Phase I Study of Brentuximab Vedotin for the Prevention of Acute GvHD after Unrelated Allogeneic Stem Cell Transplantation

After exposure to allo-antigens, CD30 expression is induced on a distinct population of T cells that are predominantly proliferating and secreting IL-5 and IFN-γ. Blockade of the CD30/CD30L pathway in vivo results in reduced severity of GVHD mediated by CD4 T cells.(Blazar et al.) CD30 is up-regulated in murine regulatory T cells (Tregs) which are important in protecting the host against acute GVHD.(Zeiser et al.) In a mouse model, early blockade of CD30 signaling (< 4 days after transplant), but not late (> 4 days), led to increased GVHD. In our preclinical studies, activated mouse and human T cells demonstrated significant up-regulation of CD30 expression 4 and 5 days after in vitro activation with CD3/CD28 beads, respectively. We hypothesized Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody conjugated with monomethylauristatin E (MMAE), could be used to eliminate allo-reactive T-cells and prevent GvHD in humans. To date 17 subjects ages 29 – 65, undergoing unrelated donor allogeneic stem cell transplant for hematologic malignancies (MDS, ALL, AML, and NHL) with 6 – 8 of 8 locus matched or mismatched donor have been enrolled. A 3+3 study design was used starting with a cohort of no BV, 0.3mg/kg, 0.6mg/kg, 1.2 mg/kg and 1.8 mg/kg BV IV Q3wks x 4 doses starting on day +7. Standard mini-methotrexate and tacrolimus GvHD prophylaxis was used. CD34 dose of ≥2x106 was required to receive study drug. All recipients had primary engraftment. Time to ANC engraftment in the observation cohort was 8 – 19 days. Median time to ANC engraftment in treatment cohorts was 11 days (Range 10 – 16 days). One subject in cohort 1 (0.3 mg/kg BV) had secondary loss of engraftment and was replaced. One subject in cohort 3 (1.2mg/kg BV) withdrew consent for treatment after developing a rash possibly related to BV and was replaced. No DLTs have been observed. The most common grade 3 / 4 adverse events were cytopenias, abdominal cramping, diarrhea, nausea and febrile neutropenia. The median number of cycles of BV received was 2 (Range 1 – 4). 3 subjects have been treated in the final cohort (1.8 mg/kg BV). Acute GvHD has been observed in 11/17 study subjects to date. One case of grade 2 acute GvHD was observed in the observation cohort. In treatment cohorts grade II-IV acute GvHD incidence was 54% (7/13). Grade III – IV acute GvHD occurred in 38% (5/13) of subjects. BV when given starting at day +7 after transplant does not affect engraftment and has minimal toxicity. Its effect on acute GvHD based on this small cohort of subjects is hard to determine with confidence but grades III – IV acute GvHD have been observed including 2 subjects at the highest dose tested. The timing of CD30 targeted therapies after transplant may be critical as previously identified in mouse models. Ongoing studies are evaluating peripheral blood T cell subsets and the proportions of Tregs and effector T-cells after transplant and treatment with BV.