution at steady state, and terminal half-life (t1/2) (if feasible or appropriate) as appropriate 
● Complete response rate (CRR) at the end of the study treatment, as determined by the Independent Review Committee (IRC) using 
Lugano Response Criteria for Malignant Lymphoma as key efficacy endpoint  
● Objective response rate (ORR), defined as complete response (CR) or partial response (PR) at the end of the study treatment, as 
determined by investigator and IRC using Lugano Response Criteria for Malignant Lymphoma 
● CRR (CR, complete response unconfirmed [CRu]) at the end of study treatment, as determined by IRC using International Working Group 
(IWG) Response Criteria for Non-Hodgkin’s lymphoma (NHL) 1999 Guidelines  
● CRR at the end of the study treatment, as determined by the investigator using Lugano Response Criteria for Malignant Lymphoma 
● Safety outcomes as assessed by adverse events, including rituximab administration-related reactions (ARRs), laboratory assessments, 
and vital signs; and immunogenicity as assessed by anti-rituximab antibodies and anti-rHuPH20 antibodies 
Study Design 
Description of Study 
This is a Phase II, multicenter, randomized, controlled, open-label, China-only study to investigate the PK, efficacy, and safety of rituximab SC in 
combination with CHOP versus rituximab IV in combination with CHOP in previously untreated patients with CD20 positive DLBCL.  This study will 
be conducted at approximately 8 sites in China.  Approximately 50 patients will receive eight cycles of rituximab SC or rituximab IV combined with 
six or eight cycles of standard CHOP chemotherapy.  Centers must choose whether they plan to administer six or eight cycles of CHOP 
chemotherapy prior to study start.  Previous results have demonstrated that a fixed rituximab SC dose at 1400 mg is expected to achieve non-
inferior Ctrough values to the rituximab IV regimen (375 mg/m2) prior to Cycle 8 (Study BO22334).  In this study, a sample size of 50 patients 
(approximately 18 evaluable patients per arm) who have completed Cycle 7 will be adequate for testing non-inferiority for the estimated ratio 
Ctrough,SC/Ctrough,IV.  Previously untreated patients with CD20 positive DLBCL will be randomized into the following two treatment groups at a 1:1 
ratio (crossover to the experimental arm is not permitted): 
● RSC-CHOP:  Cycle 1 rituximab IV plus seven cycles of rituximab SC in combination with six or eight cycles of CHOP chemotherapy 
administered every 3 weeks; rituximab IV will be used at the standard dose of 375 mg/m2 and rituximab SC will be given at a dose of 
1400 mg as confirmed in the Phase III Study BO22334. 
● RIV-CHOP:  eight cycles of rituximab IV in combination with six or eight cycles of CHOP chemotherapy administered every 3 weeks; 
rituximab IV will be used at the standard dose of 375 mg/m2. 
Eligible patients will be stratified during randomization according to International Prognostic Index (IPI) scores (IPI 0-2 versus IPI 3−5).   
Patients will be assessed for disease response by the investigator and IRC, on the basis of regular clinical and laboratory examinations, physical 
examinations, computed tomography (CT) scans, positron emission tomography (PET)-CT scans, and bone marrow examinations, according to 


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17/Statistical Analysis Plan YO42207 
the Lugano Response Criteria for Malignant Lymphoma.  PET-CT and dedicated CT scans will be obtained at screening and 6-8 weeks after 
completion of study treatment, or sooner in the event that a patient discontinues early.  An interim assessment will be obtained after Cycle 4 and 
should include PET-CT and dedicated CT.  If local practice prohibits obtaining both assessments after Cycle 4, PET-CT alone (preferred) or CT 
alone may be obtained at this time point.  During the follow-up period, imaging (may be CT only) will be performed every 3 months, i.e., Week 12 
and 24 after last treatment, in accordance with study visits and will include the neck (if involved at baseline), chest, abdomen, and pelvis.   
After the end of study treatment, patients will be followed-up every 3 months for 6 months (i.e., 12 and 24 weeks after the last dose of study 
treatment).  Assessments will include clinical evaluation of tumor response/progression, PK and immunogenicity (blood sampling), physical 
examination, standard hematologic and biochemistry assessments, vital signs and weight measurements, liver and spleen size and B-symptoms 
assessments. 
Safety will be evaluated by monitoring all adverse events, and abnormalities identified through physical examination, vital signs, and laboratory 
assessments.  Such events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5 (NCI 
CTCAE v5.0).  Laboratory safety assessments will include the routine monitoring of hematology and blood chemistries. 
Number of Patients 
Approximately 50 patients with previously untreated CD20 positive DLBCL will be enrolled in this study. 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
● Able and willing to provide written informed consent and to comply with the study protocol 
● Age ≥18 and ≤80 years at time of signing Informed Consent Form 
● Previously untreated CD20 positive DLBCL histologically documented 
● Patients with an IPI score of 1 to 5 or IPI score of 0 with bulky disease, defined as one lesion ≥7.5 cm 
● At least one bi-dimensionally measurable lesion defined as ≥1.5 cm in its largest dimension on CT scan  
● Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 
● Left ventricular ejection fraction (LVEF) ≥50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram 
● A negative serum pregnancy test or a negative urine pregnancy test within 7 days prior to study treatment must be available both for pre-
menopausal women (including those who have had a tubal ligation) and for women who are less than 2 years after the onset of menopause; if 
negative serum pregnancy test is within 14 days of study treatment start, a confirmatory urine pregnancy test must be available within 7 days 
prior to study treatment start 
● For men who are not surgically sterile, agreement to use a barrier method of contraception during the treatment period and until ≥12 months 
after the last dose of rituximab SC or rituximab IV or according to institutional guidelines for CHOP chemotherapy, whichever is longer, and 
agreement to request that their partners use an additional method of contraception, such as oral contraceptives, intrauterine device, barrier 
method, or spermicidal jelly 


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18/Statistical Analysis Plan YO42207 
● For women of reproductive potential who are not surgically sterile, agreement to use adequate methods of contraception, such as oral 
contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly during the treatment period and 
until ≥12 months after the last dose of rituximab SC or rituximab IV or according to institutional guidelines for CHOP chemotherapy, whichever 
is longer 
● Adequate hematologic function confirmed within 14 days prior to randomization which is independent to stimulating factors and transfusion 
(unless related to lymphoma infiltration of the bone marrow) 
● Hemoglobin ≥9.0 g/dL 
● Absolute neutrophil count (ANC) ≥1.5 ⋅ 109/L 
● Platelet count ≥75  ⋅ 109/L 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
● Transformed NHL or types of NHL other than DLBCL and its subtypes according to World Health Organization classification 
● History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine 
products  
● Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines 
● Prior therapy for DLBCL, with the exception of nodal biopsy or local irradiation or surgery for diagnosis 
● Prior treatment with cytotoxic drugs or rituximab for another condition (e.g., rheumatoid arthritis) or prior use of an anti-CD20 antibody 
● Current or recent (within the 30 days prior to starting study treatment) treatment with another investigational drug or participation in another 
investigational therapeutic study 
● Ongoing corticosteroid use, >30 mg/day of prednisone or equivalent 
● Patients receiving corticosteroid treatment with ≤30 mg/day of prednisone or equivalent must be documented to be on a stable dose for 
duration of at least 4 weeks prior to randomization. 
● Primary central nervous system (CNS) lymphoma, blastic variant of mantle cell lymphoma, or histologic evidence of transformation to a Burkitt 
lymphoma, primary mediastinal DLBCL, primary effusion lymphoma, and primary cutaneous DLBCL 
● History of other malignancy that could affect compliance with the protocol or interpretation of results 
● Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix 
are eligible. 
● Patients with a malignancy that has been treated but not with curative intent will also be excluded unless the malignancy has been in 
remission without treatment for ≥5 years prior to enrollment. 


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19/Statistical Analysis Plan YO42207 
● Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including 
but not limited to significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction 
within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history 
of bronchospasm) 
● Any of the following abnormal laboratory values: 
● Creatinine >1.5 ⋅ upper limit of normal (ULN) (unless creatinine clearance normal) or calculated creatinine clearance <40 mL/min (using 
the Cockcroft-Gault formula) 
● Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 ⋅ ULN 
● Total bilirubin ≥1.5 ⋅ ULN; patients with documented Gilbert disease may be enrolled if total bilirubin is ≤3.0 ⋅ ULN 
● International normalized ratio (INR) ≥1.5 ⋅ ULN in the absence of therapeutic anticoagulation 
● Partial thromboplastin time (PTT) or activated Partial thromboplastin time (aPTT) >1.5 ⋅ ULN in the absence of a lupus anticoagulant 
● Positive test results for chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] serology)  
● Patients with occult or prior HBV infection (defined as negative HBsAg and positive total hepatitis B core antibody [HBcAb]) may be 
included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing during the treatment period and the 
follow-up period.  
● Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing) 
● Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 
● Known history of human immunodeficiency virus (HIV) seropositive status or infection 
● Signs or symptoms of other active and/or severe infection 
● Evidence of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion 
of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications 
● Any co-existing medical or psychological condition that would compromise ability to give informed consent 
End of Study and Length of Study 
The end of study is defined as the date when the last patient last visit (LPLV) occurs.  LPLV is expected to occur approximately 6 months after the 
last patient enrolled has received the last study treatment, or sooner, if all patients have progressed, died, or withdrawn from the study.  The 
Sponsor has the right to terminate the study at any time. 
Investigational Medicinal Products 
Test Product (Investigational Drug) 
The experimental investigational medicinal product of the study is rituximab SC supplied as a ready-to-use liquid formulation with a nominal 
content of 120 mg/mL rituximab.  The drug product contains 2000 U/mL rHuPH20 acting as a permeation enhancer, histidine/histidine-HCl 


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20/Statistical Analysis Plan YO42207 
(buffer), α,α-trehalose (bulking agent), methionine (stabilizer), and polysorbate 80 (surfactant) in Water for Injection (WFI) at a pH of 5.5.  
Rituximab SC will be administered by SC injection on Day 1 of Cycles 2 to 8 to patients randomized to the RSC-CHOP treatment arm. 
Comparator 
The comparator investigational medicinal product of the study is rituximab IV provided as 500 mg/50 mL liquid-filled vials with a nominal content 
of 10 mg/mL rituximab.  The drug product contains sodium acetate (buffer), sodium chloride (tonicity adjustment), and polysorbate 80 (surfactant) 
in WFI at a pH of 6.5.  Rituximab IV will be administered by IV infusion on Day 1 of Cycles 1 to 8 to patients randomized to the RIV-CHOP 
treatment arm and on Day 1 of Cycle 1 to patients randomized to RSC-CHOP treatment arm. 
Non-Investigational Medicinal Products 
The CHOP chemotherapy will be prepared according to the standard practice at the institution. 
Statistical Methods 
Primary Analysis 
All PK analyses will be based on all patients for whom PK assessments were made.  PK analyses will be analyzed as treated.  Patients will be 
excluded from the PK analysis population if they significantly violate the inclusion or exclusion criteria, deviate significantly from the protocol, or if 
data are unavailable or incomplete, where the PK analysis might be influenced.  Excluded cases will be documented, including the reason for 
exclusion.  All decisions on exclusions from the analysis will be made prior to database closure. 
The primary PK endpoint is the ratio of Ctrough,SC/Ctrough,IV during Cycle 7.  The serum rituximab Ctrough at Cycle 7 will be measured at pre-dose of 
Cycle 8.  The lower limit of the two-sided 90% confidence interval (CI) should be above 0.80 in order to show non-inferiority of Ctrough,SC versus 
Ctrough,IV. 
Determination of Sample Size   
Under the assumption of a coefficient of variation equal to 0.5 and assuming that the true Ctrough of rituximab SC formulation is 20% above the 
rituximab IV formulation (i.e., mean Ctrough,SC to be 20% above Ctrough,IV), 20 patients in each treatment arm are needed in order to achieve 80% 
power with one-sided alpha of 0.05 (i.e., 2-sided 90% confidence interval [CI]).  Assuming that 20% of patients would not have valid PK data at 
Cycle 8 pre-dose, a total of approximately 50 patients will be enrolled into the study. 
 


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21/Statistical Analysis Plan YO42207 
 
Appendix 2       
Schedule of Activities 
 
Assessment/Procedure 
Screening 
Treatment Period 
End of Treatment 
Follow−Up  
(6 months) 
C1−3 
C4 
C5−8 
TCV 
ETTV a 
Days 
−28 to −1 
Days 
−14 to −1 
D1 
D1 
Interim 
Assessment 
D19 ( ± 3) 
D1 
6−8 weeks 
after last 
treatment 
4−8 weeks 
after last 
treatment 
12 weeks and  
24 weeks after last 
treatment 
Written informed consent b 
x 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
x 
 
 
 
 
 
 
 
 
Demographic information and 
medical history 
 
x 
 
 
 
 
 
 
 
Height 
 
x 
 
 
 
 
 
 
 
BSA 
 
x 
 
 
 
 
 
 
 
Weight 
 
x 
x 
x 
 
x 
x 
x 
x 
Vital Signs 
 
x 
x 
x 
 
x 
x 
x 
x 
Complete physical exam c 
x 
 
 
 
 
 
 
 
 
Targeted physical exam d 
 
 
x 
x 
x 
x 
x 
x 
x 
ECOG performance status e 
 
x 
x 
x 
 
x 
 
 
x 
DLBCL diagnosis, staging, 
and IPI score f 
x 
 
 
 
 
 
 
 
 
B symptoms 
 
x 
x 
x 
 
x 
x 
x 
x 
Tumor assessment g 
x 
 
 
 
x 
 
x 
x 
x 
12-lead-ECG and LVEF 
x 
 
 
 
 
 
x 
x 
x 


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22/Statistical Analysis Plan YO42207 
Hematology and serum 
chemistry h 
 
x 
x 
x 
x 
x 
x 
x 
x 
Coagulation (aPTT or PTT, 
PT, and INR) 
 
x 
 
 
 
 
 
 
 
Pregnancy test (if applicable) i 
 
x 
 
 
 
 
 
 
x 
Serology testing for HCV, 
HBV j 
 
x 
 
 
 
 
 
 
 
Hepatitis B DNA on PCR (as 
indicated) k 
 
x 
x 
x 
 
x 
x 
x 
x 
Lumbar puncture for CSF (as 
indicated) l 
x 
 
 
 
 
 
 
 
 
Bone marrow 
aspirate + biopsy (as 
indicated) m 
x 
 
 
 
 
 
x 
x 
 
Study treatment n 
 
 
x 
x 
 
x 
 
 
 
Rituximab PK sample o 
 
 
x 
x 
 
x 
 
x 
x p 
Anti-rHuPH20 antibody 
sample q 
 
 
xr 
xr 
 
xr 
 
x 
x s 
Anti-rituximab antibody 
sample  
 
 
xr 
xr 
 
xr 
 
x 
x s 
Sample for quantitative 
immunoglobulins (lgA, lgG, 
and lgM) 
 
x 
 
 
 
 
 
x 
x 
Adverse events t 
x 
x 
x 
x 
x 
x 
x 
x 
x  
Concomitant medications u 
x 
x 
x 
x 
x 
x 
x 
x 
x 
BSA = body surface area; C = cycle; CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone; CSF = cerebrospinal fluid; D = day; 
DLBCL = diffuse large B-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; ETTV = early treatment termination visit, 
FACS = fluorescence-activated cell sorting; HBV = hepatitis B virus; HCV = hepatitis C virus; IPI = International Prognostic Index; IV = intravenous; 
LVEF = left ventricular ejection fraction; TCV = treatment completion visit, SC = subcutaneous. 


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23/Statistical Analysis Plan YO42207 
Note:  After the end of the study treatment period, all patients will be followed until the end of the study according to local practice for resolution of 
adverse events related to rituximab therapy, survival, disease status, and whether a new lymphoma treatment has been started.  The visit window 
during each cycle of study treatment is ±3 days.  The window for the treatment discontinuation/early treatment termination and post-treatment study 
visits is ± 1 week (unless otherwise specified). 
a Patients who discontinue the study treatment prematurely are required to return to the clinic for an early termination visit within 4−8 weeks after 
the last dose of study treatment. 
b Written informed consent must be obtained prior to any study-specific procedures (including screening evaluations) performed or any prohibited 
medications being withheld for purposes of study participation.  Please see Section 4.5.1 for more details. 
c Includes evaluation of the head, eyes, ears, nose, and throat, and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
and neurologic systems.  See Section 4.5.3 for more details. 
d A targeted physical examination should be limited to systems of primary relevance, including cardiovascular, respiratory, those associated with 
symptoms, and those with tumor assessment (lymph nodes, liver, and spleen). 
e ECOG performance status must be ≤ 2 for inclusion of the patient into the study. 


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24/Statistical Analysis Plan YO42207 
f Diagnosis of DLBCL before treatment must have included histological diagnosis and initial CD20 expression confirmation.  See Section 4.1.1 for 
more details. 
g Tumor assessments will be based on PET-CT scans (or MRI scans, if CT scans are contraindicated) of the neck (if clinically indicated), chest, 
abdomen, and pelvis where applicable.  PET-CT scans will be obtained at screening, interim response assessment (i.e., Day 19 [±3 days] of 
Cycle 4) and End of Treatment assessment (6−8 weeks after the last dose of study treatment or 4−8 weeks after last dose of study treatment for 
early discontinuation).  All other imaging may be CT only (i.e., follow-up period [12 and 24 weeks after the last dose of study treatment]). 
h Hematology will include hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent or absolute differential count.  At screening, 
serum chemistry will include sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, phosphorus, total bilirubin, total protein, albumin, 
AST, ALT, LDH, alkaline phosphatase, uric acid, and calculated creatinine clearance.  During Cycles 1–8 and the follow-up period, serum 
chemistry will include sodium, potassium, creatinine, calcium, total bilirubin, total protein, albumin, AST, ALT, LDH, alkaline phosphatase, and uric 
acid. 
i A negative serum pregnancy test or a negative urine pregnancy test within 7 days prior to study treatment must be available both for pre-
menopausal women (including those who have had a tubal ligation) and for women who are less than 2 years after the onset of menopause; if a 
negative serum test within 14 days prior to study treatment, a confirmatory urine pregnancy test must be within 1 week prior to study treatment 
start.  
j Patients known to have HIV, hepatitis C, active hepatitis B, or signs or symptoms of other active and/or severe infection must not be included in 
the study.  Serology should be performed according to clinical judgment before and during treatment with rituximab.  Patients found to have HIV, 
hepatitis C, or active hepatitis B must either not start or must stop rituximab therapy and enter active follow-up.  Local guidelines for patient 
consent to viral testing must be adhered to. 
k Patients with occult or prior HBV infection may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA 
testing. 
l Lumbar puncture is indicated for patients with high-risk disease or with one or more of the following sites of involvement: paranasal sinuses, 
testicular, paramenigeal, peri-orbital, CNS, paravertebral, or bone marrow. 
m Bone marrow examinations are required at screening and should include biopsy for morphology.  Repeat bone marrow examinations are required 
if the bone marrow was involved with tumor at screening and the repeat bone marrow examination is required to confirm a radiological 
assessment of complete response at the end of therapy. 
n See details on administration schedule of the study treatment in Section 4.3.2. 
o See details on rituximab PK sample in Appendix 2. 
p Samples for rituximab PK will be collected 24 weeks after last rituximab administration. 
q Only patients who are randomized to rituximab SC will be assessed for anti-rHuPH20 antibodies. 
r Samples are drawn within 2 hours pre-dose. 
s Samples for anti-rituximab antibodies and anti-rHuPH20 antibodies will be collected 12 weeks and 24 weeks after last rituximab dose.t After 
informed consent has been obtained but prior to initiation of study drug, only serious adverse events caused by a protocol-mandated intervention 
should be reported.  After initiation of study drug, all adverse events will be reported until 28 days after the final dose of study drug.  After this 


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25/Statistical Analysis Plan YO42207 
period, the Sponsor should be notified if the investigator becomes aware of any serious adverse event that is believed to be related to prior study 
drug treatment (see Section 5.6). 
u Any medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 28 days prior to initiation of study drug to study termination.  Any new lymphoma 
treatment initiated after the baseline visit will be recorded as concomitant treatments. 
 
 


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