GRAVITAS-119: Itacitinib in Combination With Calcineurin Inhibitor-Based Interventions for the Prophylaxis of 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 impact and safety of itacitinib in combination with calcineurin inhibitor (CNI)-based interventions for the prophylaxis of graft-versus-host-disease (GVHD).

Official Title
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GRAVITAS-119: A Single-Arm, Open-Label, Phase 1 Study of Itacitinib in Combination With Calcineurin Inhibitor-Based Interventions for the Prophylaxis of Graft-Versus Host Disease

Conditions
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Hematologic Malignancies

Intervention / Treatment
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* Drug: Itacitinib
* Drug: Calcineurin inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with acute leukemia, chronic myelogenous leukemia, or myelodysplasia with no circulating blasts and < 5% blasts in the bone marrow. Subjects with non-Hodgkin lymphoma, including but not limited to chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B cell, or mantle cell lymphoma must have chemosensitive disease at time of transplant. Subjects with Hodgkin lymphoma with chemosensitive disease at the time of transplant. Must be candidates for reduced-intensity conditioning regimens. Must be candidates for peripheral blood stem cell transplants. Karnofsky Performance Status score ≥ 70% or Eastern Cooperative Oncology Group Performance Status score of 0 to 2. Serum creatinine ≤ 2.0 mg/dL or creatinine clearance ≥ 40 mL/min measured or calculated by Cockcroft-Gault equation. Be willing to avoid pregnancy or fathering children. Exclusion Criteria: Has previously received an allogenic hematopoietic stem cell transplant. Presence of an active uncontrolled infection. Known HIV infection. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection that requires treatment or at risk for HBV reactivation. Prior malignancies. Severe organ dysfunction. Prior treatment with a JAK inhibitor or with an investigational agent, device, or procedure within 21 days of enrollment. Currently breastfeeding. Known allergies, hypersensitivity, or intolerance to any of the study medications. Receipt of live (including attenuated) vaccines during the study, or anticipation of need for such a vaccine during the study. History of primary idiopathic myelofibrosis or any severe marrow fibrosis that would prolong neutrophil engraftment to > 28 days after transplant. Post-transplant maintenance therapy for the hematologic malignancy or plans to initiate maintenance therapy during study treatment.

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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Itacitinib + Calcineurin Inhibitor (CNI) -Based Interventions<br>Itacitinib in combination with a CNI-based intervention. | Drug: Itacitinib<br>* Itacitinib administered orally once daily at the protocol-defined dose.<br>* Other names: INCB039110;Drug: Calcineurin inhibitor<br>* The CNI-based prophylaxis regimen will be identified by the investigator before the subject's enrollment and will consist of the combination of tacrolimus/methotrexate, cyclosporine A/mycophenolate mofetil or tacrolimus plus post-treatment cyclophosphamide. Antithymocyte globulin may be included at the treating investigator's discretion with the tacrolimus/methotrexate or cyclosporine A/mycophenolate mofetil combinations.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with hematologic recovery when itacitinib is added to GVHD prophylaxis treatment | Hematologic recovery defined as demonstrating both neutrophil recovery (ANC ≥ 500/mm^3 for 3 consecutive measurements) and platelet recovery (platelet count ≥ 20,000/mm^3 with no requirement for platelet transfusion in the preceding 3 days). | Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GVHD relapse-free survival rate | Defined as the proportion of subjects who do not experience Grade III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD) requiring systemic therapy, malignancy relapse or progression, or death due to any cause. | Days 100, 180 and 365 | 
| Relapse-free survival | Defined as the interval between enrollment and malignancy relapse or progression, or death, whichever occurs first. | Up to 1 year | 
| Transplant-related mortality | Defined as the proportion of subjects who die due to causes other than malignancy relapse or progression. | Up to 1 year | 
| Median time to neutrophil and platelet engraftment | Defined as the median time to achieve neutrophil and platelet engraftment. | Up to Day 28 | 
| Percentage of participants who achieve neutrophil and platelet engraftment | Defined as the median time to achieve engraftment and hematologic recovery at prespecified time points. | Up to Day 28 | 
| Donor Chimerism |  | Up to Day 28 | 
| Proportion of subjects who are diagnosed with Grade II-IV aGVHD, by each grade and by Grade III/IV | Measured to assess the incidence of aGVHD. | Days 100 and Days 180 | 
| Proportion of subjects who are diagnosed with cGVHD by grade (mild, moderate, or severe) | Measured to assess the incidence of cGVHD. | Up to 1 year | 
| Infection rate | Defined as the proportion of subjects who demonstrate an infection and/or cytomegalovirus reactivation. | Up to 1 year | 
| Overall survival | Defined as the interval between enrollment and death due to any cause. | Up to 1 year | 
| Participants with Grade 3-5 treatment-emergent adverse events (TEAEs) | TEAE is defined as either an adverse event (AE) reported for the first time or worsening of a pre-existing condition after the first dose of study treatment. | Up to approximately 200 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute leukemia, chronic myelogenous leukemia, myelodysplasia, chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular, marginal zone, diffuse large B-cell, Hodgkin's lymphoma, mantle cell lymphoma, Janus kinase inhibitor, graft-versus-host disease