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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2012 by University Hospital, Saarland
Sponsor:
Collaborator:
German High-Grade Non-Hodgkin's Lymphoma Study Group
Information provided by (Responsible Party):
University Hospital, Saarland
ClinicalTrials.gov Identifier:
NCT01478542
First received: November 18, 2011
Last updated: October 16, 2012
Last verified: October 2012
  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.


Condition Intervention Phase
CD20+ Aggressive B-Cell Lymphoma
Drug: Conventional Vincristine
Drug: Liposomal Vincristine
Drug: Ricover-scheme rituximab
Drug: optimised rituximab-schedule
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by University Hospital, Saarland:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: 9 years ] [ Designated as safety issue: No ]

    "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:
  • 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. [ Time Frame: 9 years ] [ Designated as safety issue: No ]

    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.

    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



Estimated Enrollment: 1152
Study Start Date: November 2011
Estimated Study Completion Date: October 2019
Estimated Primary Completion Date: October 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Favourable Prognosis F-A
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.
Drug: Conventional Vincristine
Experimental: Favourable F-B
Induction therapy with 4 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 2 mg/sqm, 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.
Drug: Liposomal Vincristine
Active Comparator: Less Favourable LF-A
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.
Drug: Conventional Vincristine Drug: Ricover-scheme rituximab
Experimental: Less Favourable LF-B
Induction therapy with 6 cycles of R-CHLIP-14 (Rituximab 375 mg/sqm, Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 2 mg/sqm, 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.
Drug: Liposomal Vincristine Drug: Ricover-scheme rituximab
Experimental: Less Favourable LF-C
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.
Drug: Conventional Vincristine Drug: optimised rituximab-schedule
Experimental: Less Favourable LF-D
Induction therapy with 6 cycles of CHLIP-14 (Cyclophosphamide 750 mg/sqm, Doxorubicin 50 mg/sqm, liposomal Vincristine 2 mg/sqm, 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.
Drug: Liposomal Vincristine Drug: optimised rituximab-schedule

Detailed Description:

Primary objective of study:

"OPTIMAL>60 Less Favourable" 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.

    "OPTIMAL>60 Favourable": 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.

    Secondary objectives:

    "OPTIMAL>60 Favourable" and "OPTIMAL>60 Less Favourable":

  5. Comparison of the prognostic value of a pre-treatment FDG-PET (PET-0) with conventional CT/MRT.
  6. Comparison of the FDG-PET-based individualised treatment strategy in OPTIMAL>60 with the fixed (pre-defined) treatment strategy in RICOVER>60.
  7. 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).
  Eligibility

Ages Eligible for Study:   61 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
    • 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 basalioma of the skin and carcinoma in situ)
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01478542

Contacts
Contact: DSHNHL Central Study Office +4968411623084 DSHNHL@uks.eu

  Show 51 Study Locations
Sponsors and Collaborators
University Hospital, Saarland
German High-Grade Non-Hodgkin's Lymphoma Study Group
Investigators
Principal Investigator: Michael G. Pfreundschuh, Professor Saarland University, Saarland University Hospital
  More Information

No publications provided

Responsible Party: University Hospital, Saarland
ClinicalTrials.gov Identifier: NCT01478542     History of Changes
Other Study ID Numbers: DSHNHL 2009-1
Study First Received: November 18, 2011
Last Updated: October 16, 2012
Health Authority: Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University Hospital, Saarland:
DLBCL
Liposomal Vincristine (Marqibo)
Optimised Rituximab
Toxicity
Elderly Patients
FDG-PET
Bulky Disease
Radiation
age >60 years
First line Therapy

Additional relevant MeSH terms:
Lymphoma, B-Cell
Aggression
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Behavioral Symptoms
Rituximab
Vincristine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 22, 2014