A Phase I Weekly Dosing Study of Brentuximab Vedotin in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies

Abstract

Purpose: The antibody-drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a proteasecleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies.Experimental Design: In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles.Results: The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n ¼ 24), with 34% (n ¼ 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study.Conclusions: Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted. Clin Cancer Res; 18(1); 248-55. Ó2011 AACR.

Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease

“…Based on our results, weekly dosing, which appeared safe in patients with lymphoma, 12 resulted in profound neutropenia due to accumulation of free MMAE. With a revised dosing schedule of every other week, BV can be safely given to patients for the treatment of SR-aGVHD.…”

Brentuximab vedotin in relapsed/refractory Hodgkin's lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials

“…All patients received at least three doses of BV and were included in the safety analysis; patients received a median of eight cycles of BV (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. In general, the treatment was well tolerated and the toxicity profile was very similar to that previously published.…”

“…[3][4][5] However, curing HL patients who have refractory disease after salvage chemotherapy, who relapse after ASCT, or those who are not candidates for ASCT, remains a clinical challenge due to limited effective treatments; such patients currently have a median overall survival of 2-3 years. Although there are several promising agents currently under investigation in HL, [6][7][8][9][10] novel therapies that are well tolerated with minimal long-term complications are needed for these patients.…”

Targeted Drug Brentuximab Vedotin for Treatment of Relapsed or Refractory Cd30-Positive Hodgkin’s Lymphoma

“…Они были полу-чены из исследований I фазы SGN35-0001 [28], SGN35-0002 [29], японского исследования TB-BC010088 [30] и программы дорегистрационного использования препа-рата по запросу врача (Named Patient Program, NPP).…”

“…Исследования по отдельности не были включены в об-зор, так как все они содержат менее 20 пациентов с ЛХ, получивших БВ в дозе 1,8 мг / кг (в японском исследова-нии -12 пациентов [30], в исследовании SGN35-0001 c эскалацией дозы -12 пациентов [28], в исследовании SGN35-0002 -0 пациентов [29]). …”