GRAVITAS-309: Itacitinib and Corticosteroids as Initial Treatment for Chronic Graft-Versus-Host Disease

Study Overview
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Brief Summary
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The purpose of this study is to assess the efficacy and safety of itacitinib in combination with corticosteroids as first-line treatment for moderate or severe chronic graft-versus-host disease (cGVHD).

Official Title
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GRAVITAS-309: A Phase 2/3 Study of Itacitinib and Corticosteroids as Initial Treatment for Chronic Graft-Versus-Host Disease

Conditions
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Chronic Graft-versus-host Disease

Intervention / Treatment
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* Drug: Itacitinib
* Drug: Placebo
* Drug: Methylprednisolone
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active, clinically diagnosed, moderate or severe cGVHD per NIH Consensus Criteria Underwent allogeneic stem cell transplantation (allo-HCT) Karnofsky Performance Status score ≥ 60%. Evidence of myeloid and platelet engraftment. Willingness to avoid pregnancy or fathering children based on protocol-defined criteria. Exclusion Criteria: Has received more than 3 days/72 hours of systemic corticosteroid treatment for cGVHD. Has received any other systemic treatment for cGVHD, including extracorporeal photopheresis (ECP). Prior treatment with a Janus kinase (JAK) inhibitor for acute GVHD, unless the participant achieved complete or partial response and has been off JAK inhibitor treatment for at least 8 weeks before randomization. cGVHD occurring after a nonscheduled donor lymphocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Evidence of relapsed primary malignancy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: In Part 2 of the study, participants in the placebo group will be allowed to cross over to the experimental group after completion of the primary analysis.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 : Dose determination of itacitinib<br>itacitinib administered in combination with corticosteroids. | Drug: Itacitinib<br>* In Part 1dose determination participants will receive itacitinib administered orally once daily at the protocol-defined dose according to cohort enrollment. In Part 1 expansion, participants will receive either itacitinib administered orally either once daily or twice a day or corticosteroid alone based on the assigned treatment regimen according to cohort enrollment. In Part 2, participants will receive the recommended dose from Part 1 expansion.<br>* Other names: INCB039110;Drug: Methylprednisolone<br>* Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.<br>* Other names: Medrol, Medrol Dosepak, Solu-Medrol;Drug: Prednisone<br>* Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.<br>* Other names: Deltasone, Prednicot, predniSONE Intensol, Rayos, Sterapred, Sterapred DS;|
| Experimental: Part 1 : Dose expansion of itacitinib<br>itacitinib administered in combination with corticosteroids or corticosteroids alone. | Drug: Itacitinib<br>* In Part 1dose determination participants will receive itacitinib administered orally once daily at the protocol-defined dose according to cohort enrollment. In Part 1 expansion, participants will receive either itacitinib administered orally either once daily or twice a day or corticosteroid alone based on the assigned treatment regimen according to cohort enrollment. In Part 2, participants will receive the recommended dose from Part 1 expansion.<br>* Other names: INCB039110;Drug: Placebo<br>* In Part 2, participants will receive matching placebo.<br>Drug: Methylprednisolone<br>* Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.<br>* Other names: Medrol, Medrol Dosepak, Solu-Medrol;Drug: Prednisone<br>* Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.<br>* Other names: Deltasone, Prednicot, predniSONE Intensol, Rayos, Sterapred, Sterapred DS;|
| Placebo Comparator: Part 2 : itacitinib recommended dose from part 1<br>itacitinib or placebo administered in combination with corticosteroids | Drug: Itacitinib<br>* In Part 1dose determination participants will receive itacitinib administered orally once daily at the protocol-defined dose according to cohort enrollment. In Part 1 expansion, participants will receive either itacitinib administered orally either once daily or twice a day or corticosteroid alone based on the assigned treatment regimen according to cohort enrollment. In Part 2, participants will receive the recommended dose from Part 1 expansion.<br>* Other names: INCB039110;Drug: Methylprednisolone<br>* Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.<br>* Other names: Medrol, Medrol Dosepak, Solu-Medrol;Drug: Prednisone<br>* Administered in Parts 1 and 2 as background reference therapy at a dose level that is commensurate with institutional guidelines based on organ involvement and severity of disease.<br>* Other names: Deltasone, Prednicot, predniSONE Intensol, Rayos, Sterapred, Sterapred DS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 : Dose Determination: Number of dose-limiting toxicities | To identify an appropriate dose of itacitinib in combination with corticosteroids as initial treatment for moderate or severe cGVHD. | 28 days | 
| Part 2 : Response rate | Defined as the proportion of participants demonstrating a complete response (CR) or partial response (PR) per National Institutes of Health (NIH) consensus guideline. | Month 6 | 
| Part 1 : Dose Expansion: Number of dose-limiting toxicities | To identify an appropriate dose of itacitinib in combination with corticosteroids as initial treatment for moderate or severe cGVHD. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1, 1 expansion, and Part 2: Cmax of itacitinib when administered in combination with corticosteroids | Maximum observed concentration. | Up to 28 days | 
| Part 1, 1 expansion, and Part 2: Cmin of itacitinib when administered in combination with corticosteroids | Minimum observed plasma or serum concentration over the dose interval. | Up to 28 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft-versus-host-disease, itacitinib, Janus kinase inhibitor, corticosteroids