OP0172 BRENTUXIMAB VEDONTIN FOR SKIN INVOLVEMENT IN REFRACTORY DIFFUSE CUTANEOUS SYSTEMIC SCLEROSIS, INTERIM RESULTS OF A PHASE IIB OPEN-LABEL TRIAL

Abstract

Background:Systemic sclerosis (SSc) is an autoimmune disease affecting multiple organs causing morbidity and mortality. Treatments targeting SSc skin often have limited success. The presence of CD30+ lymphocytes in skin biopsies and increased levels of serum CD30 have been reported in SSc patients1. This could constitute a new therapeutic target.Objectives:To explore the efficacy and safety of brentuximab vedotin, a chimeric anti-CD30 antibody drug conjugate, in patients with severe active diffuse cutaneous SSc who failed multiple treatments.Methods:This Phase IIb, single center, open-label, investigator-initiated trial will recruit 10 patients. Brentuximab vedotin 0.6 mg/Kg was infused intravenously every 3 weeks for 48 weeks. Inclusion criteria were age ≥18 years, meeting the 2013 ACR/EULAR SSc classification criteria, modified Rodnan skin score (mRSS) ≥15 with <5 years since the first non-Raynaud’s symptom and/or skin worsening despite immunosuppression. Patients were allowed to continue their standard of care medications for SSc except for rituximab. Patients with severe cardiac or pulmonary SSc involvement, severe infections, significant peripheral neuropathy, or active malignancy were excluded. The primary objective was a decrease in mRSS of ≥8 at 48 weeks. The main secondary endpoint was MRSS at 24 weeks. Differences were assessed by paired t tests. Data were compared to 16 age, disease duration, mRSS and past/present use of immunosuppressors-matched controls (ratio 2-3:1) from the Canadian Scleroderma Research Group (CSRG) registry.Results:Eight of 10 patients have been recruited to date; two are in the first 8 weeks and one was withdrawn at her request after developing influenza at week 12. Five subjects (60% female) have reached week 24, and 3 have completed 48 weeks. The mRSS is shown in Table 1. The ΔMRSS for patients treated with brentuximab between weeks 0 and 24 was 8.2 ([CI 95% 2.8, 13.6], p = 0.013) and from 0 to 48 was 15.3 ([CI 95% 8.2, 22.5], p = 0.012). Whereas, the ΔMRSS for the CSRG controls was 3.1 ([CI 95% -2, 8.2], p = 0.211) at 48 weeks. Assuming that mRSS would at least be the same from week 24 to 48 in the 2 cases who are between 24 and 48 weeks with brentuximab, we compared the 5 cases vs controls (Figure 1). ΔMRSS for Brentuximab was 12.2 ([CI 95% 5.9, 18.5], p = 0.006. No cases have developed a peripheral neuropathy and only one SAE (influenza).Table 1.N (SD)NAgeDisease durationmRSS week 0mRSS week 24mRSS week 48mRSS week 48**Case560.2 (9.3)4.5 (2.1)33 (5.2)24.8 (6)15.7 (3)20.8 (8.3)Control1658.5 (8.3)4.9 (2.1)31.3 (5.9)N/D28.1 (7.5)28.1 (7.5)p0.7310.7750.559N/D0.0130.079mRSS = modified Rodnan skin score, N/D = no data, ** = comparisons including 5 cases, assuming stability in MRSS from week 24 to 48 in cases 5 and 6Figure 1.Conclusion:Brentuximab vedontin already achieved the primary endpoint at 24 weeks, after half of the intended recruitment sample reached this landmark. A comparison with CSRG controls showed that mRSS only decreased significantly in patients treated with brentuximab. This interim report suggests that brentuximab vedontin might effectively improve skin involvement in patients with diffuse SSc and severe skin involvement.