ALBERT

Description: Introduction: cGVHD exhibits both autoimmune and fibrotic features across multiple organ systems. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor that (1) decreases human T cell IL-21 and IL-17 secretion via STAT3, IRF4 and RORγt regulation; (2) increases percentages and function of Foxp3+ T regulatory cells via a STAT5-dependent mechanism; and (3) reverses established cGVHD in 2 distinct preclinical models. KD025 modulates the immune system by shifting the Th17/Treg balance towards homeostasis. Methods: KD025-208 enrolled 3 sequential cohorts (C) (C1: 200 mg QD, C2: 200 mg BID and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy. Treatment is in 28-Day continuous cycles until disease progression or unacceptable toxicity. The primary endpoint is the overall response rate (ORR) as per 2014 NIH response criteria in the mITT population. Additional endpoints include duration of response (DOR), corticosteroid (CS) dose reductions, failure free survival (FFS) and Lee Symptom Scale (LSS) score. Results: 17, 16 and 21 pts were enrolled in C1, C2, and C3 between Sep-2016 and Mar-2018. Data as of 8-Mar-2019 are included, reflecting a median duration of follow up of 112, 97 and 64 weeks (wks), respectively. At enrollment, median age was 52 yrs, median time from cGVHD diagnosis to treatment was 20 mos, and patients had received a median of 2 prior lines of therapy. 71% of patients were refractory to the last line of therapy prior to enrollment. 50% of pts had cGVHD in ≥4 organs. The median duration of treatment was 37, 33 and 39 wks, respectively. As of 30-Jun-2019, 24% of pts had received 〉18 months of KD025 therapy. 14 pts remain on KD025 treatment. Reasons for discontinuation included cGVHD progression (18), pt voluntary withdrawal (7), relapse of underlying disease (5), investigator decision (5), AE (3) and death (2). ORR (95% CI) was 65% (38%, 85%) in C1, 69% (41%, 89%) in C2, and 62% (38%, 82%) in C3, i.e. 65% (51%, 77%) across all 3 cohorts. Responses were achieved across key subgroups with ORRs of 62% (24/39) in pts with ≥2 prior lines of systemic therapy, 70% (19/27) in pts with ≥4 organs involved and 60% (25/42) in pts with severe cGVHD. CRs were observed in all affected organs except lung; PRs were observed in lung. Responses were rapid, and often achieved within 8 wks, although 4/35 responses occurred after 24 wks. Of note, organs with fibrotic manifestations such as lungs, joints and eyes responded after 24 weeks in some pts. Responses were durable, with a Kaplan-Meier (K-M) median DOR of 34 weeks across all cohorts. 57% of responders sustained a response for ≥20 wks. The K-M median DOR was 34 wks in pts with ≥2 prior lines of systemic therapy. FFS at 6, 12, 18 and 24 mos was 76%, 47%, 40% and 33%, respectively. Baseline median CS dose was 0.21 mg/kg/day of prednisone equivalent. During treatment with KD025, the median CS dose was reduced by 50%. 67% of pts reduced CS dose and 20% discontinued CS completely. The median CS dose reduction was 66% in responders and 25% in non-responders. 52% of pts reported a clinically meaningful improvement (≥7-point reduction) in LSS score during treatment with KD025 with a median time to improvement of 9 wks and a duration for responders of 21 wks. 63% of responders and 32% of non-responders reported a meaningful improvement in LSS score. KD025 was well tolerated with a median Relative Dose Intensity of 98%. Dose reductions/interruptions occurred in 21/54 pts; median duration of interruption was 8.5 days (range 3-20). AEs were consistent with those expected in cGVHD pts receiving CS. Common AEs were URI (35%), diarrhea (31%), nausea (31%), fatigue (30%), dyspnea (28%), increased LFTs (24%), and peripheral edema (22%). 63% had a Grade ≥3 AE; the most common was dyspnea (13%).