Sequential Trial on Reduced Intensity Conditioning (RIC) Allogeneic Transplantation (EMN-alloRIC)
The aim of the current study is to improve the outcome of patients with hematologic malignancies (in a phase I trial) and more specifically multiple myeloma (in a phase II trial) by 2 interventions: reduce the risk of graft-versus-host disease (GVHD) and improve the efficacy of the procedure decreasing the risk of relapses after transplant.
Currently, the standard approach used in most centers to prevent graft-versus-host disease after allogeneic transplantation is based on the combination of a calcineurin inhibitor (cyclosporine or tacrolimus) plus a short course of methotrexate. Unfortunately, this strategy is far from ideal, since the risk of acute GVHD is in the range of 30-40% among patients receiving a matched related donor transplantation and even higher among patients receiving transplantation from an unrelated donor while the incidence of chronic GVHD is 60-70% among patients receiving peripheral blood progenitor cells from either a related or unrelated donor.
As far as the patients with multiple myeloma (MM) is concerned, although the development of new drugs has markedly changed the outcome and management of these patients, allogeneic transplantation so far appears to be the only curative option, especially among those patients relapsing after first line treatment. Nevertheless, still new strategies within the allogeneic transplant setting are needed to improve its results.
Relapses may occur either extramedullary (very common in this setting) or systemic. In order to reduce the risk of systemic relapses the investigators will use maintenance therapy with Lenalidomide (Len) which, together with bortezomib (Bz) should contribute to eradicate minimal residual disease (MRD). In case the patient do not obtain complete remission or near complete remission after transplant, in addition to the maintenance therapy, the investigators will use four intensification cycles with VRD (Bz-Len-Dexamethasone).
In summary, the goal is to optimize the efficacy of allogeneic transplantation by two interventions: one focused on reducing the risk of relapse and the other on reducing the incidence of GVHD.
Drug: Bz (Bortezomib)
Drug: Len (lenalidomide)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||European Myeloma Network Sequential Phase I / Phase II Trial on RIC Allogeneic Transplantation: an Optimized Program for High Risk Relapsed Patients|
- Phase I trial: Safety of Len + Bz in patients with hematologic malignancies Phase II trial: Safety and efficacy of an optimized strategy of allogeneic transplantation in multiple myeloma undergoing allogeneic transplantation. [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: Yes ]
For phase I trial: safety of Len + Bz. The phase I trial safety criteria will be evaluated in terms of (1) engraftment defined as > 500 granulocytes / microL and > 20.000 platelets / microL x 3 consecutive days will be required for 9/10 patients, (2) incidence of neuropathy grades 3-4 attributed to Bz > 20% (3) incidence of gastrointestinal toxicity attributed to Bz > 20%.
For phase II trial: safety evaluated through adverse events and toxicity and efficacy evaluated as reduction of relapse rate as defined by the EBMT criteria.
- Incidence of GVHD with this combination (phase I and II) [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: Yes ]Evaluation of a novel combination of Bz plus Len to prevent GVHD after allogeneic transplantation in patients with haematologic malignancies/MM
- Phase II: response and relapse rate of this approach [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: Yes ]Reduction of relapse rate as defined by the EBMT (European Group for Blood, and Marrow Transplant)criteria.
- Phase II: safety of the procedure [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: Yes ]For all patients safety will be assessed by the reporting of adverse events starting with the first study-related procedure and up to 30 days after the treatment period. The severity of adverse events will be assessed using National Cancer Institute (NCI) common toxicity criteria (CTC).
- Evaluate the efficacy on survival [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]Evaluate the efficacy of the procedure in terms of event free and overall survival
- Efficacy of positron emission tomography (PET scan)and local radiotherapy [ Time Frame: Up to one year after transplant ] [ Designated as safety issue: No ]Analyze the prognostic value and efficacy of imaging studies using PET scan and local radiotherapy in involved fields prior to or after (> 100 days) conditioning
|Study Start Date:||November 2011|
|Study Completion Date:||July 2016|
|Primary Completion Date:||May 2016 (Final data collection date for primary outcome measure)|
Experimental: Bortezomib + Lenalidomide
After conditioning treatment and graft versus host disease prophylaxis with Bz 1.3 mg/m2 on days +1, +4 and +7 plus sirolimus/rapamycin at a dose of 6 mg po on day -5 and then 4 mg per day in order to maintain serum levels in the range of 6-12 ng /mL, a maintenance therapy with Bz 1.3 mg/m2 on days 1, 8 and 15 in cycles of 56 days up to 6 cycles post-transplant and on day +180 Len will be started at a dose of 5 mg and will be maintained until relapse.
Drug: Bz (Bortezomib)
Bz 1.3 mg/m2 on days +1, +4 and +7. Maintenance therapy and dose reduction pre-specified.
Other Names:Drug: Len (lenalidomide)
Len at a dose of 6 mg po on day -5 and then 4 mg per day in order to maintain serum levels in the range of 6-12 ng /mL.
Maintenance therapy and dose reduction pre-specified.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01460420
|Medizinische Klinik and Poliklinik II, University Hospital|
|S Giovanni Battista Hospital|
|Azienda Ospedaliera Universitaria di Udine|
|Hospital Clinic i Provincial,|
|Hospital Santa Creu I Sant Pau,|
|Hospital Universitario Ramón y Cajal|
|Madrid, Spain, 28034|
|Hospital Gregorio Marañón,|
|Hospital Clinico Universitario Salamanca,|
|Hospital Universitario Virgen del Rocío,|
|Karolinska University Hospital, Huddinge|
|Principal Investigator:||Jose-Antonio Perez-Simon, MD-PhD||University Hospital Virgen del Rocio|