E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CD20+ diffuse large B-cell lymphoma or CD20+ follicular non-Hodgkin’s lymphoma grade 1, 2 or 3a |
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E.1.1.1 | Medical condition in easily understood language |
follicular non-Hodgkin’s lymphoma and diffuse large B-cell lymphoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
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 |
The primary objective for this Study is as follows:
To evaluate the incidence of AARs following multiple doses of rituximab SC during Induction and/or Maintenance therapy in patients with CD20+ DLBCL or CD20+ follicular NHL, who have previously received at least one dose of rituximab IV.
AARs are defined as all AEs occurring within 24 hours of rituximab SC administration and which are considered related to Study drug. AARs include IIRRs, injection-site reactions, administration site conditions and all symptoms thereof. |
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E.2.2 | Secondary objectives of the trial |
•To evaluate the safety of rituximab SC
•To evaluate the efficacy of rituximab SC
•to evaluate the pharmacokinetic of rituximab SC: in FL and DLBCL patients:
-population PK parameter, effects of subject characteristics on the rituximab population PK parameters, effects of the covariates related to disease at baseline, interindividual variability,relationship of Ctrough (pre-dose concentration) over time and CR/CRu at 4-8 weeks after the last dose of Induction treatment (concentration defined over time trial), and only for DLBDL patients also rituximab exposures (concentration over time) during the 2 different scheduling of rituximab SC R-CHOP14 or R-CHOP 21
•Patient-reported outcome is measured using Rituximab Administration Satisfaction Questionnaire (RASQ-SC) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet the following criteria for Study entry:
1. Signed, written informed consent form
2. Age ≥ 18 and ≤ 80 years at time of enrolment
Rituximab – Roche S.p.A.
Protocol ML28881 (MABRELLA) - Version 1, 18 March 2013 45
3. Histologically confirmed, CD20+ DLBCL or CD20+ follicular NHL grade 1, 2 or 3a, according to the WHO classification system
4. Currently being treated with rituximab IV in the Induction or Maintenance setting, having received at least one full dose of rituximab IV, defined as standard full dose of rituximab IV 375 mg/m2 administered without interruption or early discontinuation because of tolerability issues
5. Expectation and current ability for the patient to receive at least four additional cycles of treatment during the Induction phase or six additional cycles of treatment during the Maintenance phase (patients with follicular NHL)
6. Induction only: An International Prognostic Index (IPI) score of 1-4 or IPI score of 0 with bulky disease, defined as one lesion ≥ 7.5 cm, or Follicular Lymphoma International Prognostic Index (FLIPI) (low, intermediate or high risk) (see Appendix 4)
7. Induction only: At least one bi-dimensionally measurable lesion defined as ≥ 1.5 cm in its largest dimension on computed tomography (CT) scan
8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 (see Appendix 4) |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from Study entry:
Cancer-Related Criteria
1. Transformed lymphoma or follicular lymphoma (FL) IIIB
2. Primary central nervous system lymphoma, histologic evidence of transformation to a Burkitt lymphoma, primary effusion lymphoma, primary mediastinal DLBCL, DLBCL of the testis, or primary cutaneous DLBCL
3. History of other malignancy that could affect compliance with the protocol or interpretation of results. This includes a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission without treatment for ≥ 5 years prior to dosing. Note: Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are eligible for the Study.
Prior or Concomitant Treatments
4. Ongoing corticosteroid use > 30 mg/day of prednisone or equivalent.
Note: (i) patients receiving corticosteroid treatment with ≤ 30 mg/day of prednisone or equivalent must be on a documented stable dose of at least 4 weeks duration prior to randomization; (ii) a pre-phase of high dose prednisolone (e.g. 100 mg/day for 3 to 5 days) is acceptable for patients with aggressive NHL.
Laboratory Assessments at Screening
5. Inadequate renal function, defined as:
- Creatinine > 1.5 times the upper limit of normal (ULN) (unless normal creatinine clearance), or calculated creatinine clearance < 40 mL/min (using the Cockcroft-Gault formula)
6. Inadequate hematologic function, defined as:
- Haemoglobin < 9 g/dL
- Absolute neutrophil count < 1.5 x 109/L
- Platelet count < 75 x 109/L
7. Inadequate hepatic function, defined as:
- Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN
- Total bilirubin ≥ 1.5 x ULN. Note: patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 x ULN
Other Prior or Current Medical Conditions or Treatments
8. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
9. For patients with DLBCL - Contraindication to any of the individual components of CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone), including prior receipt of anthracyclines
10. Other serious underlying medical conditions, which, in the Investigator‘s judgment, could impair the ability of the patient to participate in the Study (e.g., significant cardiovascular disease, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease)
11. Recent major surgery (within 4 weeks prior to dosing, other than for diagnosis
12. Active and/or severe bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics except if for tumour fever) within 4 weeks prior to dosing
13. Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (must be ruled out during screening):
- Positive test results for chronic hepatitis B infection (defined as positive HBsAg serology)
Patients with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody [HBcAb] and negative or positive HBsAg with HBV DNA undetectable) may be included. These patients must be followed closely.
Patients need to receive antiviral therapy according to the local clinical practice.
- Positive test results for hepatitis C (hepatitis C virus [HCV] antibody serology testing)
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
14. History of human immunodeficiency virus (HIV) seropositive status
General Criteria
15. Inability to provide informed consent and comply with protocol requirements.
16. Life expectancy of less than 6 months
17. Pregnant or breastfeeding patients. A negative serum pregnancy test is required for women of childbearing potential within 7 days prior to dosing or within 14 days if with a confirmatory urine pregnancy test within 7 days prior to dosing. Women of childbearing potential are defined as pre-menopausal women or women who are < 2 years after the onset of menopause and are not surgically sterile
18. Fertile men or women of childbearing potential who do not agree to use a highly effective measure of contraception (such as oral contraceptives, intrauterine device or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) throughout the Study and for at least 12 months after the last dose of rituximab. |
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E.5 End points |
E.5.1 | Primary end point(s) |
-safety endpoint:AARs, including IIRRs, AEs, AEs of grade ≥ 3, SAEs, routine laboratory parameters, vital signs, concomitant medications, premature withdrawal from the Study and from Study medication due to AEs and ECOG performance status.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint of safety endpoints: at every visit
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E.5.2 | Secondary end point(s) |
-efficay endpoint:the efficacy of rituximab SC will be evaluated during Induction and/or Maintenance in terms of EFS, PFS, CR/Cru, DFS and OS and will be analysed for the FAS and for the Per Protocol populations.
-PK endpoint: Descriptive statistics (mean, standard deviation, median and minimum and maximum values), will be computed for all PK parameters: Ctrough, AUC, Cmax, , and CL/F (clearance/fraction of absorbed drug).
-patient satisfaction outcome endpoint:Patient-assessed satisfaction will be evaluated using the Rituximab Administration Satisfaction Questionnaire (RASQ-SC). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint of efficacy enpoints: at baseline visit, final staging and end of study visit.
Timepoint of PK endpoints:
DLBCL patients:
Induction Collection timelines:
1.Baseline: pre-dose of rituximab SC administration
2.Cycle 7 – Day 1: pre-dose of rituximab SC administration
3.Cycle 7 – Day 7 (± 3 days)
4.Cycle 7 – Day 14 (± 3 days)
4.Cycle 8 – Day 1: pre-dose of rituximab SC administration
FL patients:
Induction Collection timelines:
1.Baseline: pre-dose of rituximab SC administration
2.Cycle 8 – Day 1: pre-dose of rituximab SC administration
Maintenance Collection timelines:
1.Baseline = pre-dose of rituximab SC administration
2.Cycle 12 – Day 1: pre-dose of rituximab SC administration
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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 | No |
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 | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Patient satisfaction outcome |
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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 | No |
E.8.1.1 | Randomised | No |
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 | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 40 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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 the Study is defined as the date when the last patient, last visit (LPLV) occurs. LPLV is expected to occur maximum 49 months after the last patient is enrolled; the study could be end in advance if there aren safety risks for the patients. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |