Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial

Zeiser, Robert; Socié, Gérard; Schroeder, Mark A.; Abhyankar, Sunil; Vaz, Carlos Pinho; Kwon, Mi; Clausen, Johannes; Volodin, Leonid; Giebel, Sebastian; Chacón, Manuel; Meyers, Gabrielle; Ghosh, Monalisa; Deeren, Dries; Sanz, Jaime; Morariu-Zamfir, Rodica; Arbushites, Michael; Lakshminarayanan, Mani; Barbour, April M.; Chen, Yi-Bin

doi:10.1016/s2352-3026(21)00367-7

Cited by 35 publications

(47 citation statements)

References 30 publications

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“…In a randomized phase III trial, the addition of itacitinib, a selective JAK1 inhibitor, to corticosteroids did not significantly improve Day 28 ORR for grade II-IV acute GVHD as compared to corticosteroids with placebo (NCT03139604). 59 Similarly, in chronic GVHD, the addition of ibrutinib in the front-line treatment of moderate/severe disease failed to improve response rates as compared to placebo when used in combination with corticosteroids (NCT02959944). 60 An ongoing phase III trial is randomizing patients with newly diagnosed moderate or severe chronic GVHD to treatment with itacitinib or placebo in combination with corticosteroids (NCT03584516).…”

Section: Future Directionsmentioning

confidence: 99%

Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease

2022

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Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplantation (HCT) and is associated with significant morbidity and mortality. For many years, there have been few effective treatment options for patients with GVHD. First-line systemic treatment remains corticosteroids, but up to 50% of patients will develop steroid-refractory GVHD and the prognosis for these patients is poor. Elucidation of the pathophysiological mechanisms of acute and chronic GVHD has laid a foundation for novel therapeutic approaches. Since 2017, there have now been 4 approvals by the US Food and Drug Administration (FDA) for GVHD. Ruxolitinib, an oral selective JAK1/2 inhibitor, received FDA approval for the treatment of steroid-refractory acute GVHD in 2019 and remains the only agent approved for acute GVHD. There are currently 3 FDA approvals for the treatment of chronic GVHD: (1) ibrutinib, a BTK inhibitor traditionally used for B-cell malignancies, was the first agent approved for chronic GVHD after failure of one or more lines of systemic therapy, (2) belumosudil, an oral selective inhibitor of ROCK2, for patients with chronic GVHD who received at least 2 prior lines of treatment, and (3) ruxolitinib for chronic GVHD after failure of one or two lines of systemic therapy. In this review, we highlight the clinical data which support these FDA approvals in acute and chronic GVHD with a focus on mechanism of actions, clinical efficacy, and toxicities associated with these agents.

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Section: Future Directionsmentioning

confidence: 99%

Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease

2022

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“…An interim analysis from the phase III clinical trial (NCT03139604) 31 S1). The MRs were not included for further analysis.…”

Section: Part 2 (Validation Cohort)mentioning

confidence: 99%

“…34 Overall, 74.0% of participants with treatmentnaive acute GVHD responded to itacitinib at Day 28. 31…”

Section: Part 2 (Validation Cohort)mentioning

confidence: 99%

“…A total of 13 candidate biomarkers, listed in Figure 2, were validated against serum samples taken at baseline from a validation cohort representing the first 210 participants enrolled in a phase III trial. 31 Responses for the validation cohort were classified per protocol (Figure 3). Based on standard-risk score, 7 78% of participants were considered standard risk and 22% were considered high risk.…”

Section: Part 2: Validation Of Candidate Predictive Biomarkersmentioning

confidence: 99%

“…30 A phase III study (NCT03139604) evaluated itacitinib plus corticosteroids as an initial treatment for acute GVHD. 31 Although the study did not meet its primary end-point (Day 28 observed response), assumptions used in powering the study led to over enrolment of patients with standard-risk or Grade II acute GVHD and over performance of the placebo group based on historical data of corticosteroid monotherapy. 31 Thus, additional data will be required to determine if itacitinib provides clinical benefit for patients with acute GVHD.…”

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A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft‐versus‐host disease

et al. 2022

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Summary A broad proteomic analysis was conducted to identify and evaluate candidate biomarkers potentially predictive of response to treatment with an oral selective Janus kinase 1 (JAK1) inhibitor, itacitinib, in acute graft‐versus‐host disease (GVHD). Plasma samples from 25 participants (identification cohort; NCT02614612) were used to identify novel biomarkers that were tested in a validation cohort from a placebo‐controlled, randomised trial (n = 210; NCT03139604). The identification cohort received corticosteroids plus 200 or 300 mg itacitinib once daily. The validation cohort received corticosteroids plus 200 mg itacitinib once daily or placebo. A broad proteomic analysis was conducted using a proximity extension assay. Baseline and longitudinal comparisons were performed with unpaired t‐test and one‐way analysis of variance used to evaluate biomarker level changes. Seven candidate biomarkers were identified. Monocyte‐chemotactic protein (MCP)3, pro‐calcitonin/calcitonin (ProCALCA/CALCA), together with a previously identified prognostic acute GVHD biomarker, regenerating islet‐derived protein (REG)3A, stratified complete responders from non‐responders (participants with progressive disease) to itacitinib, but not placebo, potentially representing predictive biomarkers of itacitinib in acute GVHD. ProCALCA/CALCA, suppressor of tumorigenicity (ST)2, and tumour necrosis factor receptor (TNFR)1 were significantly reduced over time by itacitinib in responders, potentially representing response‐to‐treatment biomarkers. Novel biomarkers have the potential to identify patients with acute GVHD that may respond to itacitinib plus corticosteroid treatment (NCT02614612; NCT03139604).

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Itacitinib Population Pharmacokinetics and Exposure‐Response in Patients With Acute Graft‐Versus‐Host Disease

Chen

Xun

Yuska

et al. 2023

The Journal of Clinical Pharma

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This article presents the population pharmacokinetic (PopPK) analysis and exposure‐response analyses for the primary efficacy end point—acute graft‐versus‐host disease (aGVHD) day 28 response—and select safety measures (incidence of thrombocytopenia, hypertriglyceridemia, and cytomegalovirus infection) from a phase 3 randomized, double‐blind study comparing itacitinib plus corticosteroids versus placebo plus corticosteroids for the treatment of aGVHD. The PopPK data set contained sparse data from patients with aGVHD and select enriched data from healthy volunteers. The structural model was a 2‐compartment model with first‐order elimination and dose‐dependent nonlinear absorption with dual first‐order absorption pathways with lag times. Strong cytochrome P450 (CYP) 3A inhibitor coadministration, moderate renal impairment, and participant population (healthy volunteers vs patients with aGVHD) were covariates on apparent clearance. Participant population was also a covariate on apparent intercompartmental clearance and lag time of the secondary absorption compartment. Apparent clearance decreased 42% with coadministration of strong CYP3A inhibitors. Simulations supported the following dose reductions with concomitant use of a strong CYP3A inhibitor: 300 mg once daily to 200 mg once daily, 400 mg once daily to 300 mg once daily, and 600 mg once daily to 400 mg once daily. No dose adjustment is recommended for any other covariate based on the magnitude of impact when they were retained in the model. The exposure‐response relationship was characterized between itacitinib exposure and probability of aGVHD day 28 response using a linear logistic regression model. Both itacitinib exposure and aGVHD risk status were significant predictors of response. There was no relationship between itacitinib exposure and thrombocytopenia, hypertriglyceridemia, or cytomegalovirus infection.

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Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial

Cited by 35 publications

References 30 publications

Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease

Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease

A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft‐versus‐host disease

Itacitinib Population Pharmacokinetics and Exposure‐Response in Patients With Acute Graft‐Versus‐Host Disease

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