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Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

ABSTRACT: Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.

SUBMITTER: Cutler C

PROVIDER: S-EPMC8641099 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

Cutler Corey C Lee Stephanie J SJ Arai Sally S Rotta Marcello M Zoghi Behyar B Lazaryan Aleksandr A Ramakrishnan Aravind A DeFilipp Zachariah Z Salhotra Amandeep A Chai-Ho Wanxing W Mehta Rohtesh R Wang Trent T Arora Mukta M Pusic Iskra I Saad Ayman A Shah Nirav N NN Abhyankar Sunil S Bachier Carlos C Galvin John J Im Annie A Langston Amelia A Liesveld Jane J Juckett Mark M Logan Aaron A Schachter Levanto L Alavi Asif A Howard Dianna D Waksal Harlan W HW Ryan John J Eiznhamer David D Aggarwal Sanjay K SK Ieyoub Jonathan J Schueller Olivier O Green Laurie L Yang Zhongming Z Krenz Heidi H Jagasia Madan M Blazar Bruce R BR Pavletic Steven S

Blood 20211201 22

Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registra ...[more]

PMID: 34265047

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Project description:Chronic graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) owing to both the disease itself and the immunosuppressive agents used for treatment. Response criteria endorsed by the National Institutes of Health (NIH) Consensus Conference on Clinical Trials in chronic GVHD include both clinician-documented measures and patient-reported outcomes (PROs) since both are considered clinical benefits by the Food and Drug Administration. The correlation between clinically assessed responses in organs and PRO improvements in organ-specific symptoms has not been investigated in depth. We used data from 2 published studies of belumosudil, an oral rho-associated coiled-coil-containing protein kinase-2 (ROCK2) inhibitor, for chronic GVHD to test the correlation between clinical and PRO outcomes. Participants completed PROs at enrollment and every 1 to 2 cycles according to the study design. Individual organ responses (complete plus partial response) and clinically meaningful changes in PROs were defined according to published methods. Generalized estimating equation methods were used to correlate changes in PROs associated with clinical responses according to NIH criteria, accounting for missing information and repeated measures. Data from all doses in both trials were included without stratification. The liver and genital tract were not included owing to a lack of site-specific PROs. Our pooled analysis of clinical and PRO data included 170 patients enrolled in 2 belumosudil studies (NCT02841995, n = 54; NCT03640481, n = 132) for whom we had baseline PROs, at least 1 follow-up PRO, and at least 1 response assessment. There was a strong positive correlation between complete and partial organ and overall responses and changes in PRO symptom scores, as well as clinically meaningful improvements. For all organs except joints, esophagus, and lower gastrointestinal tract, there was at least 1 PRO statistically correlated with NIH organ response. These data support the use of PROs for response assessment to document clinically meaningful benefit in chronic GVHD clinical trials.

Project description:BackgroundChronic graft-versus-host disease (cGVHD) is an immune-related disorder that is the most common complication post-allogenic hematopoietic stem cell transplant. Corticosteroids with or without calcineurin inhibitors (CNIs) remain the mainstay of cGVHD treatment for first-line therapy. However, for many patients, cGVHD symptoms cannot be effectively managed and thus require second-line therapy. Currently, there is no approved treatment for second-line cGVHD treatment in China. In this study, belumosudil, a highly selective and potent rho-associated coiled-coil-containing protein kinase-2 inhibitor demonstrated to be effective for cGVHD in the United States and other Western countries, is investigated in patients with cGVHD in China for its overall benefit-risk balance.MethodsThis multicenter, open-label phase II study evaluated the safety, efficacy, and pharmacokinetics of oral belumosudil 200 mg once daily in cGVHD patients who had been treated with at least one line of systemic therapy in China. The primary endpoint was overall response rate (ORR); each individual patient's response was assessed by the investigator using the 2014 National Institutes of Health consensus criteria. Secondary endpoints were duration of response (DOR), time to response (TTR), changes in Lee Symptom Scale (LSS) score, organ response rate, corticosteroid dose change, CNI dose change, failure-free survival, time-to-next-treatment, overall survival, and safety.ResultsThirty patients were enrolled in the study with a median follow-up time of 12.9 months. ORR was 73.3% (95% confidence interval: 54.1-87.7%) and all responders achieved partial response. Median DOR among responders was not reached and median TTR was 4.3 weeks (range: 3.9-48.1). Fifteen patients (50.0%) achieved clinically meaningful response in terms of reduction in LSS score by ≥ 7 points from baseline. Corticosteroid and CNI dose reductions were reported in 56.7% (17/30) and 35.0% (7/20) of patients, respectively. Most treatment-emergent adverse events (TEAEs) were mild to moderate in severity, with 11 patients (36.7%) experiencing grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAE was pneumonia (n = 5, 16.7%).ConclusionsBelumosudil treatment demonstrated a favorable benefit-risk balance in treating cGVHD patients who previously have had standard corticosteroid therapy in China where approved second-line setting is absent.Trial registrationClinicalTrials.gov identifier NCT04930562.

Dataset Information

Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

Publications

Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

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