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Brentuximab Vedotin at day -8 together with standard BeEAM (Bendamustine, Cytarabine, Etoposide and Melphalan) chemotherapy at days -7 to -1 followed by reinfusion of autologous stem cells at day 0

BeEAM Regimen:

Bendamustine intravenously once daily on days -7 and -6 at 200 mg/m2/day; Cytarabine (ARA-C) 400 mg/m2/day intravenously once daily from day -5 to day-2; Etoposide 200 mg/m2/day intravenously once daily from day -5 to day -2; and Melphalan 140 mg/m2/day intravenously once on day -1, followed by reinfusion of autologous stem cells at day 0

Brentuximab Vedotin 1.8 mg/kg at day -8 together with standard BeEAM chemotherapy at days -7 to -1

BeEAM Regimen:

Bendamustine intravenously once daily on days -7 and -6 at 200 mg/m2/day; Cytarabine (ARA-C) 400 mg/m2/day intravenously once daily from day -5 to day-2; etoposide 200 mg/m2/day intravenously once daily from day -5 to day -2; and Melphalan 140 mg/m2/day intravenously once on day -1, followed by reinfusion of autologous stem cells at day 0

Brentuximab Vedotin at day -8 together with standard BeEAM chemotherapy at days -7 to -1 followed by ASCT on day 0

standard BeEAM chemotherapy at days -7 to -1 followed by ASCT on day 0

BeEAM Regimen

Thomas Pabst, MD

The trial assess the maximum tolerated dose of a single-dose of Brentuximab Vedotin added to standard BeEAM chemotherapy (comprising Bendamustin, Etoposide, Cyclophosphamide and Melphalan) before autologous stem cell transplantation in CD30+ malignant lymphomas.

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.

The BAL trial consists in two parts:

* single arm prospective phase I part;
* randomized two-arm open-label prospective phase II part.

Brentuximab Vedotin and BeEAM High-dose Chemotherapy in Lymphomas

Brentuximab Vedotin and BeEAM High-dose Chemotherapy (B-BeEAM) With Autologous Stem Cell Transplantation for CD30+ Lymphomas, a Phase I/II Study

To identify the maximum tolerated dose of Brentuximab Vedotin added to standard BeEAM high-dose chemotherapy testing three dose levels.

Number of patients with disease-free survival 12 months after ASCT (DFS1) between CD30+ lymphoma patients treated with the standard BeEAM high-dose chemotherapy versus brentuximab together with BeEAM (B-BeEAM) high-dose chemotherapy. A clinically meaningful increase of the efficacy of the combination therapy (B-BeEAM) is defined in this study as an increase of the rate of disease free survival (DFS1) one year after ASCT from 70% with BeEAM alone to ≥ 90% with the combination of Brentuximab Vedotin and BeEAM.

Number of patients with disease-free survival 12 months after ASCT

Number of patients experiencing complete or partial remission

Number of patient experiencing toxicity (Adverse events)

Number of days until neutrophils recovery 0.5 G/L (from day - 8)

Number of patients experiencing infectious complications

Spots Global Cancer Trial Database for beeam regimen