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)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Drug: Rituximab IV
* Drug: Rituximab SC
* Drug: Rituximab IV
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone
* Drug: Paracetamol
* Drug: Diphenhydramine hydrochloride or alternative antihistamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) Participants with an International Prognostic Index (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 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 For women of reproductive potential who are not surgically sterile, agreement to use adequate methods 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 Adequate hematologic function confirmed within 14 days prior to randomization Exclusion Criteria: Transformed non-Hodgkin's lymphoma (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 treatment with another investigational drug or participation in another investigational therapeutic study Ongoing corticosteroid use (>30 mg/day of prednisone or equivalent) 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 Evidence of significant, uncontrolled concomitant diseases including but not limited to significant cardiovascular disease or pulmonary disease Any of the following abnormal laboratory values: creatinine >1.5 upper limit of normal (ULN), aspartate aminotransferase (AST) / alanine aminotransferase (ALT) >2.5ULN, total bilirubin >1.5ULN, prothrombin time - international normalized ratio (PT-INR) / partial thromboplastin time (PTT) / activated partial thromboplastin time (aPTT)>1.5ULN Positive test results for chronic hepatitis B (HBV) and or hepatitis C (HCV) infection; Participants 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; Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA Known history of human immunodeficiency virus (HIV)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab IV+CHOP<br>Participants will receive 8 cycles of IV rituximab in combination with 6 or 8 cycles of CHOP chemotherapy administered every 3 weeks. | Drug: Rituximab IV<br>* Rituximab will be administered intravenously through Cycle 1-8 at a standard dose of 375 mg/m^2 (milligram per square meter).<br>* Other names: MabThera;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered IV at a dose of 750 mg/m^2<br>Drug: Doxorubicin<br>* Doxorubicin will be administered IV at a dose of 50 mg/m^2<br>Drug: Vincristine<br>* Vincristine will be administered IV at a dose of 1.4 mg/m^2<br>Drug: Prednisone<br>* Prednisone will be administered orally at a dose of 100 mg/day<br>Drug: Paracetamol<br>* All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab<br>Drug: Diphenhydramine hydrochloride or alternative antihistamine<br>* All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab<br>|
| Experimental: Rituximab SC+CHOP<br>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. | Drug: Rituximab SC<br>* Rituximab will be administered subcutaneously through Cycle 2-8 at a dose of 1400 milligram (mg).<br>* Other names: MabThera;Drug: Rituximab IV<br>* Rituximab will be administered intravenously in Cycle 1 at a standard dose of 375 mg/m^2.<br>* Other names: MabThera;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered IV at a dose of 750 mg/m^2<br>Drug: Doxorubicin<br>* Doxorubicin will be administered IV at a dose of 50 mg/m^2<br>Drug: Vincristine<br>* Vincristine will be administered IV at a dose of 1.4 mg/m^2<br>Drug: Prednisone<br>* Prednisone will be administered orally at a dose of 100 mg/day<br>Drug: Paracetamol<br>* All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab<br>Drug: Diphenhydramine hydrochloride or alternative antihistamine<br>* All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subcutaneous Serum Rituximab Trough Concentration (Ctrough SC) and Intravenous Serum Rituximab Trough Concentration (Ctrough IV) | 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. | At Cycle 7 (one cycle=21 days), 21 days after study treatment administration, up to 21 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed SC and IV Rituximab Area Under the Curve (AUCsc and AUCiv) | 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. | 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 | 
| Maximum Observed Serum Concentration (Cmax) of Rituximab |  | 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 | 
| Time to Cmax (Tmax) of Rituximab |  | 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 | 
| Trough Serum Concentration (Ctrough) of Rituximab | 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). | At Cycles 2 and 7 (one cycle=21 days), 21 days after study treatment administration, up to 21 weeks | 
| Area Under the Curve (AUC) of Rituximab | AUC is the area under the serum concentration curve over the dosing interval of 21 days during Cycle 2 and Cycle 7. | 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 | 
| Complete Response Rate (CRR) as Determined by the Independent Review Committee (IRC) Using Lugano Response Criteria (LRC) for Malignant Lymphoma | 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. | 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) | 
| Objective Response Rate (ORR), Complete Response (CR) or Partial Response (PR), as Determined by Investigator and IRC Using Lugano Response Criteria (LRC) for Malignant Lymphoma | 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. | 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) | 
| CRR, as Determined by IRC Using International Working Group (IWG) Response Criteria for Non-Hodgkin's Lymphoma (NHL) 1999 Guidelines | 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. | 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) | 
| CRR, as Determined by the Investigator Using Lugano Response Criteria for Malignant Lymphoma | 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. | 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) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | 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) | 
| Number of Participants With Rituximab Administration-related Reactions (ARRs) | 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. | Up to 24 hours after the last dose of study treatment (up to approximately 24 weeks) | 
| Number of Participants Positive for Anti-drug Antibodies (ADAs) to Rituximab | 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. | From baseline up to 6 months after the last dose of study treatment (up to approximately 1 year) | 
| Number of Participants Positive for Anti-rHuPH20 Antibodies | 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. | From baseline up to 6 months after the last dose of study treatment (up to approximately 1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mabthera, Rituximab, SC, Subcutaneous, DLBCL