A Study on Pharmacokinetics (PK), Efficacy and Safety of Subcutaneous (SC) Versus Intravenous (IV) Rituximab, in Combination With CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) in Previously Untreated Participants With CD20 Positive Diffuse Large B-Cell Lymphoma (DLBCL)

For this pharmacokinetics (PK) primary outcome measure the serum rituximab Ctrough for SC and IV administrations were measured at Cycle 7, 21 days after study treatment administration for Cycle 7 (pre-dose of Cycle 8). Geometric mean ratio and 90% confidence interval were estimated based on an ANCOVA model adjusted for tumor load at baseline and are reported in the statistical analysis.

Time frame: At Cycle 7 (one cycle=21 days), 21 days after study treatment administration, up to 21 weeks

Population: The Per Protocol PK population included all enrolled participants who adhered to the protocol and were assigned to arms as treated. Exclusions were made for the following reasons: missing Ctrough Cycle 7 sample, Cycle 7 Ctrough sample collected with more than 3 days deviation from planned date on Day 22, given a dose that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), a Cycle 7 dose delay of more than 7 days, an assay error impacting Cycle 7 Ctrough measurement.

AUC is the area under the serum concentration curve over the dosing interval of 21 days during Cycle 2 and Cycle 7.

Time frame: During Cycles 2 and 7 (one cycle=21 days): pre-dose, within 15 minutes of end of infusion, 24 hours post-dose, Days 3, 7, 15, 21, up to 21 weeks

Population: PK analyses were based on all participants with at least one PK assessment. PK analyses were analyzed as treated. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete, where the PK analysis might be influenced.

Per LRC, CR based on positron emission tomography- computed tomography (PET-CT) was defined as complete metabolic response (MR) in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass, on 5-point scale (5PS), where, 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; no new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. Per LRC, CR based on CT was defined as complete radiologic response in lymph nodes and extralymphatic sites with target nodes/nodal masses regressing to ≤ 1.5 centimeters (cm) in longest transverse diameter (LDi) and no extralymphatic sites of disease; absence of non-measured lesion; organ enlargement regressing to normal; no new lesions; normal bone marrow by morphology, if indeterminate, immunohistochemistry (IHC) negative.

Time frame: 6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation (up to approximately 32 weeks)

Population: The intent-to-treat (ITT) population consisted of all randomized participants. Participants are assigned to the treatment group to which they were randomized.

CRR was assessed according to the IWG Response Criteria for NHL 1999 guidelines and included CR and CR unconfirmed (CRu). CR was defined as complete disappearance of all clinical and radiographic evidence of disease and disease-related symptoms, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. CRu was defined as disappearance of clinical and radiographic evidence of disease and absence of splenomegaly, with regression of lymph nodes by \> 75 % but still \>1.5 cm in size, and indeterminate bone marrow assessment.

Time frame: 6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation (up to approximately 32 weeks)

Population: The ITT population consisted of all randomized participants. Participants are assigned to the treatment group to which they were randomized.

Per LRC, CR based on PET-CT was defined as complete metabolic response (MR) in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass, on 5-point scale (5PS), where, 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; no new lesions and no evidence of FDG-avid disease in bone marrow. Per LRC, CR based on CT was defined as complete radiologic response in lymph nodes and extralymphatic sites with target nodes/nodal masses regressing to ≤ 1.5 centimeters (cm) in longest transverse diameter (LDi) and no extralymphatic sites of disease; absence of non-measured lesion; organ enlargement regressing to normal; no new lesions; normal bone marrow by morphology, if indeterminate, IHC negative.

Time frame: 6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation (up to approximately 32 weeks)

Population: The ITT population consisted of all randomized participants. Participants are assigned to the treatment group to which they were randomized.

Time frame: At Cycles 2 and 7 (one cycle=21 days): pre-dose, within 15 minutes of end of infusion, 24 hours post-dose, Days 3, 7, 15, 21, up to 21 weeks

Population: PK analyses were based on all participants with at least one PK assessment. PK analyses were analyzed as treated. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete, where the PK analysis might be influenced.

Reported here is the number of participants who had a positive ADA assay result at baseline or post-baseline. The post-baseline results are divided in treatment-enhanced ADAs and treatment-induced ADAs. Treatment-enhanced ADAs are participants with a positive ADA result at baseline who had one or more post-baseline titer results that was at least 0.60 titer unit greater than the baseline titer result. Treatment-induced ADAs include participants with negative or missing baseline ADA result(s) and at least one positive post-baseline ADA result.

Time frame: From baseline up to 6 months after the last dose of study treatment (up to approximately 1 year)

Population: The immunogenicity analysis population consisted of all participants with at least one anti-drug antibody (ADA) assessment. Participants were grouped according to treatment received or, if no treatment was received prior to study discontinuation, according to treatment assigned.

Reported here is the number of participants who had a positive anti-rHuPH20 antibody assay result at baseline or post-baseline. The post-baseline results are divided in treatment-enhanced anti-rHuPH20 antibodies and treatment-induced anti-rHuPH20 antibodies. Treatment-enhanced anti-rHuPH20 antibodies are participants with a positive anti-rHuPH20 antibody result at baseline who had one or more post-baseline titer results that was at least 0.60 titer unit greater than the baseline titer result. Treatment-induced anti-rHuPH20 antibodies include participants with negative or missing baseline anti-rHuPH20 antibody result(s) and at least one positive post-baseline anti-rHuPH20 antibody result.

Time frame: From baseline up to 6 months after the last dose of study treatment (up to approximately 1 year)

Population: The immunogenicity analysis population consisted of all participants with at least one anti-rHuPH20 assessment. Participants were grouped according to treatment received or, if no treatment was received prior to study discontinuation, according to treatment assigned.

AE: any untoward medical occurrence in a subject administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. New disease, exacerbation of existing disease, recurrence of an intermittent medical condition not present at baseline, any deterioration in a laboratory value or other clinical test associated with symptoms or leading to a change in study/concomitant treatment or discontinuation from study drug as well as events related to protocol-mandated interventions are considered AEs. SAEs: any event that met any of these criteria: fatal, life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, medically significant or required intervention to prevent any of the outcomes listed here.

Time frame: AEs were reported up to 28 days after the last dose (up to approximately 7 months), and SAEs were reported up to 6 months after the last dose of study treatment (up to approximately 1 year)

Population: The safety analysis population consisted of all randomized participants who received at least one dose of study drug, with participants grouped according to treatment received.

Adverse events occurring within 24 hours after administration of rituximab (rituximab IV or rituximab SC) and considered related to the study drug, were considered as ARRs. ARRs could 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.

Time frame: Up to 24 hours after the last dose of study treatment (up to approximately 24 weeks)

Population: The safety analysis population consisted of all randomized participants who received at least one dose of study drug, with participants grouped according to treatment received.

ORR=CR+PR. Per LRC: CR by PET-CT: complete MR in lymph nodes and extralymphatic sites with a score of 1, 2, or 3 with or without residual mass; no new lesions, no FDG-avid disease in bone marrow; CR by CT: complete radiologic response in lymph nodes and extralymphatic sites with target nodes/nodal masses regressing to ≤ 1.5 cm in LDi, no extralymphatic disease; absence of non-measured lesion; organ enlargement regressing to normal; no new lesions; normal bone marrow; PR by PET-CT: partial MR in lymph nodes and extralymphatic sites with a score of 4 or 5 with reduced uptake compared with baseline + residual masses of any size; no new lesions, residual uptake higher than in normal bone marrow but reduced compared with baseline; PR by CT: ≥ 50% decrease in sum of the product of the perpendicular diameters (SPD) of up to 6 target nodes and extranodal sites; non-measured lesion absent/normal, regressed, but no increase; spleen regressed by \>50 % in length beyond normal; no new lesions.

Time frame: 6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation (up to approximately 32 weeks)

Population: The ITT population consisted of all randomized participants. Participants are assigned to the treatment group to which they were randomized.

The area under the curve (AUC) for serum rituximab concentration versus time after dosage was measured for SC and IV administrations during Cycle 7. Geometric mean ratio and 90% confidence interval were estimated based on an ANCOVA model adjusted for tumor load at baseline and are reported in the statistical analysis.

Time frame: During Cycle 7 (one cycle=21 days): pre-dose, within 15 minutes of end of infusion, 24 hours post-dose, Days 3, 7, 15, 21, up to 21 weeks

Population: The Per Protocol PK population included all enrolled participants who adhered to the protocol and were assigned to arms as treated. Exclusions were made for the following reasons: missing Ctrough Cycle 7 sample, Cycle 7 Ctrough sample collected with more than 3 days deviation from planned date on Day 22, given a dose that deviated from the planned dose by \>20% within 3 cycles (from Cycle 5), a Cycle 7 dose delay of more than 7 days, an assay error impacting Cycle 7 Ctrough measurement.

Time frame: At Cycles 2 and 7 (one cycle=21 days): pre-dose, within 15 minutes of end of infusion, 24 hours post-dose, Days 3, 7, 15, 21, up to 21 weeks

Population: PK analyses were based on all participants with at least one PK assessment. PK analyses were analyzed as treated. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete, where the PK analysis might be influenced.

Ctrough was measured at Cycle 2 and Cycle 7, 21 days after study treatment administration for each cycle (pre-dose of Cycle 3 and Cycle 8, respectively).

Time frame: At Cycles 2 and 7 (one cycle=21 days), 21 days after study treatment administration, up to 21 weeks

Population: PK analyses were based on all participants with at least one PK assessment. PK analyses were analyzed as treated. Participants were excluded from the PK analysis population if they significantly violated the inclusion or exclusion criteria, deviated significantly from the protocol, or if data were unavailable or incomplete, where the PK analysis might be influenced.