In:
Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 602-602
Abstract:
Introduction: cGVHD remains a leading cause of post-transplant morbidity / mortality, exhibiting features of both autoimmune and fibrotic diseases across multiple organ systems. cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of inflammatory cytokines including IL-17 and IL-21. Moreover, a persistent reduction in the number of regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. In vitro data have demonstrated that KD025 (1) attenuates IL-21 and IL-17 secretion in human CD4+ T cells via STAT3, IRF4 and RORγt regulation, and (2) leads to increased percentages of Foxp3+ CD4+ T cells via a STAT5-dependent mechanism and upregulates the suppressive function of human Tregs. These MOA suggest that KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards a Treg phenotype. No studies have examined KD025 effects in patients with dysregulation associated with high Th17 and low Tregs. Methods: KD025-208 enrolled 3 cohorts (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 cycles until disease progression or unacceptable toxicity. The primary endpoint is the overall response rate (ORR) (% pts achieving partial response (PR) or complete response (CR)) as per 2014 NIH response criteria. Secondary endpoints include duration of response (DOR) and corticosteroid (CS) dose reductions. Exploratory endpoints include Lee Symptom Scale (LSS) score and pharmacodynamics (PD). Peripheral blood samples were collected from all pts at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. The intracellular expression of IL-17A and FOXP3 on viable CD3+ CD4+ cells was determined by using multicolor flow cytometry. Results: Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, median time from cGVHD diagnosis to KD025 treatment of 19 months, and a median of 3 prior treatment regimens. Median duration of treatment was 37 (C1) and 33 (C2) weeks (wks). KD025 demonstrated an ORR of 65% in C1 and 63% in C2. ORR in key subgroups is shown below. Responses were rapid (76% achieved at first assessment at 8 wks) and durable with 82% (C1) and 50% (C2) of responders sustaining response for ≥20 wks. Responses including CRs were observed across all affected organ systems except lung (mouth, eyes, joints/ fascia, skin, upper GI, lower GI, esophagus, liver). A previously reported lung PR was deemed on review to be IPF with no cGVHD involvement. During treatment with KD025, median CS dose was reduced by 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score, including both responders (67%) and non-responders (42%). KD025 has been well tolerated. AEs reported were generally consistent with those expected in pts with advanced cGVHD treated with CS. Common AEs were increased LFTs (42%), URI (33%), anemia (27%), nausea (24%), diarrhea (24%) and fatigue (21%). Increased LFTs did not lead to treatment discontinuation, commonly occurred prior to KD025 dosing and were often considered attributable to cGVHD. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 (33%) pts, none considered related to KD025 treatment. There was no apparent increased risk of infection. Exploratory PD analyses of PBMCs across C1 and C2 revealed an early increase in the percentage of CD4+ Treg cells by C2D1 of KD025 treatment with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C4D1 and C6D25. Conclusion: Treatment with KD025 has demonstrated encouraging clinical responses in cGVHD pts with little toxicity. Responses have been clinically meaningful as evidenced by durability, reductions in CS doses and improvement in LSS score. Exploratory PD data indicate treatment with KD025 may modulate immune homeostasis by restoring the Th17/Treg balance. Figure. Figure. Disclosures Jagasia: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra:Kadmon Corporation, LLC: Consultancy. Bachier:Sanofi: Speakers Bureau; Seattle Genetics: Speakers Bureau. Weisdorf:Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Equillium: Consultancy; SL Behring: Consultancy; FATE: Consultancy. Green:Kadmon Corporation, LLC: Employment. Schueller:Kadmon Corporation, LLC: Employment. Zanin-Zhorov:Kadmon Corporation, LLC: Employment. Weiss:Kadmon Corporation, LLC: Employment. Eiznhamer:Kadmon Corporation, LLC: Employment. Aggarwal:Kadmon Corporation, LLC: Employment. Blazar:Kadmon Corporation, LLC: Consultancy, Research Funding. Lee:Takeda: Research Funding; Kadmon: Research Funding; Amgen: Consultancy, Research Funding; Mallinckrodt: Honoraria; Incyte: Consultancy; Pfizer: Consultancy; Onyx: Research Funding.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood-2018-99-111896
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2018
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
