Clinical Trials /

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

NCT01478542

Description:

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.

Related Conditions:
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

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

  • ORG STUDY ID: DSHNHL 2009-1
  • NCT ID: NCT01478542

Conditions

  • CD20+ Aggressive B-Cell Lymphoma

Interventions

DrugSynonymsArms
Conventional VincristineFavourable Prognosis F-A
Liposomal VincristineFavourable F-B - Recruitment completed
Ricover-scheme rituximabLess Favourable LF-A - Recruitment completed
optimised rituximab-scheduleLess Favourable LF-C - Recruitment completed

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Favourable Prognosis F-AActive ComparatorInduction 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.
  • Conventional Vincristine
Favourable F-B - Recruitment completedExperimentalInduction 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.
  • Liposomal Vincristine
Less Favourable LF-A - Recruitment completedActive ComparatorInduction 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.
  • Conventional Vincristine
  • Ricover-scheme rituximab
Less Favourable LF-B - Recruitment completedExperimentalInduction 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.
  • Liposomal Vincristine
  • Ricover-scheme rituximab
Less Favourable LF-C - Recruitment completedExperimentalInduction 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.
  • Conventional Vincristine
  • optimised rituximab-schedule
Less Favourable LF-D - Recruitment completedExperimentalInduction 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.
  • Liposomal Vincristine
  • optimised rituximab-schedule

Eligibility Criteria

        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.
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:61 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:9 years
Safety Issue:
Description:"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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital, Saarland

Trial Keywords

  • DLBCL
  • Liposomal Vincristine (Marqibo)
  • Optimised Rituximab
  • Toxicity
  • Elderly Patients
  • FDG-PET
  • Bulky Disease
  • Radiation
  • age >60 years
  • First line Therapy
  • Vitamin D

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