Multiple Complete Responses in a Phase 1 Dose-Escalation Study of the Antibody-Drug Conjugate SGN-35 in Patients with Relapsed or Refractory CD30-Positive Lymphomas.

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Background: The antibody-drug conjugate SGN-35 is being developed as a targeted therapy for Hodgkin lymphoma (HL) and other CD30-expressing hematologic malignancies. SGN-35 binds to CD30 and is internalized into the tumor cell, with subsequent release of the antitubulin agent monomethyl auristatin E (MMAE). Binding of released MMAE to tubulin disrupts the microtubule network, prompting cell cycle arrest and apoptosis.

Methods: A multicenter phase 1 dose-escalation study was conducted in 45 patients with refractory or recurrent CD30-positive hematologic malignancies, including HL (n=42), systemic anaplastic large cell lymphoma (sALCL; n=2), and angioimmunoblastic T cell lymphoma (n=1). Median age was 36 (range 20–87) and most patients (93%) had an ECOG performance status of 0/1. Patients had a median of 3 prior chemotherapy regimens (range 1–7); 73% of patients previously received an autologous stem cell transplant. SGN- 35 dose levels ranged from 0.1 to 3.6 mg/kg (2-hr outpatient IV infusion, premedications not required) every 3 weeks. Patients with stable disease or better after 2 doses were eligible to receive additional doses of SGN-35. The study has completed enrollment and a weekly SGN-35 dosing regimen is currently being investigated.

Results: The most common adverse events (occurring in ≥20% of patients) were fatigue, pyrexia, nausea, and diarrhea. Dose-related neutropenia was observed. The maximum tolerated dose was 1.8 mg/kg every 3 weeks. One patient treated at 3.6 mg/kg developed febrile neutropenia and presumed sepsis and died 14 days after the 1st dose of SGN-35. Exposure to SGN-35 increased relative to dose level, and the terminal elimination half-life was 5.0 ± 1.8 days at 1.8 mg/kg. Approximately 75% of patients reporting B symptoms at baseline experienced symptom resolution on study. Most patients (86%) had reductions in target lesion size. Among 28 evaluable patients treated at doses ≥1.2 mg/kg, the objective response rate (CR+PR) was 46% (n=13) and the complete remission rate was 25% (n=7). Two additional PRs were observed in the 0.6 mg/kg cohort. Median response duration to date is 22 weeks (range, 0.1+ to 38+ weeks). Thirteen patients continue on study.

Conclusions: The antibody-drug conjugate SGN-35 induced durable objective responses in heavily pretreated Hodgkin lymphoma and systemic ALCL patients at well-tolerated doses, providing evidence of selective tumor targeting. Pivotal studies with SGN-35 are planned.