E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
untreated advanced stage B-cell NHL or B-AL. |
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E.1.1.1 | Medical condition in easily understood language |
untreated advanced stage B-cell NHL or B-AL. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10006595 |
E.1.2 | Term | Burkitt'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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067194 |
E.1.2 | Term | Burkitt's leukemia |
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 |
Phase III study:
For the patients with advanced stage B-cell NHL/B-AL (stage III and LDH > Nx2, any stage IV or B-AL) to test whether adding 6 injections of rituximab to standard LMB chemotherapy regimen improves the EFS compared with LMB chemotherapy alone.
November 2015: the first interim analysis allowed to answer positively
Phase II study:
To determine the efficacy of DA-EPOCH-R in children and adolescent PMLB in terms of EFS.
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E.2.2 | Secondary objectives of the trial |
In Phase III and phase II studies:
-To study the complete remission (CR) rate and the overall survival (OS).
-To evaluate safety on all study arms: including toxic deaths, adverse events recorded using the NCI-CTC V4 (non haematological toxicity grade>3, infections grade 3 to 5), cardiac toxicity (CTC grade 2-5 and evolution of left ventricular ejection fraction and left ventricular shortening fraction), number of days with platelets transfusion, number of days with red cells transfusion, rituximab infusion reactions and intensive care unit admission.
-To study the rate of patients with Ig (IgM, IgA, IgG) level abnormally low and lymphocyte count abnormally low at 1 year and until 5-year follow-up, and to study the need for immunoglobuline infusions and levels of post (previous and re-)vaccination antibodies at 1 year.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
BIOLOGICAL STUDIES, especially MDD and MRD (the MDD/MRD will be based on the patients included in the study)
Parallel biological studies will be performed, for phase III on tumour cells, and/on characteristics of the patients which might modulate response to treatment with or without rituximab. These studies will not concern all the patients of the trial and will be organized by country, some studies being done in several countries altogether.
COST EFFECTIVENESS ANALYSIS (november 2015: this study is halted paralely to the halt of the randomization)
The aim of the economic study is to compare the cost-effectiveness ratio between two therapeutic strategies: chemotherapy with anti-CD20 antibody Rituximab (arm 2) versus chemotherapy without Rituximab (arm 1).
Pharmacokinetics (PK) analysis will be performed in some European centers on a subset of at least 30 patients from selected sites, which must include at least 15 patients in each of two age ranges; 3 to 11 years and 12 to 18 years of age and at least 4 in the range 6 months<3 years. Centers who will participate to this PK study will receive specific instructions for blood specimen collection, processing and shipping. Specific tubes to collect blood samples will be provided by Roche. |
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E.3 | Principal inclusion criteria |
HISTOLOGY AND STAGING DISEASE
Phase III study:
-Histologically or cytologically proven B-cell malignancies, either Burkitt lymphoma or B-AL (=Burkitt leukaemia = L3-AL) or diffuse large B-cell NHL or aggressive mature B-cell NHL non other specified or specifiable.
-Stage III with elevated LDH level (“B-high”), [LDH > twice the institutional upper limit of the adult normal values (> Nx2)] or any stage IV or B-AL.
Phase II study:
-Histolo-cytologically proven PMLBL.
-PMLBL without CNS involvement.
GENERAL CONDITIONS
-6 months to less than 18 years of age at the time of consent.
-Males and females of reproductive potential must agree to use an effective contraceptive method during the treatment, and after the end of treatment: during twelve months for women, taking into account the characteristics of rituximab and during five months for men, taking into account the characteristics of methotrexate.
INITIAL WORK-UP
-Complete initial work-up within 8 days prior to treatment.
OTHERS
-Able to comply with scheduled follow-up and with management of toxicity.
-Signed informed consent from patients and/or their parents or legal guardians.
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E.4 | Principal exclusion criteria |
-Follicular lymphoma, MALT and nodular marginal zone are not included into this therapeutic study.
-In phase II study (PMLBL) patients with CNS involvement are not eligible.
-Patients with congenital immunodeficiency, chromosomal breakage syndrome, prior organ transplantation, previous malignancy of any type, or known positive HIV serology.
-Evidence of pregnancy or lactation period.
-There will be no exclusion criteria based on organ function.
-Past or current anti-cancer treatment except corticosteroids during less than 7 days deviation in total .
-Tumor cell negative for CD20 (absence of result due to technical problems in the presence of other characteristics suggestive of BL/DLBCL, including genetic and phenotypic features, is not an exclusion criteria)
-Prior exposure to rituximab.
-Severe active viral infection, especially hepatitis B. Severe infection (such as sepsis, pneumonia, etc..) should be clinically controlled at the time of randomisation. Contact the national co-investigator for further advice if necessary.
- Hepatitis B carrier status history of HBV or positive serology
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E.5 End points |
E.5.1 | Primary end point(s) |
Minimum time to death from any cause, presence of viable cells in residue after 6th DA-EPOCH course, relapse, progressive disease, or second malignancy measured from randomization. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Survival (S): Time to death from any cause, measured from the time of randomization
- Complete Remission Rate at the assessment time
- For group B patients: response in 3 categories:
-CR at assessment time (after CYM1)
-slow responder = CR at CYVE2 but not after CYM1
-no CR
- Acute (at each course) and long term toxicity:
toxic deaths, adverse events of NCI-CTC V4 (non haematological toxicity grade>3, infections grade 3 to 5), cardiac toxicity (CTC grade 2-5 and abnormal left ventricular ejection fraction (LV-EF) or abnormal left ventricular shortening fraction (LV-SF)), number of platelets transfusion and of red cells transfusion, intensive care unit admission, rituximab infusion reactions.
According to the recommendations of several authors (Steinherz 1992, Kremer-Van Dalen 2006) the cardiotoxicity is defined as following:
LV-EF < 55 % or LV-SF <28% or a fall > 20 % of baseline for one of these two criteria.
- Immune reconstitution assessed by Ig (G, A and M) level and lymphocyte counts at 1 year and every year during follow-up until normal level, post vaccination antibody levels (tetanus, polio, diphtheria, haemophilus influenza and pneumococcus) and need for immunoglobulin infusion.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
it depends on the endpoints (see E.5.2) |
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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 | 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) | Yes |
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 | 35 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 170 |
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 |
Canada |
Hong Kong |
United States |
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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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Last visit of the last subject |
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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 | 10 |
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 | 10 |
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 |