A Phase III Randomized Controlled Study Comparing High-dose Rituximab (500 mg/m²) Combined With CHOP Regimen Versus Standard-dose Rituximab (375 mg/m²) Combined With CHOP Regimen in Male Patients With Newly Diagnosed Advanced Diffuse Large B-cell Lymphoma
Phase: PHASE3
Conditions: Lymphoma, Large B-Cell, Diffuse
Sponsor: Xia Yi

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Summary of the Scheme
Sponsor: Suzhou Xinda Pharmaceutical Co., LTD
Protocol No: B2024-380
Study Protocol: R-CHOP
Research stages: stage III
Version number: 2.1
Release date: 2024/07/05
Popular title
High doserituxan (500 mg/m²) joint men CHOP regimen for
advanced DLBCL treated first phase III clinical study.
Official title
A phase III randomized controlled trial comparing high-doserituximab
(500mg/m²) plus CHOP with standard-doserituximab plus CHOP in treatment-
naive men with advanced diffuse large B-cell lymphoma.
Objective
Main Objective:
To compare the MODIFIED progression-free survival (modified-PFS) of
high-dose rituximab (500mg/m²) plus CHOP versus standard-dose rituximab
plus CHOP in previously untreated (TN) stage III-IV male DLBCL patients.
Secondary Objective:
To compare other efficacy indicators (EFS, OS, ORR and CRR), safety and
PK characteristics of high-dose rituximab (500mg/m²) combined with CHOP
regimen versus standard-dose rituximab combined with CHOP regimen in
previously untreated (TN) stage III-IV male DLBCL patients
Endpoint
Primary endpoints:
MODIFIED-PFS as assessed by an independent review Committee (IRC).
Secondary endpoints:
ORR,
CRR,
DOR,
EFS,
and
OS;Adverse
events
and
laboratory
abnormalities assessed by IRC and investigator, respectively; ;EORTC QLQ-
C30 and EQ-5D-5L questionnaires were used to assess the quality of life of the
subjects.
Estimate the
target
This study clinical problem is the main focus ofthe high doserituxan (500 mg/m
² ) combined CHOP scheme can improve the preious untreated (TN) of
patients with stage III - IV male DLBCL MODIFIED - PFS (IRC) assessment.
Population
By randomly into group, Ann Arbor III - IV clinical stage and age < y 75 male
patients with adanced DLBCL treated first.
Treatment

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Subjects first accept for 6 cycles (21 days (d) as a treatment cycle 】high
dose (500 mg/m²) or standard dose (375 mg/m²) joint CHOP regimen for
rituxan, then two cycle (21 d for a treatment cycle) high dose or standard
dose of rituxan maintenance treatment.
Variables
Progression-free survival (MODIFIED-PFS), defined as the time from the
date of randomization to disease progression or relapse after CR or death from
any cause, whichever occurred first.
Events and treatment strategies
The treatment strategy was adopted for early discontinuation of treatment
before the occurrence of MODIFIED-PFS events or change in combination
therapy, that is, continue to follow up to the end of the study until disease
progression or recurrence or death after CR. Patients who did not have
MODIFIED-PFS events at the end ofthe study were treated as censored, and the
censoring time was the time of the last assessment. Evaluator for baseline after
there is no time, MODIFIED - PFS delete lost time as random time.
For MODIFIED - PFS incidents before start a new antineoplastic therapy
or use significantly affect MODIFIED - PFS ending for a drug or treatment, and
so on and so forth will adopt the strategy of hypothetical variables, namely
according to delete processing, delete lost time for events with time.
* does not include the intrathecal injection in patients at high risk of CNS
diseases prevention and involvement of the local radiotherapy for testicular
lesions inpatients with testicular.
Group level summary
Hazard ratios (HRS) estimated by COX models.
Study Sites
Sun Yat-sen University Cancer Center and other research centers
Study
Group
Men with advanced, treatment-naive DLBCL

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Dosage
regimen
The dosing regimens for the combination phase and the single-agent
maintenance phase ofthe study are detailed in Figure 1.
Figure 1. Dosing Regimens
1 cycle to 6 cycles
Rituximab 500 mg/m2 in the high-dose group and 375 mg/m2 in the
standard-dose group intravenously on day 1 (IV) (continuation the next day if
needed)
Cyclophosphamide: 750 mg/m2, IV 1 or 2 days
More gentle than star: 50 mg/m2, IV 1 or 2 days
Vincristine: 1.4 mg/m2 IV on day 1 or 2 (maximum total dose 2 mg/
cycle)
Oral prednisone: 100 mg/day, 1 to 5 days for a daily (QD)
Cycle 7 and 8 cycles
Rituxan: high dose group of500 mg/m2, the standard dose of375 mg/m2,
day 1 IV (if need 2 days to complete)
Study
Design
This study is a multicenter, randomized controlled phase III clinical study,
Main evaluation high-dose rituxan (500 mg/m²) in combination with CHOP
plan comparison standard dose rituxan combined CHOP scheme in preious
untreated
(TN)
in
male
patients
with
DLBCL
MODIFIED
improved
progression-free surial (MODIFIED - PFS). Before the start ofthe signed written
informed consent and randomization, all participants shall provide sufficient
tumor tissue biopsy samples for central laboratory by HE staining and IHC
testing identified as DLBCL patients. Eligible subjects according to the
proportion of 1:1 were randomly into the experimental group (rituxan 500
mg/m2) or control group (rituxan 375 mg/m2), participants will receive 6 cycles
R - CHOP treatment (21 d for a cycle), and the subsequent 2 cycle lastsrituxan
treatment (21 d for a cycle). No crossover between the two groups was
performed during the study.
The overall study design is detailed in Figure 2

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Figure 2. The overall design
Research
Process
1) Screening period/baseline period (-28 days to -1 day)
Participants will experience less than 28 days before randomization
screening period, as shown in the flow chart of research 2. Confirmed by the
researchers in accordance with the inclusion criteria and do not accord with
standard of exclusion, participants will be randomly
assigned to the
experimental group according to the ratio of 1:1 (rituxan 500 mg/m2) or
control group (rituxan 375 mg/m2).
Subjects should be in the 24 hours after randomization to research
therapy (if there are special circumstances
should communicate with
bidders in advance).
Common adverse reactions of prevention:
1) Tumor lysis syndrome (TLS) : Exist for risk factors of subjects,
including high tumor burden, lymph, lactate dehydrogenase (LDH) higher
than the upper limit of normal (ULN) 2 times, dissolve the spontaneous
tumor syndrome, peripheral blood lymphocyte count absolutely obvious
rise, disease significantly affects the bone marrow, high uric acid hematic
disease history, don't Piao alcohol treatment is invalid and kidney function
not entire, It is recommended that TLS prevention measures, including
hydration, urate-lowering medication, and correction/monitoring of serum
uric acid, creatinine, and electrolytes, should be given before the initiation
of treatment.
2) Reactivation ofhepatitis virus: For subjects who are HBsAg positive
or HBcAb positive and HBV-DNA negative at screening, HBV-DNA levels
should be monitored regularly during the trial and preventive antiviral
therapy (such asentecavir or tenofovir) should be given. Suggest preventive
antiviral treatment until the end of the study medication after 6 to 12 months
or rituxan treatment at least 18 months after the end (shall be subject to
late), specific Suggestions under the guidance of specialized subject doctor
treatment and follow-up. Participants who were positive for hepatitis C
virus antibody (HCV) and negative for HCV-RNA at screening were
required to have continuous monitoring of HCV-RNA levels during the
course of the trial if they had not received systemic anti-HCV therapy.

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2) treatment (combination, a total of 6 cycles, two separate cycle
rituxan maintenance treatment, every 21 days for a cycle)
This stage study of supervision and inspection process can be found in
the flow chart of research (phase III), and subsequent adjustments may
according to the condition of the preliminary data and execute.
This study is not allowed to cross the treatment group.
3) early withdrawal from treatment/end of treatment (EOT) visit
If subsequent participants will no longer accept treatment, the test
program should be as soon as possible after participants stopped test
drugs/treatment (combination during the proposal in the exit / 7 to 14 days
after the end of treatment, single drug maintenance phase Suggestions in
the last 7 days) after the treatment of EOT visit evaluation, Including a
complete physical examination, ECG, ECOG score, vital signs, weight,
adverse events and drug combination information collection, recycling
agents and participants log card, laboratory examination, electrocardiogram
(ECG), serum pregnancy test (female) with fertility potential safety
evaluation and curative effect evaluation (if applicable).
If a participant discontinued treatment for toxicity or other reasons at
a visit and did not subsequently continue protocol-specified treatment, that
visit was considered to be an EOT visit.
4) after the follow-up treatment
Security: follow-up after the subjects complete solution treatment or
exit, must record all AE and drug combination to 28 days after the last
delivery or start a new antineoplastic therapy before (before), unless some
subjects refused, death, lost to follow-up or withdraw his knowledge, and
so on and so forth. The safety visit could not be repeated if it occurred
within 7 days of the EOT visit. All preexisting or new-onset AEs or SAEs
within 28 days of the last dose were followed until resolved, stabilized, or
returned to baseline, unless they were considered by the investigator to be
unlikely to resolve because of the patient's illness.
The effectiveness and survival follow-up: After the subjects complete
solution treatment or exit, for disease has not been progress of subjects, to
recommend to evaluate tumor (1 year for every 12 weeks (plus or minus 7
days) for a, 2-5 years of every 24 weeks (+ / - 14 days) once, only when the
clinical indications for 5 years later). However, safety assessment was not
performed (provided that the post-treatment safety follow-up had been
completed and there were no AEs or SAEs considered by the investigator

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to be required for follow-up). In the event of disease progression or start
using systemic antitumor drugs or other treatments, is as far as possible
before
starting the new antineoplastic therapy of tumor
assessment
conducted within 60 days (curative effect evaluation can avoid), to evaluate
tumor will no longer follow-up, each 12 weeks after (plus or minus 7 days)
to a telephone follow-up, Survival calls were performed every 12 weeks (±
7 days) thereafter to obtain data on overall
survival and the use of
antineoplastic therapy after the study until death, refusal to follow up, or
loss to follow-up.
Randomizatio
n
(applicable
to
the
phase
III studies)
Don't repeat hierarchical block random methods, by the proportion of 1:1
randomly generated by a blind statisticians subjects treatment allocation code
(random table). The randomization table was then uploaded to the central
randomization system for systematic configuration. The subjects' eligibility
once confirmed, by the researchers on the central randomization system, input
subjects after the relevant information of the participants random number and
the number of drug, researchers according to drug number give corresponding
treatment. Subjects will be in accordance with the proportion of 1:1 were
randomly into the experimental group (rituxan 500 mg/m²) or control group
(rituxan 375 mg/m²), participants will receive 6 cycles R - CHOP treatment
(21 d for a cycle) after 2 cyclesrituxan maintenance therapy (21 d for a cycle).
Blinded
This study was an open randomized controlled clinical trial. Subjects and
researchers have known group of experimental group and the control group, as
well as for intervention measures.
The Study
Drug Usage
and Dosage
1) R - CHOP[1]: 1-6 cycles
Drug name
Dosa\ge
Usage
Duration of medication
Day 1
2-5 days
Days 6-21
Rituximab
375 mg/m2
IV
X[2]
No
medication
Not giving
medication
500mg/m²
Cyclophosp
hamide
750 mg/m2
IV
X[2]
No
medication
Not giving
medication
Doxorubicin
50 mg/m2
IV
X[2]
No
medication
Not giving
medication
Vincristine
1.4 mg/m2
IV
(Maximum
total dose 2
mg/ cycle)
X[2]
No
medication
Not giving
medication
prednisone
100 mg/
day
PO
X
X (daily)
No
medication
IV: Intravenous administration; PO: oral medicine
Note[1]: each cycle 1 (or 2) days of R - CHOP components dosing sequence
is as follows: first of all to prednisone, followed by rituxan. Subsequent

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infusions of cyclophosphamide, vincristine, and doxorubicin were
administered according to site clinical practice and guideline
recommendations.
Note[2]: R - CHOP plan will be a total treatment for 6 cycles (21) days
for a cycle, R - CHOP of drugs (rituxan, cyclophosphamide, more gentle
than the star and vincristine) allow within two days to complete,
cyclophosphamide, more gentle than the star and vincristine can also be
used in each cycle, the second day of drug use.
Note[3]: if used before C1D1 cyclophosphamide reduced tumor, C1 can only
use the remaining doses of cyclophosphamide.
2) rituxan (R)[4] : 7-8 cycles
Drug name
Dosage
Usage
Duration of medication
Day 1
2-5 days
Days 6-21
Rituximab
375 mg/m2
IV
X
No
medicati
on
Not giving
medication
500mg/m2
IV: Intravenous administration
Note[4]: A dose of ≤10mg of dexamethasone or equivalent glucocorticoids
was allowed to prevent adverse effects before the administration of R (excess
use in special cases was determined after discussion between the investigator
and the sponsor). Rituximab was allowed to be completed on 2 consecutive
days.
Principles of
Dose
Adjustment
Recommendations for drug dose adjustments in the R-CHOP
regimen (refer to the package insert for details) :
Rituximab: the dose of rituximab was 500 mg/m 2 BSA (body surface
area) in the high-dose group and 375mg/m² in the standard-dose group, and
dose reduction was not recommended. For any level 4 adverse events or any
associated with rituxan (sure about, is likely to be relevant, may) and the
clinical significance of grade 3 adverse events, and should delay rituxan ,
until the return to baseline or completely back to normal. To prevent
infusion reactions or infusion reaction processing details see the latest
instructions.
Participants who discontinue rituximab treatment should discontinue
participation in the study.
Cyclophosphamide:
cyclophosphamide
dose
adjustment
should
follow the instructions. The most commonly reported adverse effects of
cyclophosphamide are hematologic toxicities (e.g., leukopenia, anemia, and
thrombocytopenia).
Cyclophosphamide
therapy
may
occur
after
hemorrhagic cystitis and blood in the urine, may need to stop to medicine.
Prophylactic treatment for hemorrhagic cystitis was administered according

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to the manufacturer's instructions and according to center routine.
If a participant's blood count did not meet the parameters of the general
principles, treatment with cyclophosphamide and doxorubicin was delayed.
Appear when the subjects thought associated with cyclophosphamide and
more gentle than stars hematology toxicity, suggested the next cycle day 1
adjustment in accordance with table 2 dose cyclophosphamide and more
gentle than the stars.
Table 1. Recommendations for dose Adjustments for
cyclophosphamide - or doxorubicin-Related Hematologic toxicity
Neutrophil count
Platelet count
Give the dose (later
period)
Acuity 1.0 x 109 / L
≥75×109/L
Dose unchanged
Acuity 0.5 x 109 / L,
without febrile
neutrophilic reduce
disease *
≥50×109/L
The neutrophilic
granulocyte count in
return to acuity 1.5 x 109 /
L and platelet recovery
after 75 x 10 /9 L or
higher, dose the same
< 0.5 x 109 / L and/or
febrile neutrophilic
reduce disease (unused
growth factor)
/
Start with the support of
growth factors continue to
medicine, dose the same
<0.5×109/L and/or
febrile neutropenia
(despite the use of
growth factors), first
occurred
<50×109/L (first
occurrence)
25% dose reduction
Second occurrence
<50×109/L
(second
occurrence)
Decrease the dose by
another 25%
A third occurrence
< 50 x 109 / L
(the third)
Permanent
discontinuation of
medication
Note: ANC = absolute neutrophil count
* febrile neutrophilic reduce disease is defined as the ANC < 0.5 x 109 / L
or expected to 48 hours after the ANC < 0.5 x 109 / L, and single oral
temperature 38.3 ℃or higher (axillary temperature is 38.0 ℃or higher), or
oral temperature 38.0 ℃or higher (axillary temperature is 37.7 ℃or higher)
that persists for more than 1 hour.
Doxorubicin:
Dose
adjustment
of doxorubicin
should
follow
the
instructions. More gentle than the biggest star cumulative dose limit for 450
to 550 mg/m2. The maximum cumulative dose administered to each subject
in this study was 300 mg/m 2 . Dose-limiting toxicities of doxorubicin
therapy include myelosuppression, cardiac toxicity, and gastrointestinal

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effects such as mucositis. Bone marrow inhibition usually demand reached
a low point in the 10 to 14 days after treatment, more gentle than star
hematology toxicity dosage adjustment suggestion see table 2. Cardiac
toxicity can occur at directly after the treatment, may also be in weeks or
months after the treatment or continued. More gentle than star hepatic
metabolism, and with the bile excretion. Impaired liver function results in
slower excretion of the drug, which in turn results in increased drug
toxicity. If liver function is damaged, it is suggested that in accordance with
table 3 more gentle than star dose adjustment. Dose adjustments are not
required in subjects with Gilbert's syndrome and in cases in which elevated
bilirubin is due to nonhepatic causes.
Table 2. Dose Modifications of Doxorubicin for Hyperbilirubinemia
Serum total bilirubin level
Dose adjustment measures
2.0 3.0 mg/dL, or 34.2 51.3 mu
mol/L
50% of the normal dose
> 3.0 mg/dL, or 51.3 mu > mol/L
25% of the normal dose
Vincristine, vincristine dose adjustment should follow the instructions.
If the dose of vincristine is impaired based on liver function, then the dose
of
vincristine
should
be
adjusted
according
to
Table
4.
When
hyperbilirubinemia improves, the vincristine dose can be escalated again.
For subjects and elevated bilirubin gilbert syndrome, due to the liver causes
do not require dose adjustment.
Table 3. Vincristine Dose Modifications for Hyperbilirubinemia
Serum total bilirubin level
Dose adjustment measures
2.0 3.0 mg/dL, or 34.2 51.3 mu
mol/L
75% of the normal dose
>3.0 mg/dL or 51.3 μmol/L
50% of the normal dose
In addition, the vincristine nervous system toxicity are most frequently
reported adverse reactions, related with dose and age. Vincristine should be
withheld in case of grade 3 neurotoxicity, especially if paresthesia or signs
of paresis are present. After resolution of symptoms, vincristine could be
resumed at 50% of the original dose. For any type of grade 4 neuropathy,
shall be permanently disabled vincristine. For any episode of intestinal
obstruction/constipation requiring hospitalization, the vincristine dose
should be reduced by 25% when the drug is resumed.
Prednisone: Dose adjustments of prednisone should follow the

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instructions. High-dose prednisone or equivalent for the subjects some
adverse situation in the aftermath ofthe drugs (e.g., bacterial infection, viral
infection, systemic fungal disease, high blood pressure,
diabetes and
gastrointestinal adverse conditions, such as peptic ulcer, pancreatitis and
diverticulitis) or relatively high risk of adverse conditions is aggravating,
deal with the subjects are closely monitored. If participants in the adverse
reactions associated with prednisone, and intolerance to research plan calls
for dose (100 mg/day), can be appropriately adjust the dose of prednisone,
but should be not less than 80 mg/day. In some special cases, the subjects
could not tolerate prednisone in the treatment of sudden discontinuation in
5 days. In such cases, it may be necessary to taper the dose to withdrawal.
Pharmacokinet
ic Study
A total of PK blood samples were planned to be collected from
approximately 150 subjects in the experimental and control groups.
PK blood samples were collected within 1h before administration and
2h to 6h after administration. According to the research process in each plan
blood sampling time point to 3 ml of whole blood to collect blood vessels,
according to
the biological
analysis
method
development
situation,
according to the related SOP for handling, storage and transportation of
blood samples.
Inclusion
Criteria
1, age < 75 y, male patients;
2. According to the 2017 revised WHO classification criteria, the subject
was diagnosed with DLBCL;
3.On the basis of Ann Arbor staging for stage III - IV patients;
4. No previous anti-tumor systemic therapy or local radiation therapy for
DLBCL (except previous cytoreductive therapy such as glucocorticoids and
intrathecal CNS prophylaxis)
5.Expected survival of ≥6 months.
6.the participants need to have enough blood coagulation function and
liver and kidney function, local laboratory tests need to meet the following
criteria:
A. blood coagulation function: prothrombin time (PT) and part of the
blood coagulation time (APTT) live enzymes acuities were 1.5 times the
upper limit of normal (ULN);
B. the liver: without clear liver involvement, nmda aminotransferase
(AST) and alanine aminotransferase (ALT) or less 3.0 x ULN, serum
total bilirubin 1.5 x ULN or less; If you have liver involvement, AST
and ALT acuities were 5.0 x ULN, total bilirubin 3.0 x ULN or less; If

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there is a clear Gilbert syndrome (non combined with high blood
bilirubin), total bilirubin 3.0 x ULN or less;
C. kidney: serum creatinine (Scr) 1.5 x ULN or less, or creatinine
clearance rate (Ccr) or greater 50 ml/min (according to CockcroftGault
formula or use 24 hours urine test).
When the unit of serum creatinine as mg/dL:
(140 −年龄) × 体重(kg) × [1.0, 男性; 0.85, 女性]
Ccr =
72 × 血清肌酐(mg/dL)
When the basic unit of serum creatinine is mu mol/L:
(140 −年龄) × 体重(kg) × [1.0, 男性; 0.85, 女性]
Ccr =
0.818 × 血清肌酐(μmol/L)
7.the subjects have enough bone marrow function, drug use (or random)
laboratory hematology inspection before must meet the following criteria:
A. neutrophil count (ANC) absolutely acuity 1.5 x 109 / L, in the case
of disease involving the bone marrow allows the use of growth factors
(after discussing with the sponsor decided required) to stimulate the
ANC to achieve the above standard
B. 75 x 109 / L or higher platelet (don't lose platelets within 5 days
before the screening, allows the use of TPO growth factors such as
support to the standard)
C. if disease involving autoimmune hemolytic anemia caused by bone
marrow or lymphoma, hemoglobin acuity 8.0 g/dL (80 g/L); A
hemoglobin level of 9.0 g per deciliter (90g per liter) or higher if the
disease does not involve the bone marrow (no red-cell transfusion
within 7 days before screening; Allows the use of growth factors such
as EPO support to achieve the standard).
8.All patients should use medically approved contraception for 12
months after rituximab administration (according to the marketed package
insert, as appropriate).
9. Participants voluntarily enrolled in the study and provided written
informed consent to follow the trial regimen and visit schedule.
Exclusion
Criteria
1.The researchers assessed as intolerance to R - CHOP plan and/or
subjects of any drug treatment;
2.Received any previous anti-lymphoma systemic therapy or local
radiation therapy. Note: always short-term [such as the duration of 10 days
or less] glucocorticoid (100 mg/day or less prednisone or equivalent
drugs) used for decreasing tumor treatment and prevention of its sheath
(CNS) does not

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belong to the definition of lymphoma systemic treatment.
3.Consider lymphoma involving the central nervous system (CNS)
of patients or a diagnosis of primary central nervous system
lymphoma (PCNSL). The patient was diagnosed with primary mediastinal
large B-cell lymphoma (PMBL).
4.Previous
organ
transplantation
or
hematopoietic
stem
cell
transplantation;
Planned
during
the
study
period
accept
allogeneic
hematopoietic stem cell transplantation
(allo - HSCT)
or autologous
hematopoietic stem cell transplantation (auto - HSCT).
5.For the first time use (or random) before 4 weeks before received
or during the study period or major injury, is expected to undergo a
major operation in 4 weeks of antineoplastic drugs or medical devices
clinical trials; For the first time within 14 days (or random) before using
this drug treated with warfarin or other vitamin K antagonists, 5 days
received potent and of CYP3A4
inhibitors or within 3
days to eat
grapefruit, carambola, Serbia, orange, grapefruit and grapefruit juice.
6.Has in the past three years with other malignant tumor except this
study target indication, but after radical treatment to cure
skin basal
cell carcinoma, cervical carcinoma in situ, squamous cell carcinoma of
the breast carcinoma in situ, limitations, and received radical surgery,
the researchers determined have been cured except other malignant tumors.
7.Any serious and/or failing to control systemic disease, the
researchers determine doesn't fit in the subjects of this study (including the
activity of CTCAE level 2 or more clinical severe infection, drug can not
control of high blood pressure, diabetes, unstable angina pectoris,
congestive heart failure, the need for oxygen respiratory system disease,
severe vascular embolization, Uncontrollable bleeding or important
internal bleeding, severe
liver
and
kidney
or
metabolic
diseases,
such
as
phase decompensated cirrhosis of the liver, kidney failure, etc.).
8.For
the
first
time
(or
random)
before
using
this
drug
had
significant cardiovascular
disease
within
six
months,
if
you
have
symptoms of arrhythmia,
myocardial
infarction,
stroke,
history
of
intracranial hemorrhage. Poor heart function, including the conform to
the New York heart association (NYHA) cardiac function classification
level 2 or higher, in three separate or shown on the electrocardiogram
(ecg) correction of Fridericia
formula
of
QTc
(QTcF)
greater
than
480
ms
or echocardiographic examination showed left
ventricular ejection fraction

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(LVEF) < 50%. Note: NYHA heart function classification 2 levels of
physical activity is defined as a mild restrictive, resting not self-conscious
symptom, physical activity to cause excessive fatigue, heart palpitations,
asthma, or angina pectoris; QTcF was calculated by QT/[RR^0.33], where
RR=60/ heart rate.
9. Disease states with clinical manifestations that may be difficult
to control, including but not limited to:
•
Human immunodeficiency virus (HIV) infection, syphilis infection,
HBsAg or HBcAb positive and HBV
- DNA test results above
research center, detection limit, HCV antibody positive and HCV -
RNA detection threshold test results above research center;
•
Uncontrolled systemic active bacterial, fungal, or viral infection and
active tuberculosis infection.
10. Any impact on patients with swallow medications, and seriously
affect the test drug absorption orpharmacokinetic parameters, including
difficult to control such as nausea and vomiting, short bowel syndrome.
11. In the study period can't interrupt taking/strong CYP3A inhibitors
and inducers, OATP1B1 / OATP1B3 sensitive substrates.
12. The first time (or random) before 4 weeks before using this drug
or treatment plan during the study or research accept live vaccine or
within 4 weeks after the end of live attenuated subjects.
13. The presence of A bleeding disorder (such as von Willebrand
disease or hemophilia A, hemophilia B, etc.) or a definite bleeding
tendency according to the investigator's judgment.
14. Patients with severe peripheral or central nervous system disease,
such as
a history
of progressive multifocal
leukoencephalopathy
or
ongoing confirmed progressive multifocal leukoencephalopathy.
15. During the study period need to use warfarin or other vitamin
K antagonists.
Note:
Low-dose
aspirin,
low-molecular-weight
heparin sodium were allowed; Allow new oral clotting
factor Xa
antagonists (such as pp shaaban, according to the degree of sand sand and
cut class).
16. Autoimmune disease (other than immune thrombocytopenia due
to lymphoma or autoimmune hemolytic anemia) that could not be
controlled or required treatment within 4 weeks before the first dose of
medication (or before randomization) .
17. Prior exposure to ≥150 mg/m2 doxorubicin (or other anthracyclines
converted according to cumulative cardiac toxicity).

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18. Researchers think that there are not suitable for participants
to participate in the test of other conditions.
During the
study
period
allows the
combinatio
n of
medication
and
therapy
In does not affect the research objective to observe the situation, the
subjects
during
the
study period
acceptable
reasonable best
support
treatment, including hematopoietic growth factors, blood transfusion or
blood products (such as transfusion of red blood cells and platelets), body
fluids and electrolytes supplement and appropriate antibiotic therapy, etc.
In order to reduce neutrophil reduce the risk of infection, unless the taboo
or intolerance, otherwise all into the group of subjects require the use of
granulocyte colony stimulating factor (g-csf) as a primary prevention, and
in the subsequent chemotherapy cycle duration.
This study allows the rituxan (R) drug delivery before the use of
acetaminophen, diphenhydramine
(or other appropriate antihistamines)
front
of
drugs,
and
10
mg
or
less
dexamethasone
or
equivalent
glucocorticoid to prevent infusion reactions associated with R (special cases
need excessive use, subject to the researchers decided after discussing with
the sponsor).
To allow participants in this study R - CHOP plan dosing and R to
study outside of medicine before using 20 mg/day or less during the
period
of treatment prednisone
(or
equivalent), used for lymphoma
symptoms control other than the purpose. Allows use of corticosteroids in
the first drug (up to 100 mg/day of prednisone or equivalent drug) to
control the tumor, lymphoma symptoms or minus 10 days the longest can
continue to use (such as excess or in excess of the prescribed time, need
to communicate with the sponsor of medicine), but it's important to note
that
disease
stages
must
be
completed
before
the
start
of
the
glucocorticoid treatment.
Only in R - CHOP research plan during the treatment, allows the use
of proton pump inhibitors, each period the longest use 5 days.
Drugs to prevent the development of TLS and reactivation of HBV.
Allow the cartesian pneumocystis pneumonia according to the clinical
routine preventive treatment.
Patients with CNS high risk factors (CNS-IPI score of 4 or higher)
were
allowed
CNS
prophylaxis
(e.g.,
triple
intrathecal
cytidine,
methotrexate, and dexamethasone) during the study.
Allow to testicular diseases involving patients with testicular lesions
radiotherapy.

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Medication
s
and
treatments
that
were
not
allowed
during
the
study
Any investigational medication;
Anti-tumor drugs for any indication other than the study protocol,
including Chinese herbal medicine;
Any antineoplastic treatment, including surgery, local radiotherapy
(except for patients with disease involving the testes), and stem cell
transplantation;
Live or attenuated live vaccines;
Warfarin or other vitamin K antagonists.
Criteria for
subjects to
discontinue
treatment
1. Patients or their legal representatives request to withdraw from the study,
such as patients who cannot tolerate AEs and request to withdraw from the
study treatment;
2. The investigator decided that the study treatment should be terminated
based on the best interests of the patients;
3. There is evidence of disease progression or recurrence, or the efficacy
is evaluated as SD after the completion of combination therapy;
4. Complete the prescribed cycle of treatment;
5, the researcher and/or the sponsor considers the patient compliance;
6. The use of other anti-tumor therapies, such as stem cell transplantation;
7. Patient loss to follow-up [failure to contact the subject or family member
after a minimum of 3 documented telephone calls or emails on different
calendar days within 1 month];
8. The patient died.
Study period
The projected duration of the study was 7 years. Participants could receive
the study drug and regimen until they had disease progression or relapse or
unacceptable
toxicity,
whichever
occurred
first,
after
completing
the
prescribed cycles.
Safety
Assessment
All subjects receiving the drug will be evaluated for safety.
Safety was evaluated by means ofvital signs, physical examination,
laboratory testing, electrocardiography, and reporting of adverse events and
serious adverse events.
Safety was followed up until 28 days after the completion of the protocol or
withdrawal from the study.
Evaluation
OF
Efficacy
The efficacy was evaluated according to the 2014 version ofthe Lugano criteria
for non-Hodgkin's lymphoma (NHL) (Cheson, BD et al. 2014), as described in
Appendix 3.

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Statistical
Methods
Statistical Analysis set
Full analysis set (FAS) : All cases were included as much as possible based
on the intention-to-treat (ITT) principle. The definition ofFAS for this study was
consistent with that of the population in the primary estimation objective: male,
previously untreated patients with DLBCL who had undergone randomization
and received at least one dose of a study drug were eligible for FAS.
Per-protocol set (PPS) : subjects in the full analysis set who had good
treatment adherence (70%-120%), no major protocol violations, and available
primary endpoint. PPS will be used for supplementary analysis of efficacy.
Safety data set (SS) : used at least once included in all test drugs, and drug
safety data recorded after the subjects.
Pharmacokinetic analysis set (PKS) : All subjects who received at least one
dose of trial drug, had pharmacokinetic data (biological samples were collected),
and no major protocol violations were included.
Exploratory study analysis set: Subjects with exploratory study data and no
major protocol violations in the FAS set were included.
Safety ANALYSES
Safety data sets were used for safety analysis.
The descriptive statistics and summary of adverse events occurred in the
experimental group and control group, all the adverse events (AE), level 3 and
above AE, adverse events related to study drug (TRAE), level 3 and above
TRAE, Serious adverse event (SAE), related to study drug SAE (SAR), led to
the drug suspension, dose adjustment or permanent discontinuation ofAE and
pay special attention to adverse events (AESI) will be according to the organ
systems, the preferred term and category summary of cases, the number of
cases, and the incidence.
Trends in laboratory tests, vital signs, ECOG performance status, and
electrocardiographic measurements will be explored and summarized or
compared with baseline if necessary.
Efficacy ANALYSIS
Primary estimation analysis and sensitivity analysis were performed based
on FAS, and PPS was used as supplementary analysis.
MODIFIED-PFS was defined as the time from the date of randomization
to receipt of second-line therapy, first documented recurrence, or progression.
Between-group differences in MODIFIED-PFS were analyzed using the
stratified Log-rank test, with the same stratification factors as those used at
randomization. Use the Kaplan - Meier (KM) method to estimate the

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MODIFIED - PFS curve of each team, a MODIFIED - PFS and 3 years in
MODIFIED - PFS rate, The 95% confidence interval for median modify-PFS
was estimated by the Brookmeyer-Crowley method, which used the log-log
function transformation to achieve normal approximation. MODIFIED - PFS
risk ratio (HR) and 95% confidence interval, the use of the stratified Cox
proportional hazards models to estimate, layered with stratified random factors.
In addition, considering the possibility of informative censoring of the
censored data, the control-based multiple imputation method will be considered
for sensitivity analysis after processing the censored data. Details of the
methods are provided in the statistical analysis plan.
Other efficacy indicators included EFS, ORR, CRR, DOR, OS, etc.
Defined EFS: for the first time to give medicine to disease progression or
recurrence after CR, cannot stop drug tolerance toxicity of lead to permanent,
start the anti-tumor treatment or death from any cause (with whichever) happen
first time. Patients without EFS events at the time of analysis were censored
according to the time point of the last evaluation.
ORR: ORR is defined as a percentage of all cases of CR and PR cases.
CRR: is defined as a percentage of all cases of CR cases.
DOR (for all subjects achieving response) : Defined as the time from the
first assessment of response to the first assessment of disease progression or
relapse or death from any cause.
OS: defined as time from first dose to death from any cause. Persons free
from death at the time of analysis were censored at the date they were last
known to be alive.
ORR between treatment group and comparison CRR adopts hierarchical
Cochran Mantel Haenszel compared between groups (CMH) method, and
calculate the difference between groups rate 95% CI ofreduction ofthe control
group (test group), layered with stratified random factors. At the sametime, the
Logistic model was fitted to calculate the ORR, CRR and 95% confidence
interval of each treatment group with and without stratification factors, and the
difference of ORR and CRR and 95% confidence interval between the two
groups, respectively.
The analysis methods ofDOR, EFS and OS were the same as MODIFIED-
PFS. In addition, for subjects without documented end-point events before the
data cutoff and those who did not fully follow the tumor evaluation procedure,
different specific censoring rules will be formulated, and sensitivity analyses
will be provided for different censoring treatments.

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Pharmacokinetic study: the drug concentration-time data of each subject
were calculated, the concentration-time curve was drawn, and the average
blood concentration - time curve was drawn. The pharmacokinetic parameters
were also calculated after drug administration. Based on the previously
obtained pharmacokinetic
characteristics
and models,
the
population
pharmacokinetic characteristics of the study subjects were established, and the
effects of concomitant medications and disease/physiological factors on the
pharmacokinetic characteristics of rituximab were evaluated.
Sample Size
The final enrollment will include all patients for whom data on safety,
tolerability,pharmacokinetics, and efficacy were available during the combined
study.
Independent
data
Monitoring
Committee
(IDMC)
The IDMC (composed of senior clinical experts with relevant disease
expertise and clinical trial statistics experts) was established before the entry of
the key registration clinical study. The IDMC was mainly responsible for
regularly reviewing the accumulated data ofthis clinical trial to protect the safety
of subjects, ensure the reliability of the trial, and ensure the validity of the trial
results. The specific content will be elaborated in the charter of IDMC.
Study
Protocol
Modifications
Modifications to the protocol will be made as necessary based on available
human pharmacokinetic parameters, safety, tolerability, and preliminary
efficacy data.
All amendments to the protocol had to be approved by the sponsor, the
investigators, and the ethics committee.