E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diffuse large B-cell lymphoma (DLBCL) |
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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] - Cancer [C04] |
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 | 10012825 |
E.1.2 | Term | Diffuse large B-cell lymphoma stage III |
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012824 |
E.1.2 | Term | Diffuse large B-cell lymphoma stage II |
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012826 |
E.1.2 | Term | Diffuse large B-cell lymphoma stage IV |
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 |
Time to treatment failure from date of registration.
CNS relapse rate at 1,5 years. |
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E.2.2 | Secondary objectives of the trial |
Toxicity
Clinical response rate
Incidence of CNS relapse in CSF cytology neg/flow cytometry positive cases
Incidence of CNS relapse in a subgroup of patients with more than one extranodal site and elevated LDH
Progression free survival (3 years)
Overall survival (3 years)
Molecular predictors
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age ≥ 18 - < 65 years.
Histologically confirmed CD20+ diffuse large B-cell lymphoma based on WHO
2008 Lymphoma Classification
• Follicular lymphomas grade 3b is allowed
Patients in at least stage II with age adjusted IPI score of 2 or 3:
• Stage III /IV and elevated LDH
• Stage III/IV and WHO performance status 2 - 3
• Stage II and elevated LDH and WHO performance status 2 – 3
And/or patients with
• More than one extranodal site
• Testicular lymphoma, stage IIE and higher
• Paranasal sinus and orbital lymphoma with destruction of bone
• Large cell infiltration of the bone marrow
Previously untreated, except steroids allowed
WHO performance status 0-3
Written informed consent
• Patients with at least one of the following criteriae
o More than one extranodal site and elevated LDH
o Testicular lymphoma, stage IIE and higher
o Paranasal sinus and orbital lymphoma
o Large cell infiltration of the bone marrow
o Epidural lymphoma |
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E.4 | Principal exclusion criteria |
Severe cardiac disease: cardiac function grade 3-4
Impaired liver, renal or other organ function not caused by lymphoma, which will
interfere with the treatment schedule
Pregnancy/lactation
Men and women of reproductive potential not agreeing to use an acceptable method
of birth control during treatment and for six months after completion of treatment
Patients with other severe medical problems and with an expected short survival for
non-lymphoma reasons
Known HIV positivity
Uncontrolled infectious disease, including meningeal infection
Active cancer except basal cell carcinoma and cervical carcinoma in situ during the
last five years
Earlier treatment containing anthracyclins
Psychiatric or mental disorder which make the patient unable to give an informed
consent and/or adhere to the protocol
CNS disease as diagnosed by MRI or CSF cytology. Positive CSF flow cytometry
below diagnostic threshold level by cytology is allowed
Pleural or peritoneal fluid that cannot be drained safely
Conditions that may be compatible with impaired cerebrospinal fluid flow
Hypersensitity to the active substance or any of the other ingredients
Patients participating in other clinical studies, unless followed for survival |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Time to treatment failure
Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as 1 day.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After three cycles, after last cycle and four times per year for the first two years of follow-up. After that twice per year fot another three years of follow-up. |
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E.5.2 | Secondary end point(s) |
2. Overall survival (all causes of death)
The time from the registration date to the date of death. Patients still alive or lost to follow-up are censored at the last date they were known to be alive.
3. Disease free survival
The time from the first assessment within 2 months of completion of therapy that documents response to the date of disease progression. Otherwise, the patients are censored at the last date of follow up. Patients still alive in a CR or lost to follow-up are censored at the last date they were known to be alive. Patients who die due to causes other than NHL are censored at the date of death.
4. Cause of death
During the study and after its completion the cause of death will be registered according to the following cause-of-death criteria:
a. Lymphoma
b. Treatment toxicity
c. Secondary malignancy
d. Other disease not related to 1, 2 or 3
e. Other cause |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After three cycles, after last cycle and four times per year for the first two years of follow-up. After that twice per year fot another three years of follow-up. |
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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 | Yes |
E.6.3 | Therapy | Yes |
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 | No |
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) | No |
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 | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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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Treatment will last for 7 cycles x 14 days. All patients will be followed for 5 years. Primary endpoints will be received 1.5 years (CNS relapse rate) and 3 years (TTF) from registration. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |