A Phase 2 Study of Retreatment with Brentuximab Vedotin in Patients with cHL, sALCL or Other CD30-Expressing PTCL

Background

Brentuximab vedotin is an antibody-drug conjugate composed of an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Targeted delivery of MMAE to CD30-expressing cells is the primary mechanism of action of brentuximab vedotin (Sutherland 2006). Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptotic death of the cell. In addition, the direct cytotoxicity associated with brentuximab vedotin may be augmented by secondary effects, including the bystander effect (Li 2016) and several important immuno-oncology related effects, such as immunogenic cell death (Gardai 2015; Muller 2014) and antibody-dependent cellular phagocytosis (Oflazoglu 2007). Brentuximab vedotin has been approved for several indications, including the recent US Food and Drug Administration approval for the treatment of adults with previously untreated systemic anaplastic large cell lymphoma (sALCL) and other CD30-expressing peripheral T-cell lymphomas (PTCL).

Given that CD30 expression has been shown to persist during treatment with brentuximab vedotin, and after treatment when patients have relapsed (Porpaczy 2013), there is rationale to support evaluation of brentuximab vedotin in a retreatment setting. Encouraging safety and antitumor activity were observed in a phase 1 study (Clinicaltrials.gov: NCT00947856) of brentuximab vedotin retreatment in patients with relapsed/refractory classic Hodgkin lymphoma (cHL) or sALCL. The objective response rate (ORR) for retreatment of cHL was 60% (12 of 20 evaluable patients) with a complete response (CR) rate of 30% (6 of 20 evaluable patients). For retreated sALCL, the ORR was 88% (7 of 8 patients) with a CR rate of 63% (5 of 8 patients). The estimated median duration of response (DOR) for patients with an objective response was 9.5 months, and for patients with a CR, the estimated median DOR was 12.3 months (Bartlett 2014). However, interpretation from this study is limited because it did not include patients who received brentuximab vedotin as part of frontline treatment or in patients with non-sALCL PTCL. The potential of retreatment with brentuximab vedotin to offer a meaningful treatment option throughout the continuum of these diseases is under investigation.

Study Design and Methods

This is a phase 2, multicenter, single-arm study to determine the safety and efficacy of brentuximab vedotin in patients with relapsed or refractory cHL, sALCL, or other CD30-expressing PTCL who experienced CR or partial response with a brentuximab vedotin-containing regimen and subsequently experienced disease progression or relapse. Patients who previously discontinued brentuximab vedotin due to any Grade 3 or higher toxicity or have existing Grade 2 or higher peripheral neuropathy will not be eligible. It is anticipated that approximately 50 patients will enroll in this study.

All patients will be administered 1.8 mg/kg brentuximab vedotin intravenously, up to a maximum of 180 mg, over 30 minutes once per 21-day cycle. Patients who previously required a dose reduction due to adverse events (AE) will be administered brentuximab vedotin at 1.2 mg/kg.

The primary efficacy endpoint of this study is ORR (per blinded independent central review), a direct measure of anti-tumor activity. To further assess the significance of ORR in this study, durability, CR rate, overall survival, and progression-free survival will be evaluated as secondary endpoints. Safety will be monitored throughout the trial via laboratory values and AE collection. The study's sample size was chosen to allow adequate precision of estimates of response rates and characterization of safety data. Enrollment in this study is expected in September 2019 (Clinicaltrials.gov: NCT03947255).