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.
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 .
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
108
* 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.
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori-Ematologia
Meldola, Forlì-Cesena, Italy
Clinica Humanitas
Rozzano, Milano, Italy
ASST Grande Ospedale Metropolitano Niguarda - SC Ematologia
Milan, MI, Italy
CRO Aviano
Aviano, Pordenone, Italy
ASST Valle Olona
Gallarate, Varese, Italy
A.O. SS. Antonio e Biagio e C. Arrigo
Alessandria, Italy
Clinica di ematologia AOU Umberto I Ospedali Riuniti
Ancona, Italy
ASST Spedali Civili di Brescia - Ematologia
Brescia, Italy
Ospedale Businco - SC Ematologia e CTMO
Cagliari, Italy
Ematologia 1 Ospedale S. Martino
Genova, Italy
...and 14 more locations
Complete Response (CR) Rate
Proportion of CR according to the Cheson 2007 response criteria, evaluated by PET scan
Time frame: At the end of the induction phase (6 months)
Overall Response Rate (ORR)
ORR at the end of the induction treatment is defined as Complete Response (CR) or Partial Response according to the Cheson 2007 response criteria, evaluated by PET scan
Time frame: At the end of the induction phase (6 months)
Overall Survival (OS)
OS will be defined as the time between the date of randomization and the date of death from any cause
Time frame: 36 months
Number of Patients With Treatment-Related Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety
Incidence of grade 3 or higher Toxicity measured by CTCAE v.4 during therapy
Time frame: 12 months
Mobilizing potential
Amount of CD34+ stem cell collected/Kg
Time frame: 6 months
Number of Patients completing ASCT
Proportion of randomized patients successfully completing ASCT
Time frame: 12 months
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