CD20+ Aggressive B-Cell LymphomaPhase 3OPTIMAL>60NCT01478542
OPTIMAL>60 / DR. CHOP, Improvement of Therapy of Elderly Patients with CD20+ DLBCL Using Rituximab Optimized and Liposomal Vincristine
A Phase 3 study testing Conventional Vincristine, Liposomal Vincristine and Ricover-scheme rituximab in people with CD20+ Aggressive B-Cell Lymphoma, run by Universität des Saarlandes at 127 sites in Germany.
Trial summary
The purpose of this study is to improve the outcome of elderly patients with CD20-Aggressive B-Cell Lymphoma and to reduce the toxicity of standard used Immuno-Chemotherapy by using an optimised schedule of the monoclonal antibody Rituximab, substituting conventional by Liposomal Vincristine and by a PET-guided… Read more about this study
- Who is it for?
- Ages 61 to 80 years
- Conditions the study is for
- CD20+ Aggressive B-Cell Lymphoma
- What is being tested?
- Conventional Vincristine, Liposomal Vincristine and Ricover-scheme rituximab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,152 participants
- Where
- 127 sitesGermany
- Study dates
- Nov 2011to 18 Jan 2024
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 61 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Age: 61-80 years
- All risk groups (IPI 1-5)
- Diagnosis of aggressive CD20+ B-NHL, based on an excisional biopsy of a lymph node or on an appropriate sample of a lymph node or of an extranodal involvement. It will be possible to treat the following entities in this study as defined by the new WHO classification of 200870:
- B-NHL:
- Foll. lymphoma grade IIIb
- DLBCL, not otherwise specified (NOS)
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- common morphologic variants:
- centroblastic
- immunoblastic
- anaplastic
- rare morphologic variants
- DLBCL subtypes/entities:
- T-cell/histiocyte-rich large B-cell lymphoma
- primary cutaneous DLBCL, leg type
- EBV-pos. DLBCL of the elderly
- DLBCL associated with chronic inflammation
- primary mediastinal (thymic) LBCL
- intravascular large B-cell-lymphoma
- ALK-positive large B-cell-lymphoma
- plasmoblastic lymphoma
- primary effusion lymphoma
- transformed indolent lymphoma secondary or simultaneous high grade B-cell-lymphoma
- B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
- B-cell lymphoma, unclassifiable, with features intermediate between DLCBL and Hodgkin lymphoma
- Performance status ECOG 0 - 2 after prephase treatment. The performance status of each patient must be assessed before the initiation and after the end of prephase treatment which, as experience has shown, can result in a significant improvement of the patient's performance status. The pre-treatment performance status which can range from ECOG 0 to ECOG 4 must be documented in the Staging CRF (see ISF); the performance status after the prephase treatment must be documented in the respective Prephase Treatment CRF (PT form: see ISF). A definition of the performance status is provided in Appendix 28.10.
- Written informed consent of the patient
- Contract of participation signed by the study centre and sponsor
Who cannot join
- Already initiated lymphoma therapy (except for the prephase treatment)
- Serious accompanying disorder or impaired organ function (except when due to lymphoma involvement), in particular:
- heart: angina pectoris CCS >2, cardiac failure e.g. NYHA >2 and/or EF <50% or FS<25% in nuclear medicine examination/echocardiography
- lungs: if respiratory problems are suspected the patient is to be excluded if the resultant pulmonary function test shows FeV1<50% or a diffusion capacity <50% of the reference values
- kidneys: creatinine >2 times the upper reference limit
- liver: bilirubin >2 times the upper reference limit, aspartate transaminase (AST, SGOT) or alanine transaminase (ALT, SGPT) >3 x institutional upper reference limit
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- uncontrollable diabetes mellitus (prephase treatment with predniso[lo]ne!)
- Platelets <75 000/mm3, leukocytes <2 500/mm3 (if not due to lymphoma)
- Known hypersensitivity to the medications to be used
- Known HIV-positivity
- Patients with severe impairment of immune defense
- Patients with constipation with imminent risk of ileus
- Chronic active hepatitis
- Poor patient compliance
- Simultaneous participation in other treatment studies or in another clinical trial within the last 6 months
- Prior chemo- or radiotherapy, long-term use of corticosteroids or anti-neoplastic drugs for previous disorder
- Other concomitant tumour disease and/or tumour disease in the past 5 years (except for localised skin tumors other than melanoma and carcinomas in situ of any other origin)
- CNS involvement of lymphoma (intracerebral, meningeal, intraspinal intradural) or primary CNS lymphoma
- Persistent neuropathy grade ≥2 (NCI CTC-AE v4.03) (unless due to lymphoma involvement)
- History of persistent active neurologic disorders grade >2 including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition
- Pregnancy or breast-feeding women
- Active serious infections not controlled by oral and/or intravenous antibiotics or anti-fungal medication
- Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.
- MALT lymphoma
- Non-conformity to eligibility criteria
- Persons not able to understand the impact, nature, risks and consequences of the trial (including language barrier)
- Persons not agreeing to the transmission of their pseudonymous data
- Persons depending on sponsor or investigator
- Persons from highly protected groups. Pts. with CNS lymphoma should not be included in this study.
Trial locations and contacts
127 sites in 1 country.
127 sites in 1 country
Germany127 sites
Klinik für Hämatologie und Onkologie
Aachen, 52074
Innklinikum Altötting
Altötting, 84503
Klinikum St. Marien Amberg, MVZ
Amberg
Klinikum Augsburg, Medizinische Klinik II
Augsburg
Praxis Dres. med. Brudler, Heinrich, Bangerter
Augsburg
Gemeinschaftspraxis Dres. Reichert, Janssen
Aurich
Helios Klinikum Bad Saarow, Klinik für Innere Medizin III
Bad Saarow
Sozialstiftung Bamberg, Med. Klinik V
Bamberg
Klinikum Bayreuth, Medizinische Klinik IV
Bayreuth
Charité- Universitätsmedizin Berlin, Campus Benjamin Franklin, Med. Klinik III
Berlin
Knappschaftskrankenhaus Bochum
Bochum
Johanniter Krankenhaus Bonn, Abteilung für Innere Medizin I
Bonn
Universitätsklinikum Bonn, Med. Klinik III
Bonn
Städt. Klinikum Brandenburg, Med. Klinik II
Brandenburg
Evangelisches Diakonie-Krankenhaus Bremen
Bremen
Praxis Dr. Obst
Burgwedel
Praxis Dr. Marquard
Celle
Klinikum Chemnitz, Innere Medizin III
Chemnitz
Klinikum Coburg, V. Med. Klinik
Coburg
Schwerpunktpraxis Dres. Glados/Retzlaff/Zühlsdorf/Deuticke
Coesfeld
Gemeinschaftspraxis Dres. Schmitz, Steinmetz, Severin
Cologne
Klinikum der Universität zu Köln, Klinik I für Innere Medizin
Cologne
Krankenhaus Holweide
Cologne
St. Johannes Hospital Dortmund, Med. Klinik II
Dortmund
BAG Freiberg-Richter, Jacobasch, Wolf, Illmer
Dresden
Gemeinschaftspraxis Dres. Mohm, Prange-Krex
Dresden
Universitätsklinikum Erlangen, Med. Klinik 5
Erlangen
St.-Antonius-Hospital Eschweiler, Hämatologie und Onkologie
Eschweiler
Klinikum Esslingen, Klinik für Gastroenterologie, Onkologie und Innere Medizin
Esslingen am Neckar
Klinikum der J.W. Goethe-Universität Frankfurt, Hämatologie/Onkologie
Frankfurt
Krankenhaus Nordwest Frankfurt, II. Med. Klinik
Frankfurt
Klinikum Frankfurt (Oder), Abteilung f. Innere Medizin
Frankfurt (Oder)
Praxis Dr. med. Reiber
Freiburg im Breisgau
Universitätsklinikum Freiburg, Innere Medizin I
Freiburg im Breisgau
Klinikum Fulda, Med. Klinik III
Fulda
St. Josef-Hospital Gelsenkirchen, Onkologie und Hämatologie
Gelsenkirchen
Praxis Dr. med. Schliesser
Giessen
Wilhelm-Anton-Hospital Goch, Innere Medizin
Goch
Onkologische Kooperation Harz, Onkologische Schwerpunktpraxis
Goslar
Universitätsmedizin Göttingen, Hämatologie und Onkologie
Göttingen
Universitätsmedizin Greifswald, Medizinische Universitätsklinik C, Hämatologie und Onkologie
Greifswald
Kreiskrankenhaus Gummersbach
Gummersbach
Klinikum Gütersloh
Gütersloh
Kath. Krankenhaus Hagen, St.-Marien-Hospital
Hagen
Gemeinschaftspraxis Rohrberg, Hurtz, Schmidt, Frank-Gleich
Halle
Asklepios Klinik St. Georg, Hämatologie/Onkologie
Hamburg
Hämatolog.-onkolog. Praxis Dres. Müller-Hagen, Bertram, Albertinen-Krankenhaus
Hamburg
Hämatologisch-onkologische Praxis Altona (HOPA)
Hamburg
Universitätsklinikum Hamburg-Eppendorf (UKE), II. Med. Klinik und Poliklinik, Onkologie und Hämatologie
Hamburg
Klinikum Hannover-Siloah, Klinik für Hämatologie
Hanover
Medizinische Hochschule Hannover (MHH), Zentrum für Innere Medizin, Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
Hanover
Praxis MediProjekt
Hanover
Universitätsklinikum Heidelberg, Innere Medizin V
Heidelberg
Klinikum Kreis Herford, Med. Klinik II
Herford
Onkologische Schwerpunktpraxis Dres. Freier, Sievers
Hildesheim
St. Bernward Krankenhaus Hildesheim, Med. Klinik II
Hildesheim
Saarland University Hospital
Homburg, Saarland, 66421
KMT Klinik Idar-Oberstein
Idar-Oberstein
Universitätsklinikum Jena, Klinik für Innere Medizin II
Jena
Westpfalz-Klinikum, Klinik für Innere Medizin I
Kaiserslautern, 67655
Praxis Dres Hansen, Reeb
Kaiserslautern
St. Vincentius Kliniken Karlsruhe, Med. Klinik Abt. 2
Karlsruhe
Städtisches Klinikum Karlsruhe, II. Med. Klinik, Hämatologie/Onkologie/Infektionskrankheiten
Karlsruhe
GMP Dres Siehl, Söling
Kassel
Rotes Kreuz Krankenhaus Kassel, Klinik für Interdisziplinäre Onkologie
Kassel
Klinikum Kempten-Oberallgäu, Hämatologie, Onkologie und Palliativmedizin
Kempten
Gemeinschaftsklinikum Mittelrhein, Ev. Stift St. Martin, Innere Medizin
Koblenz
Gemeinschaftspraxis Dres. Neise, Lollert
Krefeld
Praxis Dr. Strauch
Kronach
Klinikum Landshut, Med. Klinik I
Landshut
Caritas Krankenhaus Lebach
Lebach
Onkologische Schwerpunktpraxis
Leer
Klinikum St. Georg Leipzig, Abteilung für internistische Onkologie/Hämatologie
Leipzig
Klinikum Lippe-Lemgo, Med. Klinik II
Lemgo
Onkologische Schwerpunktpraxis Lörrach
Loerrach
Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Lübeck
Klinikum Magdeburg, Hämatologie/Onkologie
Magdeburg
Universitätsmedizin Mainz, III. Med. Klinik und Poliklinik
Mainz
Mannheimer Onkologie Praxis, Dres. Brust, Plöger, Schuster, Hensel
Mannheim
Universitätsklinikum Gießen und Marburg
Marburg
Johannes Wesling Klinikum, Klinik für Hämatologie, Onkologie und Palliativmedizin
Minden
Kliniken Maria-Hilf Mönchengladbach, Innere Medizin I
Mönchengladbach
GMP Dres Schröder/Sieg
Mülheim
Klinikum Großhadern, Med. Klinik 3
München
Klinikum rechts der Isar der Technischen Universität München, III. Med.Klinik
München
Städtisches Klinikum München Harlaching
München
Praxis Dres. Schmidt, Fromm, Wiesmeier, Seufert, Klapthor, Zingerle
München Pasing
Universitätsklinikum Münster, Med. Klinik A
Münster
Stauferklinikum Schwäbisch Gmünd, Zentrum für Innere Medizin
Mutlangen
Onkologische Praxis Dr. Ladda
Neumarkt
Lukaskrankenhaus Neuss, Med. Klinik II
Neuss
Kreiskliniken Esslingen, Klinikum Kirchheim-Nürtingen, Hämatologie, Internist. Onkologie und Palliativmedizin
Nürtingen
Gemeinschaftspraxis Dres. Balló, Böck
Offenbach
Ortenau Klinikum Offenburg-Gegenbach, Medizinische Klinik II
Offenburg
Klinikum Oldenburg, Hämatologie/Onkologie
Oldenburg
Onkologische Schwerpunktpraxis Dr. Hübner
Oldenburg
Pius Hospital Oldenburg, Klinik für Strahlentherapie und Internistische Onkologie
Oldenburg
Onkologische Schwerpunktpraxis im MVZ 2 GmbH, Dr. H. Eimermacher
Olpe
Klinikum Osnabrück, Med. Klinik III
Osnabrück
Paracelsus Krankenhaus Ruit, Kreiskliniken Esslingen gGmbH, Zentrum für Allgemeine Innere Medizin
Ostfildern
Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie
Paderborn
Gemeinschaftspraxis Dres. Baake, Leonhardt, Moegling, am Regio Klinikum Pinneberg
Pinneberg
Klinikum Ernst von Bergmann, Klinik für Hämatologie, Onkologie und Palliativmedizin
Potsdam
Gemeinschaftspraxis Dres. Decker, Nonnenbroich, Herbrik-Zipp
Ravensburg
Prosper-Hospital Recklinghausen, Med. Klinik I
Recklinghausen
Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie
Regensburg
Klinikum am Steinenberg, Kreiskliniken Reutlingen GmbH
Reutlingen
Elblandklinikum Riesa, Klinik für Innere Medizin II
Riesa
Klinikum Südstadt Rostock, Innere Medizin
Rostock
Universitätsklinikum Rostock, Abteilung Hämatologie/Onkologie, Klinik u. Poliklinik für Innere Medizin
Rostock
GMP Dres Jacobs, Daus, Schmits
Saarbrücken
ZAHO-Siegburg, Zentrum für ambulante Hämatologie und Onkologie Siegburg
Siegburg
Diakonie-Klinikum Stuttgart, Med. Klinik II
Stuttgart
Klinikum Traunstein, Hämatologie/Onkologie
Traunstein
Klinikum Mutterhaus der Borromäerinnen, Med. Abteilung I
Trier
Krankenhaus der Barmherzigen Brüder Trier, I. Med. Abteilung
Trier
Universitätsklinikum Tübingen, Medizinische Klinik und Poliklinik, Onkologie, Hämatologie, Immunologie und Rheumatologie
Tübingen
Universitätsklinikum Ulm, Innere Medizin III
Ulm
Katharinen Hospital Unna
Unna
Schwarzwald-Baar-Klinikum - Innere Medizin II
Villingen-Schwenningen, 78052
Praxis Onkologie Schwarzwald - Alb
Villingen-Schwenningen
Med. Versorgungszentrum Weiden, Abteilung für Onkologie
Weiden
Praxis Dres med. Perker, Sandherr
Weilheim
HSK Wiesbaden, Innere Medizin III
Wiesbaden
Evangelisches Krankenhaus Paul Gerhardt Stift, Klinik für Innere Medizin II
Wittenberg, Saxony-Anhalt, 06886
Helios Klinkum Wuppertal, Med. Klinik I
Wuppertal
Hämatologisch-Onkologische Praxis Würselen
Würselen
About this study
Official title: Improvement of Outcome and Reduction of Toxicity in Elderly Patients with CD20+ Aggressive B-Cell Lymphoma by an Optimised Schedule of the Monoclonal Antibody Rituximab, Substitution of Conventional by Liposomal Vincristine, and FDG-PET Based Reduction of Therapy in Combination with Vitamin D Substitution
The purpose of this study is to improve the outcome of elderly patients with CD20-Aggressive B-Cell Lymphoma and to reduce the toxicity of standard used Immuno-Chemotherapy by using an optimised schedule of the monoclonal antibody Rituximab, substituting conventional by Liposomal Vincristine and by a PET-guided reduction of therapy in Combination with Vitamin D Substitution.
Read the detailed description
Primary objective of study:
"OPTIMAL>60 Less Favourable" Patients with less favourable prognosis: To test whether progression-free survival (PFS) can be improved by substituting conventional by liposomal vincristine; To test whether PFS can be improved by 12 optimised applications instead of 8 2-week applications of rituximab.
"OPTIMAL>60 Favourable": Patients with favourable prognosis: Comparison of neurotoxicity of conventional and liposomal vincristine; 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.
Secondary objectives: "OPTIMAL>60 Favourable" and "OPTIMAL>60 Less Favourable":
Comparison of the prognostic value of a pre-treatment FDG-PET (PET-0) with conventional CT/MRT.
Prospective evaluation on the role of (metabolic) tumor volume to confirm or refuse the hypothesis that optimized rituximab should improve the outcome of patients with a high (metabolic) tumor volume more than that of patients with low MTV and to analyse the substitution of conventional vincristine by liposomal. • Estimation of the vincristine-related neurotoxicity ("OPTIMAL>60 Less Favourable only, since vincristine related neurotoxicity is primary objective of the study in favourable patients") and other toxicities (all patients).
Determination of the therapeutic efficacy of a vitamin D substitution.
Comparison of the FDG-PET-based individualised treatment strategy in OPTIMAL>60 with the fixed (pre-defined) treatment strategy in RICOVER>60.
Investigation of the prognostic value of different FDG-PET derived imaging biomarkers for lymphoma load (SUV, MTV, TLG).
Comparison of the vincristine related neurotoxicity before and after amendment 4.
Comparison of CNS events before and after amendment 4. Comparison of the Cheson, Lugano and RECIL response criteria. Prospective evaluation of the improvement of the prognostic value of ECOG performance status during prephase treatment.
Prospective evaluation of reference pathology biomarkes. Prospective evaluation of circulating tumor DNA (ctDNA), correlation and comparison with PET.
Prospective evaluation of the role of 2 additional cycles of CHOP/CHLIP-14 and involved node radiotherapy in PET-positive patients after 4xR-CHOP/CHLIP-14 in favourable patients.
Evaluation of the role of radiotherapy to PET-positive bulky disease patients after 6xR-CHOP/CHLIP-14 in less favourable patients.
Quality assurance of the performed radiotherapy, including in in-field and outfield relapses.
Investigation of the effect of cross-site ComBat harmonization. Analysis of FDG-PET derived biomarkers in combination with clinical and laboratory variables as distance of lesions and Ann-Arbor stage.
Estimation of the prognostic value of a pre-treatment FDG-PET (PET-0) compared to conventional imaging with CT/MRT.
Prospective evaluation of the prediction of the probability of time-to-progression (TTP) within 2 years by a convolutional neural network trained to analyze maximum intensity projection images from baseline PET.
Analysis regarding molecular subtype, transcriptomics, methylome analysis, spatious analysis of interaction of tumor cells and microenvironment by cyTOF, 3D-morphology (AI-based) or similar techniques, viruses (EBV, HHV6, HHV7), micro-RNA in tumor samples.
Analysis of ctDNA analysis by i) digital droplet PCR, ii) e.g. CAPP or similar methods and iii) methylome analysis as prognostic and predictive marker and comparison with imaging biomarkers.
Analysis special focus on refractory, relapsed courses (including specific patterns of relapse regarding location and time) compared to matched controls and regarding comparison with imaging biomarkers.
Analysis of specific BCR-antigens of aggressive B-NHL as Ars2, SAMD14/neurabin-I in tissue and blood. of initial samples of cases with refractory, relapsing course (including specific patterns of relapse regarding location and time).
Analysis of factors influencing immune effector cells e.g.KIR2DS1 and homozygous HLA-C2, PRF1 A91V or other fHLH variants and prognostic and predictive markers in comparison to RICOVER-60.
Investigation of possible prognostic, or predictive markers of treatment related toxicity as: Neurofilament light chain (NfL) to estimate vincristine-related neurotoxicity, or as clonal hematopoiesis with indeterminate potential (CHIP) and association with cardiovascular events.
Investigation of specific concomitant medication and possible impact on outcome.
Investigation of the efficacy of the modified mandatory infectious prophylaxis OPTIMAL compared to the RICOVER trial with a focus on mandatory chinolon prophylaxis.
Investigation of COVID-19-reated events Impact of interval of diagnosis to time to treatment. Comparison with similar patient populations treated in real-world or prospective clinical trials.
Analysis of EFS and PFS at 24 months (EFS24/PFS24) and its impact on subsequent outcome.
- Conditions
- CD20+ Aggressive B-Cell Lymphoma
- Being tested
- Conventional Vincristine, Liposomal Vincristine, Ricover-scheme rituximab, optimised rituximab-schedule
- Keywords
- DLBCL, Liposomal Vincristine (Marqibo), Optimised Rituximab, Toxicity, Elderly Patients, FDG-PET, Bulky Disease, Radiation, age >60 years, First line Therapy, Vitamin D
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Conventional VincristineDrug
Liposomal VincristineDrug
Ricover-scheme rituximabDrug
optimised rituximab-scheduleDrug
| Study group | Role | What they receive |
|---|---|---|
| Favourable Prognosis F-A - Recruitment completed | Active comparator | Induction therapy with 4 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHOP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy. Receives: Drug: Conventional Vincristine |
| Favourable F-B - Arm Closed | Experimental | Induction therapy with 4 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,4 mg/sqm (max. 2mg absolute), Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHLIP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy. Receives: Drug: Liposomal Vincristine |
| Less Favourable LF-A - Recruitment completed | Active comparator | Induction therapy with 6 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHOP-14 an interim restaging will be performed. Receives: Drug: Conventional Vincristine; Drug: Ricover-scheme rituximab |
| Less Favourable LF-B - Recruitment completed | Experimental | Induction therapy with 6 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHLIP-14 an interim restaging will be performed. Recruitment completed. Receives: Drug: Liposomal Vincristine; Drug: Ricover-scheme rituximab |
| Less Favourable LF-C - Recruitment completed | Experimental | Induction therapy with 6 cycles of CHOP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) combined with an optimized Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHOP-14 an interim restaging will be performed. Recruitment completed. Receives: Drug: Conventional Vincristine; Drug: optimised rituximab-schedule |
| Less Favourable LF-D - Recruitment completed | Experimental | Induction therapy with 6 cycles of CHLIP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) combined with an optimised Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHLIP-14 an interim restaging will be performed. Recruitment completed. Receives: Drug: Liposomal Vincristine; Drug: optimised rituximab-schedule |
What is being measured
The primary outcome is the main question the study is designed to answer.
Progression-free survival
"OPTIMAL>60 Less Favourable": To test the effects of substitution of conventional by liposomal vincristine and of a 2-week applications of 8x rituximab by an optimised application of 12 x rituximab stratified log rank tests will be performed for each question (stratified for IPI-factors). Proportional hazard models will be used to investigate treatment interaction and to obtain estimates for the single treatment effects (HR) adjusting for the IPI-factors.
"OPTIMAL>60 Favourable" Grade of neurotoxicity will be estimated and indicated with a 95% confidence interval (CI) separated to each type of vincristine. To investigate the 3-year PFS with 95% CI the Kaplan-Meier estimator will be used.
Measured: 9 years
Secondary outcomes (1)
for efficacy: CR-rate, PR-rate, rate of primary progressions, relapse rate, EFS and OS; rate and CTC grades of PNP. Prognostic value of the FDG-PET derived imaging biomarkers for lymphoma load: SUV, MTV, TLG.
Secondary endpoints: To analyze how (i. e. in which direction) and how often a pre-treatment FDG-PET-based assignment (PET-0) would have affected the assignment of a patient to a different stage, IPI risk group or treatment, respectively. The different FDG-PET derived imaging biomarkers for lymphoma load (SUV, MTV, TLG) will be analyzed for their relationship with CR-rate, PR-rate, rate of primary progressions, relapse rate, EFS, PFS and OS.
To compare the efficacy and side effects of the (post-induction therapy FDG-PET-based) individualised treatment strategy in OPTIMAL>60 with the fixed (pre-defined) treatment strategy in RICOVER-60.
Rates and grades of polyneuropathy will be determined according to CTC-v4.03. Comparison of the patients without vitamin-D-substitution with patients receiving a vitamin-D-substitution.
Measured: 9 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Nov 2011 (estimated)
- Study startNov 2011
- Primary completion18 Jan 2024
- Study completion18 Jan 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for CD20+ Aggressive B-Cell LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Enrolment
- 1,152 participants (actual)
Sponsor and investigators
- Lead sponsor
- Universität des Saarlandes
- Sponsor type
- University, hospital or other
- Collaborators
- German High-Grade Non-Hodgkin's Lymphoma Study Group, Spectrum Pharmaceuticals, Inc
- Responsible party
- Sponsor
- Investigators
- Lorenz Thurner, Professor, Principal investigator, Saarland University, Saarland University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01478542
- Sponsor's protocol ID
- DSHNHL 2009-1
- Acronym
- OPTIMAL>60
- Status last verified
- Jan 2025
- First submitted
- 18 Nov 2011
- Last updated
- 8 Jan 2025
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Pfreundschuh, M., Christofyllakis, K., Altmann, B., Ziepert, M., Haenel, M., Viardot, A., Neubauer, A., Held, G., Truemper, L., Dreyling, M., Kanz, L., Hallek, M., Schmitz, N., Heintges, T., Kölbel, C., Buecker, A., Ruebe, C., Hellwig, D., Berdel, C., Poeschel, V., and Murawski, N. (2017) Radiotherapy to bulky disease PET-negative after immunochemotherapy in elderly DLBCL patients: Results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL. Hematological Oncology, 35( S2): 129- 130. doi: 10.1002/hon.2437_119.
Kaddu-Mulindwa D, Altmann B, Held G, Angel S, Stilgenbauer S, Thurner L, Bewarder M, Schwier M, Pfreundschuh M, Loffler M, Menhart K, Grosse J, Ziepert M, Herrmann K, Duhrsen U, Huttmann A, Barbato F, Poeschel V, Hellwig D. FDG PET/CT to detect bone marrow involvement in the initial staging of patients with aggressive non-Hodgkin lymphoma: results from the prospective, multicenter PETAL and OPTIMAL>60 trials. Eur J Nucl Med Mol Imaging. 2021 Oct;48(11):3550-3559. doi: 10.1007/s00259-021-05348-6. Epub 2021 Apr 29.
PubMed 33928400
Study at a glance
From the registry record, last updated by the sponsor on 8 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Improvement of Outcome and Reduction of Toxicity in Elderly Patients with CD20+ Aggressive B-Cell Lymphoma by an Optimised Schedule of the Monoclonal Antibody Rituximab, Substitution of Conventional by Liposomal Vincristine, and FDG-PET Based Reduction of Therapy in Combination with Vitamin D Substitution
- ClinicalTrials.gov ID
- NCT01478542
- Acronym / sponsor ID
- OPTIMAL>60 / DSHNHL 2009-1
- Conditions
- CD20+ Aggressive B-Cell Lymphoma
- Keywords
- DLBCL, Liposomal Vincristine (Marqibo), Optimised Rituximab, Toxicity, Elderly Patients, FDG-PET, Bulky Disease, Radiation
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,152 participants (actual)
- Lead sponsor
- Universität des SaarlandesUniversity, hospital or other
- Collaborators
- German High-Grade Non-Hodgkin's Lymphoma Study Group, Spectrum Pharmaceuticals, Inc
- Study start
- Nov 2011
- Primary completion
- 18 Jan 2024 (actual)
- Study completion
- 18 Jan 2024 (actual)
- First posted
- 23 Nov 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to improve the outcome of elderly patients with CD20-Aggressive B-Cell Lymphoma and to reduce the toxicity of standard used Immuno-Chemotherapy by using an optimised schedule of the monoclonal antibody Rituximab, substituting conventional by Liposomal Vincristine and by a PET-guided reduction of therapy in Combination with Vitamin D Substitution.
Detailed description
Primary objective of study:
"OPTIMAL>60 Less Favourable" Patients with less favourable prognosis: To test whether progression-free survival (PFS) can be improved by substituting conventional by liposomal vincristine; To test whether PFS can be improved by 12 optimised applications instead of 8 2-week applications of rituximab.
"OPTIMAL>60 Favourable": Patients with favourable prognosis: Comparison of neurotoxicity of conventional and liposomal vincristine; 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.
Secondary objectives: "OPTIMAL>60 Favourable" and "OPTIMAL>60 Less Favourable":
Comparison of the prognostic value of a pre-treatment FDG-PET (PET-0) with conventional CT/MRT.
Prospective evaluation on the role of (metabolic) tumor volume to confirm or refuse the hypothesis that optimized rituximab should improve the outcome of patients with a high (metabolic) tumor volume more than that of patients with low MTV and to analyse the substitution of conventional vincristine by liposomal. • Estimation of the vincristine-related neurotoxicity ("OPTIMAL>60 Less Favourable only, since vincristine related neurotoxicity is primary objective of the study in favourable patients") and other toxicities (all patients).
Determination of the therapeutic efficacy of a vitamin D substitution.
Comparison of the FDG-PET-based individualised treatment strategy in OPTIMAL>60 with the fixed (pre-defined) treatment strategy in RICOVER>60.
Investigation of the prognostic value of different FDG-PET derived imaging biomarkers for lymphoma load (SUV, MTV, TLG).
Comparison of the vincristine related neurotoxicity before and after amendment 4.
Comparison of CNS events before and after amendment 4. Comparison of the Cheson, Lugano and RECIL response criteria. Prospective evaluation of the improvement of the prognostic value of ECOG performance status during prephase treatment.
Prospective evaluation of reference pathology biomarkes. Prospective evaluation of circulating tumor DNA (ctDNA), correlation and comparison with PET.
Prospective evaluation of the role of 2 additional cycles of CHOP/CHLIP-14 and involved node radiotherapy in PET-positive patients after 4xR-CHOP/CHLIP-14 in favourable patients.
Evaluation of the role of radiotherapy to PET-positive bulky disease patients after 6xR-CHOP/CHLIP-14 in less favourable patients.
Quality assurance of the performed radiotherapy, including in in-field and outfield relapses.
Investigation of the effect of cross-site ComBat harmonization. Analysis of FDG-PET derived biomarkers in combination with clinical and laboratory variables as distance of lesions and Ann-Arbor stage.
Estimation of the prognostic value of a pre-treatment FDG-PET (PET-0) compared to conventional imaging with CT/MRT.
Prospective evaluation of the prediction of the probability of time-to-progression (TTP) within 2 years by a convolutional neural network trained to analyze maximum intensity projection images from baseline PET.
Analysis regarding molecular subtype, transcriptomics, methylome analysis, spatious analysis of interaction of tumor cells and microenvironment by cyTOF, 3D-morphology (AI-based) or similar techniques, viruses (EBV, HHV6, HHV7), micro-RNA in tumor samples.
Analysis of ctDNA analysis by i) digital droplet PCR, ii) e.g. CAPP or similar methods and iii) methylome analysis as prognostic and predictive marker and comparison with imaging biomarkers.
Analysis special focus on refractory, relapsed courses (including specific patterns of relapse regarding location and time) compared to matched controls and regarding comparison with imaging biomarkers.
Analysis of specific BCR-antigens of aggressive B-NHL as Ars2, SAMD14/neurabin-I in tissue and blood. of initial samples of cases with refractory, relapsing course (including specific patterns of relapse regarding location and time).
Analysis of factors influencing immune effector cells e.g.KIR2DS1 and homozygous HLA-C2, PRF1 A91V or other fHLH variants and prognostic and predictive markers in comparison to RICOVER-60.
Investigation of possible prognostic, or predictive markers of treatment related toxicity as: Neurofilament light chain (NfL) to estimate vincristine-related neurotoxicity, or as clonal hematopoiesis with indeterminate potential (CHIP) and association with cardiovascular events.
Investigation of specific concomitant medication and possible impact on outcome.
Investigation of the efficacy of the modified mandatory infectious prophylaxis OPTIMAL compared to the RICOVER trial with a focus on mandatory chinolon prophylaxis.
Investigation of COVID-19-reated events Impact of interval of diagnosis to time to treatment. Comparison with similar patient populations treated in real-world or prospective clinical trials.
Analysis of EFS and PFS at 24 months (EFS24/PFS24) and its impact on subsequent outcome.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Factorial
- Masking
- None (open label)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Favourable Prognosis F-A - Recruitment completed | Active comparator | Drug: Conventional VincristineInduction therapy with 4 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHOP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy. |
| Favourable F-B - Arm Closed | Experimental | Drug: Liposomal VincristineInduction therapy with 4 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,4 mg/sqm (max. 2mg absolute), Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2 additional cycles of R-CHLIP-14 + 2xR plus additional involved-site radiotherapy, if FDG-PET negative only 4xR without radiotherapy. |
| Less Favourable LF-A - Recruitment completed | Active comparator | Drug: Conventional Vincristine, Drug: Ricover-scheme rituximabInduction therapy with 6 cycles of R-CHOP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHOP-14 an interim restaging will be performed. |
| Less Favourable LF-B - Recruitment completed | Experimental | Drug: Liposomal Vincristine, Drug: Ricover-scheme rituximabInduction therapy with 6 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive 2xR plus additional radiotherapy to the initial bulky region, if FDG-PET negative only 2xR without radiotherapy. After 3xR-CHLIP-14 an interim restaging will be performed. Recruitment completed. |
| Less Favourable LF-C - Recruitment completed | Experimental | Drug: Conventional Vincristine, Drug: optimised rituximab-scheduleInduction therapy with 6 cycles of CHOP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, conventional Vincristine 1,4 mg/sqm [max. 2mg absolute], Predniso[lo]ne 100mg/d d1-5) combined with an optimized Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHOP-14 an interim restaging will be performed. Recruitment completed. |
| Less Favourable LF-D - Recruitment completed | Experimental | Drug: Liposomal Vincristine, Drug: optimised rituximab-scheduleInduction therapy with 6 cycles of CHLIP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, 1,67 mg/sqm [uncapped], , Predniso[lo]ne 100mg/d d1-5) combined with an optimised Rituximab-schedule (375 mg/sqm, d-4, d-1, d1, d4, d14, d28, d42, d56, d91, d126, d175, d238) and then definitive (post-induction) restaging with FDG-PET. If FDG-PET positive additional radiotherapy to the initial bulky region, if FDG-PET negative omission of radiotherapy. After 3x CHLIP-14 an interim restaging will be performed. Recruitment completed. |
Who may qualify
- Ages
- 61 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- Age: 61-80 years
- All risk groups (IPI 1-5)
- Diagnosis of aggressive CD20+ B-NHL, based on an excisional biopsy of a lymph node or on an appropriate sample of a lymph node or of an extranodal involvement. It will be possible to treat the following entities in this study as defined by the new WHO classification of 200870:
- Performance status ECOG 0 - 2 after prephase treatment. The performance status of each patient must be assessed before the initiation and after the end of prephase treatment which, as experience has shown, can result in a significant improvement of the patient's performance status. The pre-treatment performance status which can range from ECOG 0 to ECOG 4 must be documented in the Staging CRF (see ISF); the performance status after the prephase treatment must be documented in the respective Prephase Treatment CRF (PT form: see ISF). A definition of the performance status is provided in Appendix 28.10.
- Written informed consent of the patient
Key exclusion criteria (29 listed)
- Already initiated lymphoma therapy (except for the prephase treatment)
- Serious accompanying disorder or impaired organ function (except when due to lymphoma involvement), in particular:
- Platelets <75 000/mm3, leukocytes <2 500/mm3 (if not due to lymphoma)
- Known hypersensitivity to the medications to be used
- Known HIV-positivity
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Conventional Vincristine | Drug | Favourable Prognosis F-A - Recruitment completed, Less Favourable LF-A - Recruitment completed, Less Favourable LF-C - Recruitment completed |
| Liposomal Vincristine | Drug | Favourable F-B - Arm Closed, Less Favourable LF-B - Recruitment completed, Less Favourable LF-D - Recruitment completed |
| Ricover-scheme rituximab | Drug | Less Favourable LF-A - Recruitment completed, Less Favourable LF-B - Recruitment completed |
| optimised rituximab-schedule | Drug | Less Favourable LF-C - Recruitment completed, Less Favourable LF-D - Recruitment completed |
Primary outcome
Progression-free survival
Time frame: 9 years
"OPTIMAL>60 Less Favourable": To test the effects of substitution of conventional by liposomal vincristine and of a 2-week applications of 8x rituximab by an optimised application of 12 x rituximab stratified log rank tests will be performed for each question (stratified for IPI-factors). Proportional hazard models will be used to investigate treatment interaction and to obtain estimates for the single treatment effects (HR) adjusting for the IPI-factors. "OPTIMAL>60 Favourable" Grade of neurotoxicity will be estimated and indicated with a 95% confidence interval (CI) separated to each type of vincristine. To investigate the 3-year PFS with 95% CI the Kaplan-Meier estimator will be used.
1 secondary outcome
for efficacy: CR-rate, PR-rate, rate of primary progressions, relapse rate, EFS and OS; rate and CTC grades of PNP. Prognostic value of the FDG-PET derived imaging biomarkers for lymphoma load: SUV, MTV, TLG.
Time frame: 9 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jan 2025.
- BackgroundPfreundschuh, M., Christofyllakis, K., Altmann, B., Ziepert, M., Haenel, M., Viardot, A., Neubauer, A., Held, G., Truemper, L., Dreyling, M., Kanz, L., Hallek, M., Schmitz, N., Heintges, T., Kölbel, C., Buecker, A., Ruebe, C., Hellwig, D., Berdel, C., Poeschel, V., and Murawski, N. (2017) Radiotherapy to bulky disease PET-negative after immunochemotherapy in elderly DLBCL patients: Results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL. Hematological Oncology, 35( S2): 129- 130. doi: 10.1002/hon.2437_119.
- Derived from this study: PubMed 33928400Kaddu-Mulindwa D, Altmann B, Held G, Angel S, Stilgenbauer S, Thurner L, Bewarder M, Schwier M, Pfreundschuh M, Loffler M, Menhart K, Grosse J, Ziepert M, Herrmann K, Duhrsen U, Huttmann A, Barbato F, Poeschel V, Hellwig D. FDG PET/CT to detect bone marrow involvement in the initial staging of patients with aggressive non-Hodgkin lymphoma: results from the prospective, multicenter PETAL and OPTIMAL>60 trials. Eur J Nucl Med Mol Imaging. 2021 Oct;48(11):3550-3559. doi: 10.1007/s00259-021-05348-6. Epub 2021 Apr 29.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Lorenz Thurner, Professor principal investigator
Saarland University, Saarland University Hospital
127 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Conventional Vincristine, Liposomal Vincristine and Ricover-scheme rituximab in people with CD20+ Aggressive B-Cell Lymphoma, run by Universität des Saarlandes at 127 sites in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 27 inclusion and 29 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 127 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Progression-free survival (time frame: 9 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01478542, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jan 2025.