OPTIMAL>60 / DR. CHOP, Improvement of Therapy of Elderly Patients With CD20+ DLBCL Using Rituximab Optimized and Liposomal Vincristine

CD20+ Aggressive B-Cell Lymphoma Clinical Trial

— OPTIMAL>60  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01478542
• Other study ID #: DSHNHL 2009-1
• Status: Completed
• Phase: Phase 3
• Start date: November 2011
• Est. completion date: January 18, 2024

Study information

• Verified date: April 2024
• Source: Universität des Saarlandes
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 reduction of therapy in Combination with Vitamin D Substitution.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1152
• Est. completion date: January 18, 2024
• Est. primary completion date: January 18, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 61 Years to 80 Years

Eligibility

Inclusion Criteria:

1. Age: 61-80 years

2. All risk groups (IPI 1-5)

3. 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)

• 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

4. 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.

5. Written informed consent of the patient

6. Contract of participation signed by the study centre and sponsor

Exclusion Criteria:

1. Already initiated lymphoma therapy (except for the prephase treatment)

2. 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

• uncontrollable diabetes mellitus (prephase treatment with predniso[lo]ne!)

3. Platelets <75 000/mm3, leukocytes <2 500/mm3 (if not due to lymphoma)

4. Known hypersensitivity to the medications to be used

5. Known HIV-positivity

6. Patients with severe impairment of immune defense

7. Patients with constipation with imminent risk of ileus

8. Chronic active hepatitis

9. Poor patient compliance

10. Simultaneous participation in other treatment studies or in another clinical trial within the last 6 months

11. Prior chemo- or radiotherapy, long-term use of corticosteroids or anti-neoplastic drugs for previous disorder

12. 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)

13. CNS involvement of lymphoma (intracerebral, meningeal, intraspinal intradural) or primary CNS lymphoma

14. Persistent neuropathy grade =2 (NCI CTC-AE v4.03) (unless due to lymphoma involvement)

15. History of persistent active neurologic disorders grade >2 including demyelinating form of Charcot-Marie-Tooth syndrome, acquired demyelinating disorders, or other demyelinating condition

16. Pregnancy or breast-feeding women

17. Active serious infections not controlled by oral and/or intravenous antibiotics or anti-fungal medication

18. Any medical condition which in the opinion of the investigator places the subject at an unacceptably high risk for toxicities.

19. MALT lymphoma

20. Non-conformity to eligibility criteria

21. Persons not able to understand the impact, nature, risks and consequences of the trial (including language barrier)

22. Persons not agreeing to the transmission of their pseudonymous data

23. Persons depending on sponsor or investigator

24. Persons from highly protected groups. Pts. with CNS lymphoma should not be included in this study.

Related Conditions & MeSH terms

• Aggression
• CD20+ Aggressive B-Cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell

Intervention

Drug:
• Conventional Vincristine

• Liposomal Vincristine

• Ricover-scheme rituximab

• optimised rituximab-schedule

Locations

Country	Name	City	State
Germany	Klinik für Hämatologie und Onkologie	Aachen
Germany	Klinikum St. Marien Amberg, MVZ	Amberg
Germany	Klinikum Augsburg, Medizinische Klinik II	Augsburg
Germany	Praxis Dres. med. Brudler, Heinrich, Bangerter	Augsburg
Germany	Gemeinschaftspraxis Dres. Reichert, Janssen	Aurich
Germany	Helios Klinikum Bad Saarow, Klinik für Innere Medizin III	Bad Saarow
Germany	Sozialstiftung Bamberg, Med. Klinik V	Bamberg
Germany	Klinikum Bayreuth, Medizinische Klinik IV	Bayreuth
Germany	Charité- Universitätsmedizin Berlin, Campus Benjamin Franklin, Med. Klinik III	Berlin
Germany	Knappschaftskrankenhaus Bochum	Bochum
Germany	Johanniter Krankenhaus Bonn, Abteilung für Innere Medizin I	Bonn
Germany	Universitätsklinikum Bonn, Med. Klinik III	Bonn
Germany	Städt. Klinikum Brandenburg, Med. Klinik II	Brandenburg
Germany	Evangelisches Diakonie-Krankenhaus Bremen	Bremen
Germany	Praxis Dr. Obst	Burgwedel
Germany	Praxis Dr. Marquard	Celle
Germany	Klinikum Chemnitz, Innere Medizin III	Chemnitz
Germany	Klinikum Coburg, V. Med. Klinik	Coburg
Germany	Schwerpunktpraxis Dres. Glados/Retzlaff/Zühlsdorf/Deuticke	Coesfeld
Germany	St. Johannes Hospital Dortmund, Med. Klinik II	Dortmund
Germany	BAG Freiberg-Richter, Jacobasch, Wolf, Illmer	Dresden
Germany	Gemeinschaftspraxis Dres. Mohm, Prange-Krex	Dresden
Germany	Universitätsklinikum Erlangen, Med. Klinik 5	Erlangen
Germany	St.-Antonius-Hospital Eschweiler, Hämatologie und Onkologie	Eschweiler
Germany	Klinikum Esslingen, Klinik für Gastroenterologie, Onkologie und Innere Medizin	Esslingen
Germany	Klinikum der J.W. Goethe-Universität Frankfurt, Hämatologie/Onkologie	Frankfurt
Germany	Krankenhaus Nordwest Frankfurt, II. Med. Klinik	Frankfurt
Germany	Klinikum Frankfurt (Oder), Abteilung f. Innere Medizin	Frankfurt (Oder)
Germany	Praxis Dr. med. Reiber	Freiburg
Germany	Universitätsklinikum Freiburg, Innere Medizin I	Freiburg
Germany	Klinikum Fulda, Med. Klinik III	Fulda
Germany	St. Josef-Hospital Gelsenkirchen, Onkologie und Hämatologie	Gelsenkirchen
Germany	Praxis Dr. med. Schliesser	Gießen
Germany	Wilhelm-Anton-Hospital Goch, Innere Medizin	Goch
Germany	Onkologische Kooperation Harz, Onkologische Schwerpunktpraxis	Goslar
Germany	Universitätsmedizin Göttingen, Hämatologie und Onkologie	Göttingen
Germany	Universitätsmedizin Greifswald, Medizinische Universitätsklinik C, Hämatologie und Onkologie	Greifswald
Germany	Kreiskrankenhaus Gummersbach	Gummersbach
Germany	Klinikum Gütersloh	Gütersloh
Germany	Kath. Krankenhaus Hagen, St.-Marien-Hospital	Hagen
Germany	Gemeinschaftspraxis Rohrberg, Hurtz, Schmidt, Frank-Gleich	Halle (Saale)
Germany	Asklepios Klinik St. Georg, Hämatologie/Onkologie	Hamburg
Germany	Hämatolog.-onkolog. Praxis Dres. Müller-Hagen, Bertram, Albertinen-Krankenhaus	Hamburg
Germany	Hämatologisch-onkologische Praxis Altona (HOPA)	Hamburg
Germany	Universitätsklinikum Hamburg-Eppendorf (UKE), II. Med. Klinik und Poliklinik, Onkologie und Hämatologie	Hamburg
Germany	Klinikum Hannover-Siloah, Klinik für Hämatologie	Hannover
Germany	Medizinische Hochschule Hannover (MHH), Zentrum für Innere Medizin, Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation	Hannover
Germany	Praxis MediProjekt	Hannover
Germany	Universitätsklinikum Heidelberg, Innere Medizin V	Heidelberg
Germany	Klinikum Kreis Herford, Med. Klinik II	Herford
Germany	Onkologische Schwerpunktpraxis Dres. Freier, Sievers	Hildesheim
Germany	St. Bernward Krankenhaus Hildesheim, Med. Klinik II	Hildesheim
Germany	Saarland University Hospital	Homburg	Saarland
Germany	KMT Klinik Idar-Oberstein	Idar-Oberstein
Germany	Universitätsklinikum Jena, Klinik für Innere Medizin II	Jena
Germany	Praxis Dres Hansen, Reeb	Kaiserslautern
Germany	Westpfalz-Klinikum, Klinik für Innere Medizin I	Kaiserslautern
Germany	St. Vincentius Kliniken Karlsruhe, Med. Klinik Abt. 2	Karlsruhe
Germany	Städtisches Klinikum Karlsruhe, II. Med. Klinik, Hämatologie/Onkologie/Infektionskrankheiten	Karlsruhe
Germany	GMP Dres Siehl, Söling	Kassel
Germany	Rotes Kreuz Krankenhaus Kassel, Klinik für Interdisziplinäre Onkologie	Kassel
Germany	Klinikum Kempten-Oberallgäu, Hämatologie, Onkologie und Palliativmedizin	Kempten
Germany	Gemeinschaftsklinikum Mittelrhein, Ev. Stift St. Martin, Innere Medizin	Koblenz
Germany	Gemeinschaftspraxis Dres. Schmitz, Steinmetz, Severin	Köln
Germany	Klinikum der Universität zu Köln, Klinik I für Innere Medizin	Köln
Germany	Krankenhaus Holweide	Köln
Germany	Gemeinschaftspraxis Dres. Neise, Lollert	Krefeld
Germany	Praxis Dr. Strauch	Kronach
Germany	Klinikum Landshut, Med. Klinik I	Landshut
Germany	Caritas Krankenhaus Lebach	Lebach
Germany	Onkologische Schwerpunktpraxis	Leer
Germany	Klinikum St. Georg Leipzig, Abteilung für internistische Onkologie/Hämatologie	Leipzig
Germany	Klinikum Lippe-Lemgo, Med. Klinik II	Lemgo
Germany	Onkologische Schwerpunktpraxis Lörrach	Lörrach
Germany	Universitätsklinikum Schleswig-Holstein, Campus Lübeck	Lübeck
Germany	Klinikum Magdeburg, Hämatologie/Onkologie	Magdeburg
Germany	Universitätsmedizin Mainz, III. Med. Klinik und Poliklinik	Mainz
Germany	Mannheimer Onkologie Praxis, Dres. Brust, Plöger, Schuster, Hensel	Mannheim
Germany	Universitätsklinikum Gießen und Marburg	Marburg
Germany	Johannes Wesling Klinikum, Klinik für Hämatologie, Onkologie und Palliativmedizin	Minden
Germany	Kliniken Maria-Hilf Mönchengladbach, Innere Medizin I	Mönchengladbach
Germany	GMP Dres Schröder/Sieg	Mülheim an der Ruhr
Germany	Klinikum Großhadern, Med. Klinik 3	München
Germany	Klinikum rechts der Isar der Technischen Universität München, III. Med.Klinik	München
Germany	Städtisches Klinikum München Harlaching	München
Germany	Praxis Dres. Schmidt, Fromm, Wiesmeier, Seufert, Klapthor, Zingerle	München Pasing
Germany	Universitätsklinikum Münster, Med. Klinik A	Münster
Germany	Stauferklinikum Schwäbisch Gmünd, Zentrum für Innere Medizin	Mutlangen
Germany	Onkologische Praxis Dr. Ladda	Neumarkt
Germany	Lukaskrankenhaus Neuss, Med. Klinik II	Neuss
Germany	Kreiskliniken Esslingen, Klinikum Kirchheim-Nürtingen, Hämatologie, Internist. Onkologie und Palliativmedizin	Nürtingen
Germany	Gemeinschaftspraxis Dres. Balló, Böck	Offenbach
Germany	Ortenau Klinikum Offenburg-Gegenbach, Medizinische Klinik II	Offenburg
Germany	Klinikum Oldenburg, Hämatologie/Onkologie	Oldenburg
Germany	Onkologische Schwerpunktpraxis Dr. Hübner	Oldenburg
Germany	Pius Hospital Oldenburg, Klinik für Strahlentherapie und Internistische Onkologie	Oldenburg
Germany	Onkologische Schwerpunktpraxis im MVZ 2 GmbH, Dr. H. Eimermacher	Olpe
Germany	Klinikum Osnabrück, Med. Klinik III	Osnabrück
Germany	Paracelsus Krankenhaus Ruit, Kreiskliniken Esslingen gGmbH, Zentrum für Allgemeine Innere Medizin	Ostfildern
Germany	Brüderkrankenhaus St. Josef Paderborn, Klinik für Hämatologie und Onkologie	Paderborn
Germany	Gemeinschaftspraxis Dres. Baake, Leonhardt, Moegling, am Regio Klinikum Pinneberg	Pinneberg
Germany	Klinikum Ernst von Bergmann, Klinik für Hämatologie, Onkologie und Palliativmedizin	Potsdam
Germany	Gemeinschaftspraxis Dres. Decker, Nonnenbroich, Herbrik-Zipp	Ravensburg
Germany	Prosper-Hospital Recklinghausen, Med. Klinik I	Recklinghausen
Germany	Krankenhaus Barmherzige Brüder Regensburg, Klinik für Onkologie und Hämatologie	Regensburg
Germany	Klinikum am Steinenberg, Kreiskliniken Reutlingen GmbH	Reutlingen
Germany	Elblandklinikum Riesa, Klinik für Innere Medizin II	Riesa
Germany	Klinikum Südstadt Rostock, Innere Medizin	Rostock
Germany	Universitätsklinikum Rostock, Abteilung Hämatologie/Onkologie, Klinik u. Poliklinik für Innere Medizin	Rostock
Germany	GMP Dres Jacobs, Daus, Schmits	Saarbrücken
Germany	ZAHO-Siegburg, Zentrum für ambulante Hämatologie und Onkologie Siegburg	Siegburg
Germany	Diakonie-Klinikum Stuttgart, Med. Klinik II	Stuttgart
Germany	Klinikum Traunstein, Hämatologie/Onkologie	Traunstein
Germany	Klinikum Mutterhaus der Borromäerinnen, Med. Abteilung I	Trier
Germany	Krankenhaus der Barmherzigen Brüder Trier, I. Med. Abteilung	Trier
Germany	Universitätsklinikum Tübingen, Medizinische Klinik und Poliklinik, Onkologie, Hämatologie, Immunologie und Rheumatologie	Tübingen
Germany	Universitätsklinikum Ulm, Innere Medizin III	Ulm
Germany	Katharinen Hospital Unna	Unna
Germany	Praxis Onkologie Schwarzwald - Alb	Villingen-Schwenningen
Germany	Schwarzwald-Baar-Klinikum - Innere Medizin II	Villingen-Schwenningen
Germany	Med. Versorgungszentrum Weiden, Abteilung für Onkologie	Weiden
Germany	Praxis Dres med. Perker, Sandherr	Weilheim
Germany	HSK Wiesbaden, Innere Medizin III	Wiesbaden
Germany	Evangelisches Krankenhaus Paul Gerhardt Stift, Klinik für Innere Medizin II	Wittenberg	Sachsen-Anhalt
Germany	Helios Klinkum Wuppertal, Med. Klinik I	Wuppertal
Germany	Hämatologisch-Onkologische Praxis Würselen	Würselen

Sponsors (3)

Lead Sponsor	Collaborator
Universität des Saarlandes	German High-Grade Non-Hodgkin's Lymphoma Study Group, Spectrum Pharmaceuticals, Inc

Country where clinical trial is conducted

Germany, 

References & Publications (1)

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., Poe

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	9 years
Secondary	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.	9 years