E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Previously untreated, CD20-positive follicular lymphoma (FL) grade 1-2, 3a |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067070 |
E.1.2 | Term | Follicular B-cell non-Hodgkin's lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061170 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Stage 1 • To estimate the ratio of trough serum concentrations of rituximab obtained at cycle 7, 21 days after subcutaneous administration to that obtained after intravenous administration (Ctrough, SC/Ctrough, IV during cycle 7 of induction treatment) Stage 2 • To estimate the overall response rate (ORR, comprising CR, CRu and PR) in each treatment arm at the end/completion of induction treatment. |
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E.2.2 | Secondary objectives of the trial |
Stage 1: To compare: • rituximab serum concentrations AUC (rituximab IV vs SC) during induction treatment • ORR of rituximab SC and IV given as part of induction treatment • To explore additional rituximab PK parameter during induction treatment Stage 1 and 2: To compare: • peripheral blood B-cell depletion and repletion after rituximab SC and IV treatment • CRR of rituximab SC and IV given as part of induction treatment • ORR and CRR of rituximab SC and IV at the end/completion of maintenance treatment • time-to-event related endpoints of rituximab SC and IV including (PFS, EFS and OS) • PK-related endpoints, the safety profile and the immunogenicity of rituximab SC and IV • To gather physician/ nurse opinions on resource savings and treatment convenience with rituximab SC compared with rituximab IV
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent and ability and willingness to comply with the visit schedule and assessments required by the protocol 2. Age ≥ 18 years 3. Histologically confirmed CD20-positive, follicular NHL grade 1, 2 or 3a, according to the WHO classification system. A tumor biopsy (lymph node, bone marrow, etc.) must have been performed within 6 months prior to screening with material available for central review. 4. No prior treatment. (Note that patients diagnosed in the past who had been on “watch and wait” can enter the trial if a tumor biopsy obtained within the last 6 months is available for central review) 5. Patients with at least one of the following signs and symptoms requiring treatment: a) Bulky disease defined as a nodal or extranodal (except spleen) mass ≥ 7 cm in its greatest diameter b) B-symptoms c) Elevated serum LDH or β2-microglobulin d) Involvement of at least 3 nodal sites (each with a diameter greater than 3 cm) e) Symptomatic spleen enlargement f) Compressive syndrome g) Pleura/peritoneal effusion 6. ECOG performance status of 0-2 7. Life expectancy of 6 months or more 8. Bi-dimensionally measurable disease (measurable by CT or MRI) 9. A negative serum pregnancy test 1 week prior to treatment must be available both for pre-menopausal women and for women who are less than 2 years after the onset of menopause, or within 14 days with a confirmatory urine pregnancy test within 1 week prior to study treatment start 10. Adequate hematological function within 28 days prior to randomization (unless related to lymphoma infiltration of the bone marrow): a) Hemoglobin (Hb) ≥ 8.0 g/dL (5 mmol/L) b) Absolute neutrophil count (ANC) ≥ 1.5 x 10exp9/L c) Platelet count ≥ 100 x 10exp9/L
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E.4 | Principal exclusion criteria |
1. Grade 3b follicular lymphoma 2. Transformation to high-grade lymphoma secondary to follicular lymphoma 3. Types of NHL other than follicular lymphoma according to the WHO classification 4. Presence or history of CNS disease (CNS lymphoma or lymphomatous meningitis) 5. Corticoid therapy during the last 4 weeks, unless the dose was below 20 mg/day prednisone equivalent 6. Presence or history of malignancies other than follicular lymphoma. (Patients with a history of curatively treated basal or squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are generally eligible. Any other cancer for which the patient has been in complete remission for at least 5 years are generally eligible) 7. Major surgery within 28 days prior to study entry (lymph node biopsy is not regarded to be a major surgery) 8. Pregnancy or nursing females 9. Fertile men or women of childbearing potential unless they agree to use effective contraception throughout the study and for at least 12 months after the last dose of rituximab 10. Any of the following abnormal laboratory values: a) Serum creatinine >2 mg/dL (197 μmol/L) b) Total bilirubin >1.5 times the upper limit of normal c) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal (or >5 times the upper limit of normal in the presence of liver involvement) 11. Active HBV or HCV infection or history of HBV infection (patients with serological evidence of current or past HBV exposure are excluded unless the serological findings are clearly due to vaccination) 12. Known HIV infection 13. Known active bacterial, viral, fungal or mycobacterial, or any major episode of infections requiring hospitalization or treatment with IV antibiotics within 4 weeks of start of study medication, or oral antibiotics within 2 weeks prior to start of study medication 14. History of organ transplantation including hematological stem cell transplantation 15. Uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of symptomatic bronchospasm) 16. Known hypersensitivity to murine products or any other study drugs or its ingredients 17. Current or recent treatment with another investigational drug or participation in another interventional clinical study within the 30 days prior study entry 18. Any other medical or psychological condition that contraindicates use of an investigational drug, that would preclude adequate collection of study data, or that would compromise the patient’s ability to give informed consent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Stage I: To estimate the ratio of trough serum concentrations of MabThera after subcutaneous administration to that obtained after intravenous administration Stage II: To estimate the overall response rate in each treatment arm at the end of induction treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage I: To estimate the ratio of trough serum concentrations of MabThera after subcutaneous administration to that obtained after intravenous administration [Time Frame: Day 21] Stage II: To estimate the overall response rate in each treatment arm at the end of induction treatment [Time Frame: Week 24 (Cycle 8)]
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E.5.2 | Secondary end point(s) |
1.) Stage I: To compare observed MabThera serum concentrations (MabThera intravenous vs. subcutaneous) during induction treatment given every 3 weeks [Time Frame: Week 24 (Cycle 8)] 2.) Stage I: To compare overall response rate of MabThera subcutaneous and MabThera intravenous given in combination with chemotherapy as induction treatment at the end/completion of induction treatment [Time Frame: Week 24 (Cycle 8)] 3.) Stage I: To explore additional MabThera pharmacokinetics parameter during induction treatment including, but not limited to, predicted pharmacokinetics parameter for induction regimens given every 4 weeks [Time Frame: Week 24 (Cycle 8)] 4.) To compare complete response rates of MabThera subcutaneous and MabThera intravenous given in combination with chemotherapy at the end/completion of the induction treatment [Time Frame: Week 24 (cycle 8)] 5.) To compare observed MabThera serum Ctrough levels during induction treatment [Time Frame: Week 24 (Cycle 8)] 6.) To compare observed MabThera serum Ctrough levels during maintenance treatment [Time Frame: 96 weeks] 7.) To compare overall response rate and complete response rate of MabThera subcutaneous and MabThera intravenous at the end/completion of maintenance treatment [Time Frame: 96 weeks] 8.) To compare peripheral blood B-cell depletion and repletion after MabThera subcutaneous and MabThera intravenous treatment [Time Frame: 96 weeks] 9.) To compare progression-free survival, event-free survival, overall survival of MabThera subcutaneous and MabThera intravenous when given in combination with chemotherapy during induction treatment followed by maintenance treatment as monotherapy [Time Frame: 96 weeks] 10.) To compare the immunogenicity of MabThera subcutaneous and MabThera intravenous [Time Frame: 96 weeks] 11.) To compare the safety profiles of MabThera subcutaneous and MabThera intravenous [Time Frame: 96 weeks] |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1.) [Time Frame: Week 24 (Cycle 8)] 2.) [Time Frame: Week 24 (Cycle 8)] 3.) [Time Frame: Week 24 (Cycle 8)] 4.) [Time Frame: Week 24 (cycle 8)] 5.) [Time Frame: Week 24 (Cycle 8)] 6.) [Time Frame: 96 weeks] 7.) [Time Frame: 96 weeks] 8.) [Time Frame: 96 weeks] 9.) [Time Frame: 96 weeks] 10.) [Time Frame: 96 weeks] 11.) [Time Frame: 96 weeks] |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 78 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Bosnia and Herzegovina |
Brazil |
Bulgaria |
Canada |
Colombia |
Croatia |
Denmark |
Finland |
France |
Georgia |
Germany |
Greece |
Italy |
Macedonia, the former Yugoslav Republic of |
Malaysia |
Mexico |
New Zealand |
Peru |
Romania |
Russian Federation |
Serbia |
Singapore |
Slovakia |
South Africa |
Spain |
Thailand |
Turkey |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is defined as the date of the last follow-up visit of the last patient in the follow up. This will occur approximately 54 months after the last patient enrolled has received the first study treatment, or sooner, if all patients have progressed, died or withdrawn from the study. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |