E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients aged 18-80 years with previously untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) |
|
E.1.1.1 | Medical condition in easily understood language |
previously untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 |
To estimate the efficacy in each treatment arm, as measured by complete response (CR) rate 4‒8 weeks after the end of treatment. |
|
E.2.2 | Secondary objectives of the trial |
• To compare patient satisfaction with rituximab administration (SC versus IV) in patients with DLBCL
• To evaluate event-free survival, disease-free survival, progression-free survival and overall survival from randomisation (at least 24 months of follow-up)
• To evaluate the safety of rituximab (SC versus IV) in patients with DLBCL. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age ≥ 18 and ≤ 80 years at time of study inclusion
• Histologically confirmed, previously untreated CD20-positive DLBCL according to the WHO classification system
• Patients with an IPI score of 1-5 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, PET-CT scan or MRI
• Adequate hematologic function described as: Haemoglobin ≥ 9 g/dL (Note: no transfusions allowed within 2 weeks prior to the
start of study drug administration), Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Platelet count ≥ 75 x 109/L
Note: Abnormalities outside the above listed are allowed if related to involvement of bone marrow by the underlying disease.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Agreement to use adequate contraception during the study treatment period and for at least 12 months after the last dose of study drug:
- For women of childbearing potential: agreement to use two adequate methods of contraception, including at least one method with a failure rate of < 1% per year (e.g., hormonal implants, combined oral contraceptives, vasectomized partner). Women of childbearing potential are defined as either pre-menopausal or women who are < 2 years after the onset of menopause and are not surgically sterile
- For men (unless vasectomized): agreement to use a barrier method of contraception |
|
E.4 | Principal exclusion criteria |
• Primary or secondary central nervous system lymphoma, blastic variant of mantle cell lymphoma, or histologic evidence of transformation to Burkitt lymphoma, primary mediastinal DLBCL, primary effusion lymphoma, primary cutaneous DLBCL, or primary DLBCL of the testis
• Transformed lymphoma or follicular lymphoma IIIB
• Prior therapy for DLBCL, with the exception of nodal biopsy or local irradiation
• History of other malignancy, except for curatively treated basal or squamous cell carcinoma or melanoma of the skin, carcinoma in situ of the cervix, or a malignancy that has been treated without curative intent and has been in remission without treatment for >/= 5 years prior to enrolment
• Inadequate renal function, defined as creatinine > 1.5 times the upper limit of normal (ULN) (unless creatinine clearance [CrCl] normal), or calculated CrCl < 30 mL/min (using the Cockcroft–Gault formula)
• Inadequate hepatic function, defined as any of the following abnormal laboratory values:
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x the ULN
- Alkaline phosphatase > 2.5 x the ULN
- Total bilirubin ≥ 1.5 x the ULN. (Patients with documented Gilbert disease may be enrolled if total bilirubin is ≤ 3.0 x the ULN.)
• Known human immunodeficiency virus (HIV) infection or HIV seropositive status
• 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 (related to the completion of the course of antibiotics except if for tumour fever) within 4 weeks prior to the start of study drug administration
• Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection (must be ruled out during screening). Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody (HBcAb) and negative or positive HBsAg with undetectable HBV deoxyribonucleic acid [DNA]) may be included but these patients must be followed closely. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) testing for HCV ribonucleic acid (RNA) is negative.
• 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)
• Recent major surgery (within 4 weeks prior to the start of study drug administration), other than for diagnostic purposes
• 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 priorreceipt of anthracyclines
• Prior treatment with cytotoxic drugs or rituximab for another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody
• Treatment with a monoclonal antibody within 3 months prior to the start of study drug administration
• Ongoing corticosteroid use at a dose of > 30 mg/day of prednisone or equivalent. The dose of corticosteroid treatment ≤ 30 mg/day of prednisone or equivalent must be stable for at least 4 weeks prior to the start of study drug administration. A pre-phase of high-dose prednisolone (e.g. 100 mg/day for 3 to 5 days) is acceptable for patients with aggressive NHL.
• Chemotherapy or other investigational therapy within 4 weeks prior to the start of study drug administration
• Inability to provide informed consent
• History of poor compliance during previous lines of therapy
• Life expectancy of less than 6 months
• A negative serum pregnancy test is required for women of childbearing potential within 7 days prior to the start of study drug administration or within 14 days if with a confirmatory urine pregnancy test within 7 days prior to the start of study drug administration. Women of childbearing potential are defined as either premenopausal or women who are < 2 years after the onset of menopause and are not surgically sterile |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of CR/CRu (measured from the day of first rituximab induction dose) will be based on the Investigator’s assessment, completed according to the International Working Group response criteria (Cheson et al. 1999) at the end of induction treatment. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of response rate will take place when all patients have completed their induction treatment. |
|
E.5.2 | Secondary end point(s) |
Event-free survival, disease-free survival, progression-free survival and overall survival (EFS, DFS, PFS and OS), patient reported outcomes, administration times and a summary of safety data. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
A preliminary analysis will be performed when all patients have completed their induction treatment.
The final analysis of secondary efficacy endpoints (EFS, DFS, PFS and OS) will be provided when the last patient has completed at least 24 months of follow-up after the end of induction treatment, or when one of the following has been documented for all randomized patients: disease recurrence, withdrawal from the study, loss to follow up or death, whichever occurs first.
|
|
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 | No |
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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 82 |
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 |
Algeria |
Argentina |
Belgium |
Brazil |
Bulgaria |
Canada |
Colombia |
Finland |
France |
Greece |
India |
Ireland |
Israel |
Italy |
Netherlands |
Peru |
Poland |
Portugal |
Russian Federation |
Saudi Arabia |
Serbia |
South Africa |
Spain |
Thailand |
Turkey |
Ukraine |
United Kingdom |
Venezuela, Bolivarian Republic of |
|
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
|
End of study is defined as the last patient last visit in the follow-up period. The study will end when all patients have been followed for at least 24 months after their last dose of study treatment, or earlier, if one of the following is documented for all treated patients: disease recurrence, withdrawal from the study, loss to follow up or death. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
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 |