The Antibody-Drug Conjugate Brentuximab Vedotin (SGN-35) Induced Multiple Objective Responses in Patients with Relapsed or Refractory CD30-Positive Lymphomas in a Phase 1 Weekly Dosing Study.

Abstract 2731 Poster Board II-707 Background: The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the antitubulin agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. In a previous phase 1 study with every 3 week dosing, 54% of patients achieved an objective response (CR/PR) at brentuximab vedotin doses ≥1.2 mg/kg [ASH 2008 abstract 1006]. Methods: To investigate the tolerability and antitumor activity of a more frequent dosing regimen, a multicenter phase 1 study was conducted in patients with refractory or recurrent CD30-positive lymphomas using a 3 + 3 dose-escalation design. Brentuximab vedotin was administered weekly for 3 weeks in 28-day treatment cycles at doses of 0.4 to 1.4 mg/kg (30-min or 2-hr IV infusions). Patients with stable disease or better (Cheson 2007) after two cycles were eligible to receive additional brentuximab vedotin treatment cycles. Results: A total of 37 patients, 31 with Hodgkin lymphoma (HL), 5 with systemic anaplastic large cell lymphoma (ALCL), and 1 with peripheral T-cell lymphoma, were enrolled and treated. Median age was 35 (range 13–82) and most patients (89%) had an ECOG performance status of 0/1. Patients received a median of 3 prior chemotherapy regimens (range 1–8); 62% previously received an autologous stem cell transplant. More than 50% of patients (21 of 37) had disease that did not respond to their most recent prior therapy. Dose-limiting toxicities included G3 diarrhea, G3 vomiting, and G4 hyperglycemia. The maximum tolerated dose was exceeded at 1.4 mg/kg. The most common treatment-related adverse events were peripheral neuropathy, nausea, fatigue, diarrhea, dizziness, and neutropenia; most were grade 1 or 2 in severity. Exposure to brentuximab vedotin (AUC) increased relative to dose level. Among efficacy evaluable patients across all dose levels, the objective response rate (ORR) was 46% (16 of 35), with 29% of patients (10 of 35) attaining a complete remission. Median duration of response to date is at least 16 weeks (range, 0.1+ to 34+); 15 patients continue on treatment. Conclusions: Weekly dosing with brentuximab vedotin was generally well tolerated and induced a high rate of objective responses in heavily pretreated patients with HL and systemic ALCL. A pivotal trial of this ADC in patients with relapsed or refractory HL has completed enrollment. Disclosures: Fanale: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is an investigational agent. Bartlett:Seattle Genetics, Inc.: Research Funding. Forero-Torres:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Horning:Seattle Genetics, Inc.: Research Funding. Franklin:Seattle Genetics, Inc.: Research Funding. Lynch:Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment.