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

• Itacitinib (Drug), also known as INCB039110: Itacitinib at the protocol-defined dose administered orally once daily (QD) plus corticosteroids.
• Placebo (Drug): Matching placebo tablets administered orally once daily (QD) plus corticosteroids.
• Prednisone (Drug), also known as Deltasone, Prednicot, predniSONE Intensol, Rayos, Sterapred, Sterapred DS: 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.
• Methylprednisolone (Drug), also known as Medrol, Medrol Dosepak, Solu-Medrol: Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.

Primary outcomes

• Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index [Day 28]: Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).

Secondary outcomes

• Nonrelapse Mortality [Month 6,9,12 and 24]: Defined as the percentage of participants who died due to causes other than malignancy relapse.
• Duration of Response [Baseline through 30-35 days after end of treatment, total particpation expected to average 24 months]: Defined as the interval from first response until GVHD progression or death.
• Cmax of Itacitinib When Administered in Combination With Corticosteroids [Protocol-defined timepoints up to Day 28]: Defined as maximum observed plasma concentration.
• Cmin of Itacitinib When Administered in Combination With Corticosteroids [Protocol-defined timepoints up to Day 28]: Defined as minimum observed plasma concentration.
• Tmax of Itacitinib When Administered in Combination With Corticosteroids [Protocol-defined timepoints up to Day 28]: Defined as time to maximum plasma concentration.
• AUC of Itacitinib When Administered in Combination With Corticosteroids [Protocol-defined timepoints up to Day 28]: Defined as area under the concentration-time curve.
• CL/F of Itacitinib When Administered in Combination With Corticosteroids [Protocol-defined timepoints up to Day 28]: Defined as oral dose clearance.
• Time to Response [End of Study, total particpation expected to average 24 months]: Defined as the interval from treatment initiation to first response
• Relapse Rate of Malignant and Nonmalignant Hematologic Disease [Randomization through end of Study, study duration expected to average 24 months]: Defined as the proportion of subjects whose underlying hematologic disease relapses
• Malignancy Relapse-related Mortality Rate [Randomization through end of Study, study duration expected to average 24 months]: Defined as the proportion of subjects whose malignancy relapses and has a fatal outcome.
• Failure-free Survival [6 months from randomization]: 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)
• Overall Survival (OS) [End of Study up to approximately 24 months]: Defined as the interval from study enrollment to death due to any cause.
• Number of Treatment-emergent Adverse Events With INCB39110 [30-35 days after end of treatment, approximately 24 months]: Adverse events reported for the first time or worsening of a pre-existing event after the first dose of study treatment
• Incidence Rate of Secondary Graft Failure [Randomization through end of Study, study duration expected to average 24 months]: 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
• Proportion of Subjects Who Discontinue Corticosteroids [Days 28, 56, 100, and 180]: Average and cumulative corticosteroid dose usage will be calculated and proportion of subjects discontinuing corticosteroids will be tabulated
• Proportion of Subjects Who Discontinue Immunosuppressive Medications [Days 56 and 100]: Summary statistics of subjects discontinuing immunosuppressive medications will be calculated
• 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]

Sex: All, ages: 18 Years to any

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.

Participant flow

Outcome results

• Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index (Primary), Number, Percentage of Participants: Itacitinib Plus Corticosteroids 74.0 (67.6 to 79.7); Placebo Plus Corticosteroids 66.4 (59.7 to 72.6) (p 0.0782)
• Nonrelapse Mortality (Secondary), Number, participants: Itacitinib Plus Corticosteroids 36; Placebo Plus Corticosteroids 37
• Duration of Response (Secondary), Median, days: Itacitinib Plus Corticosteroids 587 (513 to NA); Placebo Plus Corticosteroids NA (NA to NA)
• Cmax of Itacitinib When Administered in Combination With Corticosteroids (Secondary), Mean, nM: Itacitinib Plus Corticosteroids 796 +/- 642
• Cmin of Itacitinib When Administered in Combination With Corticosteroids (Secondary), Mean, nM: Itacitinib Plus Corticosteroids 72.5 +/- 121
• Tmax of Itacitinib When Administered in Combination With Corticosteroids (Secondary), Median, hrs: Itacitinib Plus Corticosteroids 2.1 (0.83 to 5.3)
• AUC of Itacitinib When Administered in Combination With Corticosteroids (Secondary), Mean, nM*h: Itacitinib Plus Corticosteroids 6720 +/- 6210
• CL/F of Itacitinib When Administered in Combination With Corticosteroids (Secondary), Mean, L/h: Itacitinib Plus Corticosteroids 104 +/- 76.7
• Time to Response (Secondary), Mean, days: Itacitinib Plus Corticosteroids 9.9 +/- 6.25; Placebo Plus Corticosteroids 10.1 +/- 5.37
• Relapse Rate of Malignant and Nonmalignant Hematologic Disease (Secondary), Number, percentage: Itacitinib Plus Corticosteroids 12.4; Placebo Plus Corticosteroids 11.4
• Malignancy Relapse-related Mortality Rate (Secondary), Number, percentage: Itacitinib Plus Corticosteroids 6.4; Placebo Plus Corticosteroids 7.7
• Failure-free Survival (Secondary), Number, proportion of participants: Itacitinib Plus Corticosteroids 44.29; Placebo Plus Corticosteroids 40.00
• Overall Survival (OS) (Secondary), Median, days: Itacitinib Plus Corticosteroids 365 (1 to 867); Placebo Plus Corticosteroids 348.5 (1 to 827)
• Number of Treatment-emergent Adverse Events With INCB39110 (Secondary), Number, participants: Itacitinib Plus Corticosteroids 208; Placebo Plus Corticosteroids 214
• Incidence Rate of Secondary Graft Failure (Secondary), Number, participants: Itacitinib Plus Corticosteroids 2; Placebo Plus Corticosteroids 0
• Proportion of Subjects Who Discontinue Corticosteroids (Secondary), Number, participants: Itacitinib Plus Corticosteroids 3; Placebo Plus Corticosteroids 3
• Proportion of Subjects Who Discontinue Immunosuppressive Medications (Secondary), Number, participants: Itacitinib Plus Corticosteroids 12; Placebo Plus Corticosteroids 10
• Incidence Rate of aGVHD Flares (Secondary), Number, participants: Itacitinib Plus Corticosteroids 42; Placebo Plus Corticosteroids 48
• Incidence Rate of cGVHD (Secondary), Number, participants: Itacitinib Plus Corticosteroids 25; Placebo Plus Corticosteroids 36
• Objective Response Rate (Secondary), Number, participants: Itacitinib Plus Corticosteroids 170; Placebo Plus Corticosteroids 160

Adverse events

Time frame: 30 days after last dose approximately up to 24 months

Serious adverse events by term

189 more terms not shown.

Other adverse events by term

11 more terms not shown.

29 more sites not listed.

• Results publication: Pratta M, Paczesny S, Socie G, Barkey N, Liu H, Owens S, Arbushites MC, Schroeder MA, Howell MD. A biomarker signature to predict complete response to itacitinib and corticosteroids in acute graft-versus-host disease. Br J Haematol. 2022 Aug;198(4):729-739. doi: 10.1111/bjh.18300. Epub 2022 Jun 11. PMID 35689489
• Results publication: Zeiser R, Socie G, Schroeder MA, Abhyankar S, Vaz CP, Kwon M, Clausen J, Volodin L, Giebel S, Chacon MJ, Meyers G, Ghosh M, Deeren D, Sanz J, Morariu-Zamfir R, Arbushites M, Lakshminarayanan M, Barbour AM, Chen YB. 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. Lancet Haematol. 2022 Jan;9(1):e14-e25. doi: 10.1016/S2352-3026(21)00367-7. PMID 34971577

• Study Protocol (PDF, 2018-08-13)
• Statistical Analysis Plan (PDF, 2019-07-23)

• Rodica Morariu-Zamfir, MD, Study director, Incyte Corporation

NIH grants: 2017