Clinical Trials /

Brentuximab Vedotin and BeEAM High-dose Chemotherapy in Lymphomas

NCT03187210

Description:

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.

Related Conditions:
  • Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: BAL-Trial
  • NCT ID: NCT03187210

Conditions

  • Lymphoma

Interventions

DrugSynonymsArms
Brentuximab VedotinDosis finding (Phase I)
BeEAM RegimenDosis finding (Phase I)

Purpose

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.

Detailed 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:

      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.

      Study Duration:

      Phase I part will last from 3 to 18 months (permitting the enrolment of minimum of 6
      patients). The Phase I will be stopped after the RP2D is established. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Dosis finding (Phase I)ExperimentalBrentuximab 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
  • Brentuximab Vedotin
  • BeEAM Regimen
Arm A (Phase II)Active ComparatorBeEAM 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
  • BeEAM Regimen
Arm B (Phase II)ExperimentalBrentuximab Vedotin 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
  • BeEAM Regimen

Eligibility Criteria

        Inclusion Criteria:

          -  Eligible are all CD30+ malignant lymphoma, meaning lymphoma subtypes such as Hodgkin
             lymphomas, angioimmunoblastic T-cell lymphomas (AITL), anaplastic ALK+ T-cell
             lymphomas, Sézary-syndrome, but also all other malignant CD30+ lymphoma types.

          -  Patients must be in first or second remission or second chemosensitive relapse and
             patients must be planned to undergo subsequent consolidation with standard high-dose
             chemotherapy with autologous stem cell transplantation.

          -  Patients must be aged 18-65 years, and must have given voluntary written informed
             consent.

          -  Negative pregnancy test (urine or serum) within 14 days prior to registration for all
             women of childbearing potential. Patients of childbearing potential must implement two
             effective contraceptive measures (hormonal treatment p.o. or i.m., intra uterine
             surgical devices, or latex condoms) to avoid pregnancy from the time of signing
             informed consent and for additional 12 months. No pregnant or lactating patients are
             allowed.

          -  Male patients, even if surgically sterilized, (i.e., status post vasectomy) agree to
             practice effective barrier contraception during the entire study period and through 12
             months after the last dose of study drug, or agrees to completely abstain from
             heterosexual intercourse.

          -  Absolute neutrophil count ≥ 1,500/µL unless there is known hematologic/solid tumor
             marrow involvement.

          -  Platelet count ≥ 75,000/ µL unless there is known marrow involvement of the disease.

          -  Total bilirubin must be < 1.5 x the upper limit of the normal (ULN) unless the
             elevation is known to be due to Gilbert syndrome.

          -  ALT or AST must be < 3 x the upper limit of the normal range. AST and ALT may be
             elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the
             presence of hematologic/solid tumor in liver.

          -  Serum creatinine must be < 2.0 mg/dL and/or creatinine clearance or calculated
             creatinine clearance > 40 mL/minute.

          -  Hemoglobin must be ≥ 8g/dL.

        Exclusion Criteria:

          -  Patients considered to be not fit for autologous stem cell transplantation (ASCT).

          -  Patients with other serious medical condition that interfere with the completion of
             treatment according to this protocol or that would impair tolerance to therapy or
             prolong hematological recovery. Patients with seropositivity for HIV or for Hepatitis
             B and C are not excluded from this study if they are otherwise considered fit for
             ASCT.

          -  Symptomatic neurologic disease compromising normal activities of daily living or
             requiring medications. Any sensory or motor peripheral neuropathy greater than or
             equal to Grade 2.

          -  Known history of any of the following cardiovascular conditions:

        Myocardial infarction within 2 years of registration, New York Heart Association (NYHA)
        Class III or IV heart failure (See Appendix 5). Evidence of current uncontrolled
        cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF),
        angina, or electrocardiographic evidence of acute ischemia or active conduction system
        abnormalities.

        Recent evidence (within 6 months before first dose of study drug) of a left-ventricular
        ejection fraction <50%.

          -  Patients that have not completed any prior treatment chemotherapy and/or other
             investigational agents within at least 5 half-lives of last dose of that prior
             treatment. Known hypersensitivity to recombinant proteins, murine proteins, or to any
             excipient contained in the drug formulation of Brentuximab Vedotin.

          -  Acute uncontrolled infection.

          -  Relevant co-existing disease excluding a treatment according to protocol.

          -  Concurrent malignant disease with the exception of basalioma/spinalioma of the skin,
             early-stage cervix carcinoma, or early-stage prostate cancer. • Previous treatment for
             other malignancies (not listed above) must have been terminated at least 24 months
             before registration and no evidence of active disease must be documented since then.

          -  Lack of patient cooperation to allow study treatment as outlined in this protocol.

          -  Pregnant or lactating female patients.

          -  Major coagulopathy or bleeding disorder.

          -  Major surgery less than 30 days before start of treatment.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Dose finding
Time Frame:30 days
Safety Issue:
Description:to identify the maximum tolerated dose of Brentuximab Vedotin added to standard BeEAM high-dose chemotherapy testing three dose levels.

Secondary Outcome Measures

Measure:Phase 1: disease-free survival
Time Frame:12 months
Safety Issue:
Description:Number of Patient with disease-free survival 12 months after ASCT
Measure:Overall survival
Time Frame:12 Months
Safety Issue:
Description:Number of Patient alive after 12 months
Measure:Adverse Events
Time Frame:12 months
Safety Issue:
Description:Number of Patient experiencing toxicity(Adverse events

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital Inselspital, Berne

Trial Keywords

  • CD30+ Lymphoma
  • ASCT
  • Brentuximab Vedotin

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