MabRella Study: A Study to Evaluate the Safety of Switching From Intravenous to Subcutaneous Administration of Rituximab During First-Line Treatment for Lymphoma

Study Overview
=================
Brief Summary
-----------------
This open-label, single-arm, phase IIIb study will evaluate the safety of switching from intravenous (IV) to subcutaneous (SC) administration of rituximab during first-line treatment for participants with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL) who have already received at least one full dose of rituximab IV. Participants with FL will be given 1400 mg rituximab SC during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). 1400 mg SC of rituximab will be given to participants with DLBCL once monthly for 4-7 cycles. Treatment duration is expected to last up to 7 months for participants with DLBCL and up to 32 months for participants with FL.

Official Title
-----------------
Open Label, Single-arm, Phase IIIb Clinical Trial to Evaluate the Safety of Switching From Intravenous Rituximab to Subcutaneous Rituximab During First Line Treatment for CD20+ Non-Hodgkin's Follicular Lymphoma and Diffuse Large B-cell Lymphoma.

Conditions
-----------------
Lymphoma, Non Hodgkin

Intervention / Treatment
-----------------
* Drug: Rituximab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 and ≤ 80 years at time of enrolment. Life expectancy ≥ 6 months. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3. Fertile men or women of childbearing potential must use effective contraception until at least 12 months after the last dose; women must not be pregnant. Histologically confirmed CD20+ diffuse large B-cell lymphoma (DLBCL) or CD20+ follicular Non-Hodgkin Lymphoma (FL) grade 1, 2 or 3a according to the World Health Organisation Classification system. Induction only: Participants with Follicular Lymphoma should meet Groupe D'Etude des Lymphomes Folliculaires (GELF) criteria to initiate treatment. At least tumor >/= 1.5 cm as measured by computed tomography (CT) scan. FL treatment-related criteria - Currently being treated with rituximab IV during first-line therapy and has received at least one full dose of rituximab IV. Exclusion Criteria: Transformed lymphoma. Primary central nervous system lymphoma, primary effusion lymphoma, primary mediastinal DLBCL, DLBCL of the testis, primary cutaneous DLBCL or histologic evidence of transformation to a Burkitt lymphoma. History of other cancer, including one that has been treated but not with curative intent, unless the cancer has been in remission without treatment for >/= 5 years prior to dosing. Note: Participants with a history of cured skin cancer or in situ carcinoma of the cervix are eligible for the study. Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent. Note: Participants receiving corticosteroid treatment with </= 30 mg/day of prednisone or equivalent must be on a stable regimen for at least 4 weeks prior to start of dosing. Inadequate renal, hematologic, or hepatic function. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products. For participants with DLBCL: Contraindication to any of the individual components of CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone), including prior anthracycline treatment. For participants with FL: contraindication to standard chemotherapy. Other serious underlying medical conditions. Recent major surgery (within 4 weeks prior to dosing), other than for diagnosis. Active and/or severe infections (excluding nail fungal infections) or any infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to dosing. Active Hepatitis B virus (HBV) or Hepatitis C virus (HCV) infection. Note: Participants testing positive for Hepatitis B or C virus antibodies but with an undetectable viral load may be included. History of Human Immunodeficiency Virus (HIV) positive status.

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Subcutaneous Rituximab<br>Participants with CD20+ non-Hodgkin's follicular lymphoma (FL) or diffuse large B-cell lymphoma (DLBCL), who had already received at least one full dose of intravenous (IV) rituximab will be treated with subcutaneous (SC) rituximab. Participants with FL will be administered 1400 mg rituximab during induction therapy (once monthly for 4-7 cycles) and maintenance therapy (once every 2 months for 6-12 cycles). Participants with DLBCL will be administered 1400 mg SC of rituximab once monthly for 4-7 cycles. Treatment duration is expected to last up to 7 months for participants with DLBCL and up to 32 months for participants with FL. | Drug: Rituximab<br>* 1400 mg will be injected subcutaneously (SC).<br>* Other names: Rituxan;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Administration-Associated Reactions (AARs) | AARs were defined as all adverse events (AEs) occurring within 24 hours of rituximab SC administration and which were considered related to study drug. AARs included infusion/injection-related reactions (IIRRs), injection-site reactions, administration site conditions and all symptoms thereof. Grading was completed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. | From start of treatment to end of treatment (up to 32 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With At Least One Grade >/= 3 Adverse Events (AEs) | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Pre-existing conditions which worsen during a study are also considered as adverse events. Grading was completed according to the CTCAE, version 4.0. | From start of recruitment (10 months period) up to end of treatment at 32 months (total period up to 42 months) | 
| Percentage of Participants With At Least One Grade >/= 3 Infusion/ Injection Related Reactions (IIRRs) | Grading of IIRRs was completed according to the CTCAE, version 4.0. | From start of treatment to end of treatment (up to 32 months) | 
| Percentage of Participants With At Least One Serious Adverse Event (SAE) | SAE was defined as any experience that suggested a significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here. | From start of recruitment (10 months period) up to end of treatment at 32 months (total period up to 42 months) | 
| Event-Free Survival (EFS) | EFS was defined as the time from first dose of rituximab IV to first occurrence of progressive disease (PD) or relapse, according to the International Working Group (IWG) response criteria or initiation of a non-protocol-specified anti-lymphoma therapy or death, whichever occurs first. PD: >/= 50% increase lymph nodes and nodal mass size, any new lesion, enlarged liver/spleen, reappearance bone marrow abnormalities. | From time of first dose of rituximab IV before study enrollment up to end of study (up to approximately 62 months) | 
| Progression-Free Survival (PFS) | PFS was defined as the time from first dose of rituximab IV to the first occurrence of progressive disease (PD) or relapse, according to the International Working Group (IWG) response criteria or death from any cause. PD: >/= 50% increase lymph nodes and nodal mass size, any new lesion, enlarged liver/spleen, reappearance bone marrow abnormalities. | From time of first dose of rituximab IV before study enrollment up to end of study (up to approximately 62 months) | 
| Overall Survival (OS) | OS was defined as the time from first dose of rituximab IV to death from any cause. | From time of first dose of rituximab IV before study enrollment up to end of study (up to approximately 62 months) | 
| Disease-Free Survival (DFS) | DFS was assessed in participants achieving complete response (CR) including complete response unconfirmed (Cru) and was defined as the period from the date of the initial CR/CRu until the date of relapse or death from any cause. CR: 1) disappearance of all evidence/symptoms of disease, 2) lymph nodes and nodal masses normal size, 3) enlarged spleen must have regressed in size, 4) normal bone marrow; CRu: see 1) and 3) of CR plus > 75% decrease in residual lymph node mass, indeterminate bone marrow. Reported here is the truncated mean estimate based on Kaplan-Meier analysis. | From time of first dose of rituximab IV before study enrollment up to end of study (up to approximately 62 months) | 
| Treatment Response Rate | Treatment response rate was classified according to the International Working Group (IWG) response criteria: CR/Cru, partial response (PR), stable disease (SD) and PD. CR: 1) disappearance of all evidence/symptoms of disease, 2) lymph nodes and nodal masses normal size, 3) enlarged spleen must have regressed in size, 4) normal bone marrow; CRu: see 1) and 3) of CR plus > 75% decrease in residual lymph node mass, indeterminate bone marrow; PR: >/= 50% decrease lymph nodes and nodal mass size; decrease in liver/spleen size, no new sites; SD: less than a PR, but is not PD; PD: >/= 50% increase lymph nodes and nodal mass size, any new lesion, enlarged liver/spleen, reappearance bone marrow abnormalities. | 4-6 weeks after the last dose of Induction (Up to approximately 8 months) |