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

Phase 3

Completed

Conditions: Graft-versus-host Disease (GVHD)

Interventions: Drug: Placebo
Drug: Itacitinib
Drug: Prednisone
Drug: Methylprednisolone

Registration Number: NCT03139604

Lead Sponsor: Incyte Corporation

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 439

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Itacitinib	Prednisone	Itacitinib plus corticosteroids
Placebo	Methylprednisolone	Matching placebo plus corticosteroids
Itacitinib	Methylprednisolone	Itacitinib plus corticosteroids
Placebo	Placebo	Matching placebo plus corticosteroids
Itacitinib	Itacitinib	Itacitinib plus corticosteroids
Placebo	Prednisone	Matching placebo plus corticosteroids

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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

Trial Locations

Locations (129): University of California, San Diego (UCSD) - Moores Cancer Center
🇺🇸
La Jolla, California, United States
University of Southern California
🇺🇸
Los Angeles, California, United States
University of California, Los Angeles (UCLA) - Medical Center
🇺🇸
Los Angeles, California, United States
Stanford Cancer Center
🇺🇸
Stanford, California, United States
University of Colorado - Aurora Cancer Center
🇺🇸
Aurora, Colorado, United States
University of Florida (UF) - Division of Hematology & Oncology
🇺🇸
Gainesville, Florida, United States
University of Miami - Sylvester Cancer Center
🇺🇸
Miami, Florida, United States
Florida Hospital Cancer Institute
🇺🇸
Orlando, Florida, United States
University of Illinois at Chicago
🇺🇸
Chicago, Illinois, United States
University of Chicago
🇺🇸
Chicago, Illinois, United States
Scroll for more (119 remaining)
University of California, San Diego (UCSD) - Moores Cancer Center
🇺🇸La Jolla, California, United States