| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse large B-cell lymphoma |
| Diffus-großzelliges B-Zell-Lymphom |
|
| E.1.1.1 | Medical condition in easily understood language |
| aggressive B-Cell Non-Hodgkin's Lymphoma |
| aggressives Non-Hodgkin Lymphom vom B-Zell Typ |
|
| 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 | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10005329 |
| E.1.2 | Term | Blood and lymphatic system disorders |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
Patients with less favourable prognosis:
1:To test whether progression-free survival (PFS) can be improved by substituting conventional by liposomal vincristine;
2:To test whether PFS can be improved by 12 optimised applications instead of 8 2-week applications of rituximab
Patients with favourable pro¬gnosis:
3:Comparison of neurotoxicity of conventional and liposomal vincristine;
4:Determination of PFS for the treatment strategy of reducing treatment in patients with negative FDG-PET after 4 x R-CHOP/CHLIP-14 (PET-4) and comparison with the corresponding patient population in RICOVER-60.
|
| bei Patienten mit weniger günstiger Prognose:1.Kann das progressionsfreie Überleben (PFS) durch Ersatz des konv.Vincristins (VCR) in der CHOP-Chemotherapie (CTX) durch lip.VCR verbessert werden? 2.lässt sich das PFS durch 12 optimierte Gaben des Antikörpers Rituximab (R) anstelle von 8 Gaben im Abstand von 2 Wochen in Kombination mit CHOP-14 oder CHLIP-14 CTX verbessern? b)bei Patienten mit günstiger Prognose:3.Vergleich der Neurotoxizität von konventionellem und liposomalem VCR 4.Bestimmung des PFS unter Reduktion der Therapie im Falle eines negativen FDG-PETnach 4x R-CHOP/CHLIP-14 und Vergleich mit der entsprechenden Patientenpopulation in RICOVER-60 |
|
| E.2.2 | Secondary objectives of the trial |
Comparison of the efficacy and toxicity of the individualised (post-induction therapy FDG-PET-based) treatment strategy in OPTIMAL>60 with the fixed (pre-defined) treatment strategy in RICOVER-60.
Estimation of the vincristine related neurotoxicity (less favourable patients only) and other toxicities in the favourable and less favourable group
Determination of the therapeutic efficacy of a vitamin D substitution comparing the first cohort of patients without vitamin D substitution with those patients who receive a vitamin D substitution. This shall be investigated for Vit D levels at baseline and longitudinally according to substitution and gender
Comparison of the vincristine related neurotoxicity before and after amendment
Comparison of CNS events before and after amendment #4 including toxicity
For further secondary objectives, please refer to chapter 16.1 of the protocol |
Vergleich der Wirksamkeit und Toxizität der individualisierten (FDG-PETbasierten)
Behandlungsstrategie nach der Induktionstherapie in
OPTIMAL>60 mit der festen (vordefinierten) Behandlungsstrategie in
RICOVER-60.
Abschätzung der Vincristin-bedingten Neurotoxizität (nur bei weniger
günstigen Patienten) und anderer Toxizitäten in der günstigen und
weniger günstigen Gruppe
Bestimmung der therapeutischen Wirksamkeit einer Vitamin-DSubstitution
im Vergleich zwischen der ersten Kohorte von Patienten
ohne Vitamin-D-Substitution und den Patienten, die eine Vitamin-DSubstitution
erhalten. Dies soll für den Vitamin-D-Spiegel bei
Studienbeginn und im Verlauf der Studie je nach Substitution und
Geschlecht untersucht werden.
Vergleich der vincristinbedingten Neurotoxizität vor und nach der
Amendment.
Vergleich der ZNS-Ereignisse vor und nach der Amendment #4,
einschließlich der Toxizität
Weitere sekundäre Ziele finden Sie in Kapitel 16.1 des Protokolls. |
|
| 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 |
Cf. chapter 17 of the protocol:
1) Rituximab pharmacokinetics
Another goal of this study is the acquisition of pharmacokinetic data of the different rituximab application schedules as well as of vincristine.
Please note: the recruitment for the Rituximab pharmacokinetic part is closed
Therefore, rituximab pharmacokinetic data will be obtained from about 20 male and about 20 female patients with less favourable patients treated with 2-week and optimised rituximab, respectively (i. e. to have about 80 analysable patients in total), irrespective of the type of vincristine given.
These analyses will not be performed in patients receiving HD-MTX.
Any pharmacokinetic studies will only be performed in centres with the necessary infrastructure after obtaining written informed consent from the patients.
2) Circulating lymphoma-derived DNA
Another goal of this study is the determinaton of circulating lymphoma derived DNA (ctDNA) in the blood of the patients randomised after Amendment #4. This “liquid biopsy” will be taken together with the necessary blood tests before each cycle of CHOP/CHLIP, at restaging after completion of therapy, and at each follow-up during the first two years after the end of treatment.
Any “liquid biopsy” will only be performed in patients after obtaining a seperate written informed consent. |
|
| E.3 | Principal inclusion criteria |
Elderly patients (61-80 years) with newly diagnosed aggressive CD20+ B-NHL. All risk groups with good general condition (ECOG 0-2) without majour accompanying diseases after patient's information and written patient's informed consent
Please note: only favourable patients (IPI = 1 (age)) without bulk can be included as recruitment goal for less favourable patients has been reached. |
Patienten im Alter von 61 bis 80 Jahren mit neu diagnostiziertem CD20-positivem aggressivem Lymphom aller Risikogruppen in gutem Allgemeinzustand (ECOG 0-2) ohne wesentliche Begleiterkrankungen nach Aufklärung und schriftlicher Einverständniserklärung
Bitte beachten Sie: Es können nur noch Patienten mit günstiger Prognose (IPI = 1 (Alter)) ohne Bulk eingeschlossen werden, da das Rekrutierungsziel für Patienten mit weniger günstiger Prognose bereits erreicht wurde. |
|
| E.4 | Principal exclusion criteria |
Already initiated lymphoma therapy ; Serious accompanying disorder or impaired organ function; Platelets <75 000/mm3, leukocytes <2 500/mm3; Known hypersensitivity to the medications to be used; Known HIV-positivity; Chronic active hepatitis; Poor patient compliance; Simultaneous participation in other treatment studies or in another clinical trial; Prior chemo- or radiotherapy, long-term use of corticosteroids or anti-neoplastic drugs for previous disorder; CNS involvement of lymphoma; Persistent neuropathy grade ≥2 (unless due to lymphoma involvement) ;Pregnancy or breast-feeding women Persons depending on sponsor or investigator
Persons from highly protected groups.
|
| Bereits begonnenen Behandlung des Lymphoms, schwerwiegende Begleiterkrankung; Thrombozyten <75 000/mm3, Leukozyten <2500/mm3, bekannte Allergie gegen eingesetzte Medikament, bekannte HIV-Positivität, chronisch aktive Hepatitis, schlechte Patienten-Compliance, gleichzeitige Teilnahme an anderen klinischen Prüfungen, frühere Chemo- oder Radiotherapie oder Langzeitgebrauch von Corticosteroiden oder Zytostatika bei früheren Erkrankungen, ZNS-Beteiligung des Lymphoms, Polyneuropathie Grad ≥2 (außer lymphomassoziiert), Schwangerschaft oder Stillzeit, vom Sponsor oder Prüfarzt abhängige Personen; sonstige unter besonderem Schutz stehende Personen |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Progression free survival.
PFS is defined by the time between the day of randomisation until one of the following events occurs, whichever comes first:
-Disease progression (PD)
-Relapse after achieving CR
-Progression after PR, NC or unknown
-Death due to any cause.
Patients who have not experienced an event at the time of analysis will be censored at the most recent date of disease assessment
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.11 of the protocol). |
|
| E.5.2 | Secondary end point(s) |
for efficacy: rate of complete remissions (CR rate), rate of partial responses (PR rate), rate of primary progressions, relapse rate, event-free survival (EFS) and overall survival (OS); rate and CTC grades of polyneuropathy.
Prognostic value of the FDG-PET derived imaging biomarkers for lymphoma load: SUV (standardized uptake value), SUR (standardized uptake ratio), metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUR-derived TLG (TLGSUR).
Different reference pathology biomarkers from tumor tissue and circulating tumor DNA in the plasma
for detailed information cf chapter 4.3.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| for efficacy and FDG-PET derived Imaging biomarkers: during the restagings and the follow-up assessments as planned in the protocol (cf. chapter 8.11 of the protocol). The incidence and rates of polyneuropathy will additionally be assessed before each cycle of chemotherapy. Assessment of ctDNA: before each cycle of CHOP/CHLIP, at restaging after completion of therapy, and at each follow-up during the first two years after the end of treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| 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 | 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) | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Vergleichspräparat für Marqibo (liposomales Vincristin) ist konventionelles Vincristin |
| Comparator fo Marqibo (liposomal vincristine) is conventional vincristine |
|
| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 130 |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 4 |
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