GRAVITAS-301: A Study of Itacitinib or Placebo in Combination With Corticosteroids for Treatment of Acute Graft-Versus-Host Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate itacitinib or placebo in combination with corticosteroids as first-line treatment of participants with Grade II to IV acute graft-versus-host disease (aGVHD).

Official Title
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GRAVITAS-301: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Itacitinib or Placebo in Combination With Corticosteroids for the Treatment of First-Line Acute Graft-Versus-Host Disease

Conditions
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Graft-versus-host Disease (GVHD)

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has undergone 1 allo-HSCT from any donor (related or unrelated with any degree of HLA matching) and any donor source (bone marrow, peripheral blood stem cells, or cord blood) for a hematologic malignancy or disorder. Recipients of myeloablative and reduced-intensity conditioning regimens are eligible. Clinically suspected Grade II to IV aGVHD as per MAGIC criteria, occurring after allo-HSCT and any GVHD prophylaxis regimen. Evidence of myeloid engraftment. Use of growth factor supplementation is allowed. Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min measured or calculated by Cockroft Gault equation. Willing to avoid pregnancy or fathering children. Able to give written informed consent and comply with all study visits and procedures. Able to swallow and retain oral medication. Exclusion Criteria: Has received more than 1 allo-HSCT. Has received more than 2 days of systemic corticosteroids for aGVHD. Presence of GVHD overlap syndrome. Presence of an active uncontrolled infection. Known human immunodeficiency virus infection. Active hepatitis B virus (HBV) or hepatitis C virus infection that requires treatment or at risk for HBV reactivation. Participants with evidence of relapsed primary disease, or participants who have been treated for relapse after the allo-HSCT was performed. Any corticosteroid therapy for indications other than GVHD at doses > 1 mg/kg per day methylprednisolone (or prednisone equivalent) within 7 days of randomization. Severe organ dysfunction unrelated to underlying GVHD, including: Cholestatic disorders or unresolved veno-occlusive disease of the liver. Clinically significant or uncontrolled cardiac disease. Clinically significant respiratory disease that requires mechanical ventilation support or 50% oxygen. Currently breast feeding. Received JAK inhibitor therapy after allo-HSCT for any indication. Treatment with a JAK inhibitor before allo-HSCT is permitted. Treatment with any other investigational agent, device, or procedure within 21 days (or 5 half-lives, whichever is greater) of enrollment. Any medical complications or conditions that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data. Known allergies, hypersensitivity, or intolerance to any of the study medications, excipients, or similar compounds.

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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itacitinib<br>Itacitinib plus corticosteroids | Drug: Itacitinib<br>* Itacitinib at the protocol-defined dose administered orally once daily (QD) plus corticosteroids.<br>* Other names: INCB039110;Drug: Prednisone<br>* Oral prednisone may be used to begin standard corticosteroid background treatment at the investigator's discretion, at a dose equivalent to methylprednisolone 2 mg/kg per day.<br>* Other names: Sterapred DS;Drug: Methylprednisolone<br>* Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.<br>* Other names: Solu-Medrol;|
| Placebo Comparator: Placebo<br>Matching placebo plus corticosteroids | Drug: Placebo<br>* Matching placebo tablets administered orally once daily (QD) plus corticosteroids.<br>Drug: Prednisone<br>* Oral prednisone may be used to begin standard corticosteroid background treatment at the investigator's discretion, at a dose equivalent to methylprednisolone 2 mg/kg per day.<br>* Other names: Sterapred DS;Drug: Methylprednisolone<br>* Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.<br>* Other names: Solu-Medrol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index | Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR). | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nonrelapse Mortality | Defined as the percentage of participants who died due to causes other than malignancy relapse. | Month 6,9,12 and 24 | 
| Duration of Response | Defined as the interval from first response until GVHD progression or death. | Baseline through 30-35 days after end of treatment, total particpation expected to average 24 months | 
| Cmax of Itacitinib When Administered in Combination With Corticosteroids | Defined as maximum observed plasma concentration. | Protocol-defined timepoints up to Day 28 | 
| Cmin of Itacitinib When Administered in Combination With Corticosteroids | Defined as minimum observed plasma concentration. | Protocol-defined timepoints up to Day 28 | 
| Tmax of Itacitinib When Administered in Combination With Corticosteroids | Defined as time to maximum plasma concentration. | Protocol-defined timepoints up to Day 28 | 
| AUC of Itacitinib When Administered in Combination With Corticosteroids | Defined as area under the concentration-time curve. | Protocol-defined timepoints up to Day 28 | 
| CL/F of Itacitinib When Administered in Combination With Corticosteroids | Defined as oral dose clearance. | Protocol-defined timepoints up to Day 28 | 
| Time to Response | Defined as the interval from treatment initiation to first response | End of Study, total particpation expected to average 24 months | 
| Relapse Rate of Malignant and Nonmalignant Hematologic Disease | Defined as the proportion of subjects whose underlying hematologic disease relapses | Randomization through end of Study, study duration expected to average 24 months | 
| Malignancy Relapse-related Mortality Rate | Defined as the proportion of subjects whose malignancy relapses and has a fatal outcome. | Randomization through end of Study, study duration expected to average 24 months | 
| Failure-free Survival | Defined as the proportion of subjects who are still alive, have not relapsed, have not required additional therapy for aGVHD, and have not demonstrated signs or symptoms of chronic graft-versus-host disease (cGVHD) | 6 months from randomization | 
| Overall Survival (OS) | Defined as the interval from study enrollment to death due to any cause. | End of Study up to approximately 24 months | 
| Number of Treatment-emergent Adverse Events With INCB39110 | Adverse events reported for the first time or worsening of a pre-existing event after the first dose of study treatment | 30-35 days after end of treatment, approximately 24 months | 
| Incidence Rate of Secondary Graft Failure | Defined as > 95% recipient cells any time after engraftment with no signs of relapse, OR retransplantation because of secondary neutropenia (< 0.5 × 109/L) and/or thrombocytopenia (< 20 × 109/L) within 2 months of transplantion | Randomization through end of Study, study duration expected to average 24 months | 
| Proportion of Subjects Who Discontinue Corticosteroids | Average and cumulative corticosteroid dose usage will be calculated and proportion of subjects discontinuing corticosteroids will be tabulated | Days 28, 56, 100, and 180 | 
| Proportion of Subjects Who Discontinue Immunosuppressive Medications | Summary statistics of subjects discontinuing immunosuppressive medications will be calculated | Days 56 and 100 | 
| Incidence Rate of aGVHD Flares |  | up to day 100 | 
| Incidence Rate of cGVHD |  | Days 180 and 365 | 
| Objective Response Rate |  | Days 14, 56 and 100 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute graft-versus-host disease, Janus kinase (JAK) inhibitor, itacitinib, corticosteroids, allogeneic hematopoietic stem cell transplant (allo-HSCT)