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 |
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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 |
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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 | 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 |
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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 |
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.
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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 |
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E.2.2 | Secondary objectives of the trial |
all
-progn val of pre-treatm PET with conv CT/MRT
-progn val of diff PET derived imaging biomarkers
-PET-based indivi treatm strategy in OPTIMAL>60 with fixed treatm strategy in RICOVER>60
-VCR-rel neurotox (Less Fav)&other tox (all)
-therap efficacy vit D subst by comparing the first pat w/o vit D subst with pat with vit D subst
-VCR rel neurotox &CNS events before/after A#4
- Comp Cheson, Lugano&RECIL resp crit
-Role of (M)TV
-progn value of pre- & post-prephase treatm ECOG, of ref path and plasma biomarkers
Fav pat:
Determ, if adding 2xChemo+inv-node RX can compensate for assumed worse progn of pat with pos PET after 4xR-Chemo compared to pat with neg PET after 4xR-Chemo. Comp of PET pos pat who receive 2additional R-Chemo+RX with those who do not.
Less Fav:
Determ whether assumed worse progn of pat with bulk PET-pos after CTX compared to pat with PET-neg bulk after CTX can be compensated by RX to PET-pos bulk. Comp of pat with pos PET with/without RX
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alle: Vergl progn Wert prätherap PET mit konv CT/MRT
-progn Wert. versch. PET abgeleiteter Biomarker
-Vergl.PET-bas indiv Therapiestrat OPTIMAL-Studie mit fixer Therapiestrat RICOVER-60
-VCR-ass Tox (Less Fav) u. sonst. Tox (alle)
-therap Stellenwert VitD-Substit durch Vergl Pat ohne/mit VitD-Subst
-VCR-ass. Tox, CNS-Events vor/nach A#4
-Cheson-, Lugano-& Recil-Resp Krit
-Rolle (M)TV
-progn Wert ECOG vor/nach Vorphase, refpath Biomarker, ctDNA
Fav: Prüfung, ob 2 zus Chemozyklen + inv-node RX die angenommene schlechtere Progn der Pat mit nach 4xR-Chemo pos PET im Vergl zur Progn von Pat mit neg PET kompensieren können. Vergl PET pos Pat, die zusätzlich 2x R-Chemo+RX erhalten mit PET pos Pat, die diese zusätzliche Therapie nicht erhalten
Less Fav: Prüf ob RX die angenommene schlechtere Progn der Pat mit nach CTX PET-pos Bulk im Vergl zu Pat mit PET-neg Bulk kompensieren kann sowie Vergl Therapieergebnisse Pat mit posttherap pos PET, die eine/keine Strahlentherapie erhalten |
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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 |
Cf. chapter 17 of the protocol:
1)Special investigations: rituximab and vincristine pharmacokinetics
Another goal of this study is the acquisition of pharmacokinetic data of the different rituximab application schedules as well as of vincristine.
Therefore, rituximab pharmacokinetic data will be obtained from 20 male and 20 female patients with less favourable patients treated with bi-weekly and optimised rituximab, respectively (i. e. 80 patients in total), irrespective of the type of vincristine given.
In addition, pharmacokinetic data of conventional and liposomal vincristine will be obtained in 5 male and 5 female patients with less favourable prognosis treated with conventional and liposomal vincristine, respectively in each of the 4 protocol arms (i.e. in 40 patients in total). ). The samples for pharmacokinetic data will be obtained 10 minutes before and 10 minutes after the end of the application of vincristine in cycle 1 . One additional sample will be obtained 12-24 hours after the application of vincristine in cycle 1 . At cycle 6 one sample will be taken 10 minutes before start of vincristine infusion. Even in case of any discontinuation of vincristine/Marqibo one serum sample should be taken before the application of chemotherapy in cycle 6. The schedule for the pharmacokinetic sampling must be strictly adhered to.
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. |
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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 |
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 |
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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.
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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 |
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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
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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). |
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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 |
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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. |
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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 |
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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
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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 | 11 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |