18TiP - Design of a phase 2 study of brentuximab vedotin (SGN-35) as salvage therapy for males with chemoresistant germ-cell tumors (GCT)

Date 21 November 2014
Event ESMO Symposium on Immuno-Oncology 2014
Session Welcome reception and Poster viewing
Topics Germ Cell Tumours
Cancer Immunology and Immunotherapy
Presenter Patrizia Giannatempo
Authors P. Giannatempo1, A. Anichini2, D. Raggi1, E. Cordareschi3, N. Nicolai4, M. Colecchia5, R. Salvioni4, P. Valagussa3, A. Gianni1, A. Necchi6
  • 1Medical Oncology, Fondazione IRCCS Istituto tumori, 20133 - Milan/IT
  • 2Immunotherapy, Fondazione IRCCS Istituto tumori, 20133 - Milan/IT
  • 3Medical Oncology, MICHELANGELO TECH S.R.L., 20121 - Milan/IT
  • 4Urology, Fondazione IRCCS Istituto tumori, 20133 - Milan/IT
  • 5Pathology, Fondazione IRCCS Istituto tumori, 20133 - Milan/IT
  • 6Medical Oncology, Fondazione IRCCS Istituto tumori, 20133 - m/IT

Abstract

Background

Complete responses with third-line or later salvage chemotherapy (CT) for GCT range from 5% to 10%, and nearly all patients (pts) progressing after high-dose CT will ultimately die. CD30 is expressed by embryonal carcinoma (ECA) thus lending support to a rationale for a targeted approach. SGN-35 is an antibody-drug conjugate consisting of the chimeric anti-CD30 antibody SGN-30 chemically conjugated to an antitubulin synthetic analog. The primary objective of the study will be the activity of SGN35 in refractory GCT.

Trial design

24 pts with biopsy-proven CD30+ GCT will receive intravenous SGN35 at the dose of 1.8 mg/Kg every 3 weeks until disease progression or onset of unacceptable toxicity. Further eligibility requirements will include failure of 2 or 3 platinum-based CT (including HDCT). All pts will undergo measurement of serum tumor markers, a computed tomography and a PET scan q6 weeks. An optimal Simon's 2-stage design will be applied. The primary endpoint is the objective response-rate (ORR). An ORR of 5% is not promising, while a 25% rate will be promising. In stage 1, 9 evaluable patients will be accrued. If ≥1 patient will be responding, enrollment will be extended to the 2nd stage for further 15. If, over the total of 24 stage 1 plus stage 2 pts, 3 at least will be responding, treatment will be declared worthy for further investigations. The type I and II error are set both at 0.1 (power = 90%). We will test the hypothesis that brentuximab can promote anti-tumor immunity, which might contribute to the clinical efficacy. We will use multiparametric flow cytometry to assess whether SGN-35 can: a) impact on frequency and absolute counts of all main cellular subsets; b) shift the TH1/TH2 balance, in favor of a TH1-type of response; c) reduce the frequency of circulating CD30+ regulatory T cells and CD30+ TH2 memory T cells; d) promote an increase in circulating CD161+TH17 T cells; d) reverse the condition of immune dysfunction, by assessing the expression of negative co-signaling molecules (PD-1, CTLA-4, CD160, CD244, CD57, TIM-3, LAG-3) and of activation/proliferation markers (Ki67, GranzymeB, CD69) on main T cell subsets. As of July 2014, 6 pts have been enrolled (NCT01851200).