Phase II Randomized Study With R-DHAP +/- Bortezomib as Induction Therapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) Patients Eligible to Transplantation. BR-DHAP Versus R-DHAP.
Condition: Diffuse Large B-cell Lymphoma Refractory; Diffuse Large B-cell Lymphoma Recurrent
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The probability to achieve CR with R-chemotherapy in patients failing a rituximab containing
      first line regimen is quite low, in particular in cases with non GCB profile. The bioCORAL
      trial suggest that ABC subset have a dismal outcome whichever the induction treatment. Thus
      it can be argued the addition of new molecule to the RDHAP regimen could be of value.
      Bortezomib appears the best candidate in this setting as ABC subtypes constitutively express
      NFkb, which is the target of bortezomib itself. Data from the literature suggest an
      encouraging activity of R-chemo+ bortezomib in non GCB-derived DLBCL, although in small
      series. Thus, the addition of bortezomib is here justified by the need to circumvent
      constitutional resistance to chemotherapy. Published experience of the association between
      bortezomib and cytarabine are also encouraging with acceptable cumulative toxicity.
    

Detailed description: 
      This is a prospective, multicenter, two-arm randomized phase II screening trial34 in young
      patients (18-65 years) affected by relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL)
      at diagnosis, eligible to high-dose therapy.

      Aim of the study is to to assess whether the addition of Bortezomib to R-DHAP is more
      promising than standard R-DHAP, as induction therapy before high dose chemotherapy with ASCT
      with respect to response and safety. Patients will be randomized at first relapse between: a)
      the standard salvage therapy Rituximab in association to DHAP every 28 days (R-DHAP) for 4
      cycles and b) Bortezomib in association to the same regimen (BR-DHAP). In both arms the
      induction therapy is followed by autologous stem cell transplantation or, if indicated, by
      allogeneic stem cell transplant.

      A patient is considered evaluable if it is possible to assess response by PET after 4 cycle
      or, if a patient withdraws from the study for PD, before completion of study treatment.

      After providing written informed consent, patients will be evaluated for eligibility during a
      21-day screening period. If they continue to meet eligibility criteria, they will be
      randomized to receive the first dose of BR-DHAP or R-DHAP .
    

Intervention name(s): R-DHAP; BR-DHAP
Intervention type(s): Drug; Drug
Intervention description(s): Rituximab 375 mg/sqm iv day 0 or 1
Cisplatin 100 mg/sqm iv day 1 in 6-hours infusion
Cytarabine 2000 mg/sqm in 3-hours infusion iv day 2 and day 3
Dexamethasone 40 mg day 1-4
Pegfilgrastim 6 mg sc monodose 24 hours after the end of chemotherapy or G-CSF from day 5 till stem cell harvest during mobilization's course (II o III cycle R-DHAP)
Rituximab 375 mg/sqm iv 24 hours before apheresis as purging in vivo during second courses of therapy; Rituximab 375 mg/sqm iv day 0 or 1
Bortezomib SC 1.5 mg/sqm day 1, day 4
Cisplatin 100 mg/sqm iv day 1 in 6-hours infusion
Cytarabine 2000 mg/sqm in 3-hours infusion iv day 2 and day 3
Dexamethasone 40 mg day 1-4
Pegfilgrastim 6 mg sc monodose 24 hours after the end of chemotherapy or G-CSF from day 5 till stem cell harvest during mobilization's course (II o III cycle R-DHAP)
Rituximab 375 mg/sqm iv 24 hours before apheresis as purging in vivo during second courses of therapy Chemotherapy R-DHAP and BR-DHAP will be repeated every 28 days.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diffuse Large B-cell Lymphoma (DLBCL); Bortezomib