Phase I Multicenter Trial of Brentuximab Vedotin for Steroid Refractory Acute Graft-Vs.-Host Disease (GVHD)

Background: Outcomes for patients with steroid-refractory acute GVHD remain poor with no standard therapeutic approach. Pre-clinical data demonstrate increased CD30 expression on activated CD8⁺ T-cells at diagnosis of acute GVHD. Brentuximab vedotin (BV) is an antibody-drug conjugate comprised of an anti-CD30 monoclonal antibody linked to MMAE (mono-methyl aurastatin E). We hypothesized that targeting CD30⁺ /CD8⁺ T cells could lead to control of steroid-refractory acute GVHD.

Methods: The primary endpoint of this multicenter phase I trial is to establish the maximum tolerated dose (MTD) of BV for the treatment of steroid-refractory acute GVHD. A 3+3 cohort design was conducted initially with BV given weekly x 3 doses followed by maintenance dosing with a DLT period of 4 weeks (initial dose 0.6 mg/kg IV weekly). After the first 6 patients, the trial was revised to escalating cohorts of 5 patients treated every 2 weeks x 4 doses with a DLT period of 8 weeks. The revised initial starting dose was 0.6 mg/kg IV given every 2 weeks, with planned dose escalation to 0.8 mg/kg, 1.0 mg/kg and 1.2 mg/kg.

Results: A total of 24 patients have been treated at four centers. Eighteen patients had progressive acute GVHD on initial corticosteroid therapy, while six patients experienced a flare of symptoms upon tapering of steroids. Six patients were treated with the initial weekly dosing scheme and two of these patients died from complications of neutropenic sepsis. Eighteen patients were treated with every two week dosing (n=10 at 0.6 mg/kg and n=8 at 0.8 mg/kg). The MTD was defined at 0.8 mg/kg with one DLT being observed (neutropenia). Other attributable adverse events included thrombocytopenia (grade 3, n=1), fatigue (grade 3, n=1) and ileus (grade 3, n=1). At day 28, the overall response rate was 37.5% (9 of 24 patients) with 3 complete responses (CR, 12.5%) and 6 very good partial responses (VGPR, 25%). Another 4 patients had stable disease and remained on trial with one each achieving CR and VGPR after day 28. Nine of 24 patients are currently alive with a median follow-up of 12.9 months (range, 4.7-31.5 months). Analysis of free MMAE levels showed lack of clearance with weekly dosing and this was thought to contribute to the observed cases of neutropenia. With every other week dosing, there was no significant accumulation of free MMAE.

Conclusion: Brentuximab vedotin given at 0.8 mg/kg IV every two weeks x 4 doses was established as the MTD. BV is tolerable and has promising activity in steroid-refractory acute GVHD. An additional 10 patients will be treated at the MTD and ongoing analysis is investigating if CD30 expression on lymphocyte subsets or soluble CD30 levels are associated with response.