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)

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04660799

Collaborator

(none)

Enrollment

Locations

Arms

18.2

Anticipated Duration (Months)

5.6

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Large B-Cell, Diffuse	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	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Feb 24, 2021

Actual Primary Completion Date :

May 23, 2022

Anticipated Study Completion Date :

Aug 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rituximab IV+CHOP Participants will receive 8 cycles of IV rituximab in combination with six or eight cycles of CHOP chemotherapy administered every 3 weeks	Drug: Rituximab IV Rituximab will be administered intravenously through Cycle 1-8 at a standard dose of 375 mg/m2 (milligram per square meter) Other Names: MabThera Drug: Cyclophosphamide Cyclophosphamide will be administered IV at a dose of 750 mg/m2 Drug: Doxorubicin Doxorubicin will be administered IV at a dose of 50 mg/m2 Drug: Vincristine Vincristine will be administered IV at a dose of 1.4 mg/m2 Drug: Prednisone Prednisone will be administered orally at a dose of 100 mg/day Drug: Paracetamol All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab Drug: Diphenhydramine hydrochloride or alternative antihistamine All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab
Experimental: Rituximab SC+CHOP Participants will receive 1 cycle of IV plus 7 cycles of SC in combination with six or eight cycles of CHOP chemotherapy administered every 3 weeks	Drug: Rituximab SC Rituximab will be administered subcutaneously through Cycle 2-8 at a dose of 1400 milligram (mg) Other Names: MabThera Drug: Rituximab IV Rituximab will be administered intravenously in Cycle 1 at a standard dose of 375 mg/m2 Other Names: MabThera Drug: Cyclophosphamide Cyclophosphamide will be administered IV at a dose of 750 mg/m2 Drug: Doxorubicin Doxorubicin will be administered IV at a dose of 50 mg/m2 Drug: Vincristine Vincristine will be administered IV at a dose of 1.4 mg/m2 Drug: Prednisone Prednisone will be administered orally at a dose of 100 mg/day Drug: Paracetamol All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab Drug: Diphenhydramine hydrochloride or alternative antihistamine All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab

Arm

Intervention/Treatment

Active Comparator: Rituximab IV+CHOP

Participants will receive 8 cycles of IV rituximab in combination with six or eight cycles of CHOP chemotherapy administered every 3 weeks

Drug: Rituximab IV

Rituximab will be administered intravenously through Cycle 1-8 at a standard dose of 375 mg/m2 (milligram per square meter)

Other Names:

MabThera

Drug: Cyclophosphamide

Cyclophosphamide will be administered IV at a dose of 750 mg/m2

Drug: Doxorubicin

Doxorubicin will be administered IV at a dose of 50 mg/m2

Drug: Vincristine

Vincristine will be administered IV at a dose of 1.4 mg/m2

Drug: Prednisone

Prednisone will be administered orally at a dose of 100 mg/day

Drug: Paracetamol

All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab

Drug: Diphenhydramine hydrochloride or alternative antihistamine

All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab

Experimental: Rituximab SC+CHOP

Participants will receive 1 cycle of IV plus 7 cycles of SC in combination with six or eight cycles of CHOP chemotherapy administered every 3 weeks

Drug: Rituximab SC

Rituximab will be administered subcutaneously through Cycle 2-8 at a dose of 1400 milligram (mg)

Other Names:

MabThera

Drug: Rituximab IV

Rituximab will be administered intravenously in Cycle 1 at a standard dose of 375 mg/m2

Other Names:

MabThera

Drug: Cyclophosphamide

Cyclophosphamide will be administered IV at a dose of 750 mg/m2

Drug: Doxorubicin

Doxorubicin will be administered IV at a dose of 50 mg/m2

Drug: Vincristine

Vincristine will be administered IV at a dose of 1.4 mg/m2

Drug: Prednisone

Prednisone will be administered orally at a dose of 100 mg/day

Drug: Paracetamol

All participants are required to receive 1000 mg oral paracetamol as premedication prior to starting each infusion of rituximab

Drug: Diphenhydramine hydrochloride or alternative antihistamine

All participants are required to receive 50-100 mg oral diphenhydramine hydrochloride or alternative antihistamine as premedication prior to starting each infusion of rituximab

Outcome Measures

Primary Outcome Measures

Ratio of serum SC rituximab trough concentration (Ctrough,SC) and serum IV rituximab trough concentration (Ctrough,IV) during Cycle 7 [At Cycle 7, 21 days after study treatment administration (one Cycle=21 days)]

Secondary Outcome Measures

Ratio of observed SC and IV rituximab area under the serum concentration curve (AUCsc/AUCiv) during Cycle 7 [During Cycle 7 (one Cycle=21 days)]
Area under the serum concentration-time curve (AUC) over the SC and IV rituximab dosing interval of Cycle 2 [During Cycle 2 (one Cycle=21 days)]
Trough serum concentration (Ctrough) of rituximab [Cycle 1 through Cycle 8 (one Cycle=21 days)]
Maximum observed serum concentration (Cmax) of rituximab [Cycle 1 through Cycle 8 (one Cycle=21 days)]
Total clearance (CLss) of serum rituximab [Cycle 1 through Cycle 8 (one Cycle=21 days)]
Volume of distribution at steady state (Vss) of rituximab [Cycle 1 through Cycle 8 (one Cycle=21 days)]
Terminal half-life (t1/2) of rituximab [Cycle 1 through Cycle 8 (one Cycle=21 days)]
Complete response rate (CRR) as determined by the Independent Review Committee (IRC) using Lugano Response Criteria for Malignant Lymphoma [6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation]
CRR, as determined by IRC using International Working Group (IWG) Response Criteria for NHL 1999 Guidelines [6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation]
CRR is defined as complete response (CR) or complete response unconfirmed (CRu)
CRR, as determined by the investigator using Lugano Response Criteria for Malignant Lymphoma [6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation]
Objective response rate (ORR), as determined by investigator and IRC using Lugano Response Criteria for Malignant Lymphoma [6-8 weeks after the last dose of study treatment or 4-8 weeks after last dose of study treatment for early discontinuation]
ORR is defined as complete response (CR) and partial response (PR)
Percentage of participants with adverse events (AEs) and serious adverse events (SAEs) [6 months after the last dose of study treatment]
Percentage of participants with rituximab administration-related reactions (ARRs) [6 months after the last dose of study treatment]
Percentage of participants with anti-drug antibodies (ADAs) [6 months after the last dose of study treatment]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Peking University Third Hospital	Beijing	China	100191
2	The First Hospital of Jilin University	Changchun City	China	130021
3	Fujian Provincial Cancer Hospital	Fuzhou City	China	350014
4	Cancer Center, Sun Yat-sen University of Medical Sciences; Department of Medical Oncology	Guangzhou City	China	510060
5	Harbin Medical University Cancer Hospital	Harbin	China	150081
6	The 1st Affiliated Hospital of Nanchang Unversity	Nanchang	China	330019
7	Tianjin Medical University Cancer Institute & Hospital	Tianjing	China	300060
8	Union Hospital Tongji Medical College Huazhong University of Science and Technology	Wuhan City	China	430023
9	The First Affiliated Hospital of Xian Jiao Tong University	Xi'an City	China	710061