Brentuximab Vedotin and BeEAM High-dose Chemotherapy in Lymphomas (BAL)

Description

Background and Rationale:

CD30+ lymphomas typically comprise Hodgkin lymphomas and a variety of T-cell non-Hodgkin lymphoma (T-NHL) entities including angioimmunoblastic T-cell lymphomas (AITL), anaplastic ALK+ large-cell T-cell lymphomas (ALCL), Sézary-syndrome, peripheral T-NHL NOS and other rare malignant T-cell lymphoma types.

The prognosis of patients with Hodgkin lymphoma (HL) is excellent for the majority of these usually young patients; however, HL patients relapsing after autologous stem-cell transplantation (ASCT) have a rather poor outcome, with approximately only up to 20% of the patients surviving longer than 5 years. For those in advanced stage Hodgkin's lymphoma multiple first-line and second-line treatments, including the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) - internationally, the most widely used regimen in Hodgkin's lymphoma - is expected to cure about 70-80% of patients. However, in addition to treatment failures noted for ABVD, the regimen is often associated with unpredictable bleomycin-induced lung related toxic effects that can be life-threatening. Although High Dose Chemotherapy (HDCT) with ASCT is a curative strategy for some patients with relapsing Hodgkin lymphomas, relapse or progression after ASCT is a major limitation of this procedure. For these reason, the outcome of Hodgkin lymphoma patients relapsing after ASCT is poor, and novel concepts for such patients is an unmet clinical need.

CD30+ T-NHL generally have a limited prognosis, with a minority of patients being cured after specific lymphoma treatment. The incorporation of consolidating high-dose chemotherapy with autologous stem cell transplantation for young fit patients within the first-line treatment algorithms has improved the prognosis of such patients to some extent. However, the majority of such patients still ultimately die of their disease. Again, improvement of lymphoma treatment is an urgent requirement for these patients.

Brentuximab Vedotin (BV; Adcetris®) is an antibody-drug conjugate and is licensed in Switzerland and the European Medicine Agency region for the single-agent treatment of relapsed and refractory Hodgkin lymphoma or for relapsed and refractory anaplastic T-cell lymphoma.

BeEAM high-dose chemotherapy (comprising Bendamustin, Etoposide, Cyclophosphamide and Melphalan) is the standard conditioning regimen before ASCT for lymphoma patients.

In this trial BV will be used together with BeEAM high-dose chemotherapy according to its conventional schedule in CD30+ lymphomas as conditioning regimen before ASCT.

Objective

Phase I: The primary objective of the trial is to assess the maximum tolerated dose of a single-dose of Brentuximab Vedotin added to standard BeEAM chemotherapy before autologous stem cell transplantation in CD30+ malignant lymphomas.

Phase II: The main objective of the trial is to assess differences in disease-free survival between CD30+ lymphoma patients treated with the standard BeEAM high-dose chemotherapy versus Brentuximab Vedotin together with BeEAM (B-BeEAM) high-dose chemotherapy. We aim to demonstrate an improvement by 20% of the rate of disease-free survival 1 year after ASCT (DFS1) from 70% in patients treated with BeEAM alone to 90% in patients treated with the combination of B-BeEAM.

Study Duration:

Phase I part was planned to last from 3 to 18 months (permitting the enrolment of minimum of 6 patients). The Phase I has been stopped after the RP2D (1.8mg/kg/day) was established with enrolment of 12 patient in 24 months. The Phase II will stop after the inclusion of 42 evaluable patients.

All patients will be followed up for up to 12 months after end of treatment..

This study will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) as well as all national legal and regulatory requirements.

Details