Brentuximab Vedotin for Relapsed/Refractory CD30-positive Non-Hodgkin Lymphomas
Condition: Non-Hodgkin Lymphoma
MeSH terms: Lymphoma; Lymphoma, Non-Hodgkin
Study type: Interventional
Phase: Phase 2

Summary: 
      Brentuximab vedotin is an antibody-drug conjugate targeting CD30, one of surface antigens
      expressed in lymphoma cells. Fanale MA, et al. reported the results of a phase I study with
      weekly dosing of brentuximab vedotin in patients with relapsed/refractory CD30-positive
      hematologic malignancies (Clin Cancer Res. 2012) showed tumor regression in 85% of patients.
      Thus, the overall objective response rate was 59% (24/44) including 34% (n = 14) of complete
      remissions. This study mainly included Hodgkin lymphoma (n = 38) and anaplastic large cell
      lymphoma (n = 5). However, its efficacy in other types of NHL has never been reported
      although this study enrolled one patient with peripheral T-cell lymphoma not otherwise
      specified (PTCL-NOS).

      CD30 (TNFRSF8) is a transmembrane glycoprotein of the tumor necrosis factor receptor (TNFR)
      superfamily, and it is involved in signal transduction via the activation of the NF-κB
      pathway and the mitogen-activated protein kinases (MAPKs), ultimately modulating cell growth,
      proliferation and apoptosis. CD30 is a non-lineage-specific activation marker expressed by
      scattered B and T immunoblasts. In addition, a subset of cases in virtually all T-cell
      lymphoma entities may also express CD30 but at variable and generally lower levels. In fact,
      a recent study in 22 patients with extranodal NK/T-cell lymphoma showed 75% of positive rate
      of CD30 expression (75%). Moreover, CD30 expression was also documented in the tumor sample
      of EB virus positive diffuse large B-cell lymphomas (EBV + DLBCL) of the elderly (28.9%,
      11/38). Therefore, Brentuximab vedotin may have potential benefits for patients with
      CD30-positive NHL other than anaplastic large cell lymphoma such as CD30-positive PTCLs, NOS.
      Considering the role of CD30 in signal transduction pathway associated with tumor growth and
      proliferation, its expression may be associated with tumor aggressiveness. In accordance with
      this, it is more likely that relapse or refractory NHLs may have CD30 expression, and the
      potential benefits of this promising agent as a salvage therapy deserve to be further
      investigated in these patients who have high risk of treatment failure. Thus, we designed a
      phase II study for relapsed or refractory NHL patients. This study is to explore the safety
      and activity of dosing once every 3 weeks of Brentuximab vedotin in patients with relapsed or
      refractory CD30-positive NHL other than anaplastic large cell lymphoma.
    

Detailed description: 
      The principal investigator use a Simon two-stage minimax design based on overall response
      rates. Overall disease control rates will be calculated as the percent of patients that have
      confirmed complete response (CR) or partial response (PR) or stable disease (SD) by
      radiographic response including CT and/or PET scans. We assume a P0 as 20%, and designate a
      target rate (P1) as 40%. Under the error probabilities (α=0.05, β=0.20), eighteen patients
      will be enrolled in the first stage. If overall disease control rate is ≤ 4/18 in the first
      stage, this study will be stopped. If not, this study will recruit patients up to 33
      considering 20% of drop out rate.

      Intent-to-treat analysis will be applied to all primary and secondary efficacy endpoints.
      Response rate will be analyzed based on the response criteria according to Cheson 2007
      (Cheson BD, et al. J Clin Oncol 2007; 25 (5):579-586), and data related to overall response
      rate will be analyzed by statistical analysis including Chi test to evaluate predictive
      factors for response to study drug.

      Overall rate of disease control : CR, PR and SD Progression-free survival : Time between the
      date of treatment start and the date of death due to any cause or date of disease progression
      (Up to 36months) Data related to survival rate for all patients will be analyzed based on
      log-rank test by the Kaplan-Meier method.
    

Intervention name(s): Brentuximab vedotin
Intervention type(s): Drug
Intervention description(s): Brentuximab vedotin must not be administered as an IV push or bolus. It must be administered in 100ml-250ml of 0.9% saline by intravenous infusion over 30 minutes once every 3 weeks.
Other intervention name(s): Adcetris
Intervention MeSH terms: Brentuximab Vedotin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment