Follicular Lymphoma IV/SC Rituximab Therapy (FLIRT)

Study Overview
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Brief Summary
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Patient will receive either one infusion of rituximab IV and seven administrations of rituximab SC (experimental arm) or four infusions of rituximab IV (standard arm). The hypothesis is that the use of rituximab by sub cutaneous route and the scheme of administration could: optimize rituximab exposure leading to improve response rate increase adaptative response and then improve long-term control disease.

Official Title
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A Randomized Phase III Trial Evaluating Two Strategies of Rituximab Administration for the Treatment of First Line/Low Tumor Burden Follicular Lymphoma (Follicular Lymphoma IV/SC Rituximab Therapy)

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Drug: Rituximab IV
* Drug: Rituximab SC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed follicular lymphoma CD20+ grade 1, 2 and 3a by biopsy within 4 months before signing informed consent Have a bone marrow biopsy within 4 months before the first study drug administration Have no prior therapy except surgery for diagnosis Aged 18 years or more with no upper age limit ECOG performance status 0-2 Ann Arbor Stage II, III or IV Bi-dimensionally measurable disease defined by at least one single node or tumor lesion > 1.5 cm assessed by CT scan and/or clinical examination With low-tumor burden defined as: Nodal or extra-nodal tumor mass with diameter less than 7 cm in its greater diameter And involvement of less than 3 nodal or extra nodal sites with diameter greater than 3 cm And absence of B symptoms And no symptomatic splenomegaly And no compression syndrome (ureteral, orbital, gastrointestinal…) And no pleural or peritoneal serous effusion And no cytopenia, with hemoglobin > 10 g/dL (6.25mmol/L) and absolute neutrophil count> 1.5 G/L and platelets > 100 G/L within 28 days before the randomization And LDH < ULN within 28 days before the randomization And β2 microglobulin < ULN within 28 days before the randomization Have signed an informed consent Must be covered by a social security system Exclusion Criteria: Grade 3b follicular lymphoma Ann Arbor Stage I Seropositive for or active viral infection with hepatitis B virus (HBV) HBs Ag positive HBs Ag negative, anti-HBs antibody positive and/or anti-HBc antibody positive and detectable viral DNA Note: Patients who are HBs Ag negative, anti-HBs positive and/or anti-HBc positive but viral DNA negative are eligible Patients who are seropositive due to a history of hepatitis B vaccine are eligible Known seropositive for, or active viral infection with hepatitis C virus (HCV) Known seropositive for, or active viral infection with Human Immunodeficiency Virus (HIV) Any of the following laboratory abnormalities within 28 days before the randomization: Total bilirubin or GGT or AST or ALT > 3 ULN. Calculated creatinine clearance (Cockcroft and Gault formula) < 60 mL /min Presence or history of CNS involvement by lymphoma Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the subject has been free of the disease for ≥ 3 years Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Patient with mental deficiency preventing proper understanding of the informed consent and the requirements of treatment. Adult under law-control Adult under tutelage Contraindication to use rituximab or known sensitivity or allergy to murine products Pregnant or lactating females. Concomitant disease requiring prolonged use of corticosteroids or corticosteroids administration for lymphoma within 28 days before the first study drug administration. Male and female patients of childbearing potential who cannot or do not wish to use an effective method of contraception, during the study treatment and for 12 months thereafter.

Ages Eligible for Study
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Minimum Age: 18 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: Am A : Rituximab IV<br>4 infusions of intravenous rituximab (375mg/m²) at Day 1, Day 8, Day 15 and D22 | Drug: Rituximab IV<br>* intra-venous, 375 mg/m²<br>* Other names: MabThera IV;|
| Experimental: Arm B: Rituximab SC<br>1 infusion of intravenous rituximab (375mg/m²) at Day 1, and 7 administrations of sub-cutaneous rituximab (1400mg) at Day 8, Day15, Day 22, Month 3, Month 5, Month 7 and Month 9. | Drug: Rituximab IV<br>* intra-venous, 375 mg/m²<br>* Other names: MabThera IV;Drug: Rituximab SC<br>* sub-cutaneous, 1400 mg<br>* Other names: MabThera SC;|
| Experimental: Arm C : Rituximab SC first cycle<br>8 administrations of sub-cutaneous rituximab (1400mg) at Day 8, Day15, Day 22, Month 3, Month 5, Month 7 and Month 9. | Drug: Rituximab SC<br>* sub-cutaneous, 1400 mg<br>* Other names: MabThera SC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Time from randomization into the study to the first observation of documented disease progression or death due to any cause. If a subject has not progressed or died, PFS will be censored at the time of last visit with adequate assessment | 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | time from the date of randomization to the date of death from any cause. Alive patients will be censored at their last follow-up date. | 5.5 years | 
| Response Rates | Disease response evaluation, assessment will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma) according to Cheson 1999 (M3 and M12) and according to Cheson 2014 (M12 only). The response rates will be described for each modality (CR, CRu, PR, SD and PD) and the Overall response rates (CR+CRu+PR) will also be described at the two time points (M3 & M12). | M3 and M12 | 
| Best Response Rate during the study | Best disease response, assessment of response will be based on the International Workshop to Standardize Response criteria for NHL (Criteria for evaluation of response in Non-Hodgkin's lymphoma (Cheson, 1999)). The response rates will be described for each modality (CR, CRu, PR, SD and PD) and the Overall response rates (CR+CRu+PR) will also be described | M3 and M12 | 
| Time to Next Anti-Lymphoma Treatment (TTNLT) | time from randomization to the date of first documented administration of any new anti-lymphoma treatment (chemotherapy, radiotherapy, radio-immunotherapy, immunotherapy…). Patients continuing in response or who are lost to follow-up will be censored on their last visit date. Patients who died (due to any cause) before having received a new anti-lymphoma treatment will be included in the statistical analysis with death being counted as an event. | 5.5 years | 
| Molecular Response | Bcl-2-IgH rearrangement | M3 and M12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LNH, CD20+, follicular