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

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ClinicalTrials.gov Identifier: NCT03139604
Recruitment Status : Completed
First Posted : May 4, 2017
Results First Posted : May 15, 2020
Last Update Posted : August 11, 2021
Sponsor:
Information provided by (Responsible Party):
Incyte Corporation

Study Description
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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).

Condition or disease Intervention/treatment Phase
Graft-versus-host Disease (GVHD) Drug: Itacitinib Drug: Placebo Drug: Prednisone Drug: Methylprednisolone Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 439 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Double Blind
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : July 19, 2017
Actual Primary Completion Date : May 2, 2019
Actual Study Completion Date : July 13, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Steroids

Arms and Interventions
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Arm Intervention/treatment
Experimental: Itacitinib
Itacitinib plus corticosteroids
 Drug: Itacitinib
Itacitinib at the protocol-defined dose administered orally once daily (QD) plus corticosteroids.
Other Name: INCB039110

Drug: Prednisone
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.
Other Names:
  • Deltasone
  • Prednicot
  • predniSONE Intensol
  • Rayos
  • Sterapred
  • Sterapred DS

Drug: Methylprednisolone
Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.
Other Names:
  • Medrol
  • Medrol Dosepak
  • Solu-Medrol
Placebo Comparator: Placebo
Matching placebo plus corticosteroids
 Drug: Placebo
Matching placebo tablets administered orally once daily (QD) plus corticosteroids.

Drug: Prednisone
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.
Other Names:
  • Deltasone
  • Prednicot
  • predniSONE Intensol
  • Rayos
  • Sterapred
  • Sterapred DS

Drug: Methylprednisolone
Methylprednisolone 2 mg/kg IV daily (or prednisone equivalent) or at a dose appropriate for the severity of disease as background treatment.
Other Names:
  • Medrol
  • Medrol Dosepak
  • Solu-Medrol


Outcome Measures
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Primary Outcome Measures :
  1. Overall Response Rate Based on Center for International Blood and Marrow Transplant Research (CIBMTR) Response Index [ Time Frame: 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 :
  1. Nonrelapse Mortality [ Time Frame: Month 6,9,12 and 24 ]
    Defined as the percentage of participants who died due to causes other than malignancy relapse.

  2. Duration of Response [ Time Frame: 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.

  3. Cmax of Itacitinib When Administered in Combination With Corticosteroids [ Time Frame: Protocol-defined timepoints up to Day 28 ]
    Defined as maximum observed plasma concentration.

  4. Cmin of Itacitinib When Administered in Combination With Corticosteroids [ Time Frame: Protocol-defined timepoints up to Day 28 ]
    Defined as minimum observed plasma concentration.

  5. Tmax of Itacitinib When Administered in Combination With Corticosteroids [ Time Frame: Protocol-defined timepoints up to Day 28 ]
    Defined as time to maximum plasma concentration.

  6. AUC of Itacitinib When Administered in Combination With Corticosteroids [ Time Frame: Protocol-defined timepoints up to Day 28 ]
    Defined as area under the concentration-time curve.

  7. CL/F of Itacitinib When Administered in Combination With Corticosteroids [ Time Frame: Protocol-defined timepoints up to Day 28 ]
    Defined as oral dose clearance.

  8. Time to Response [ Time Frame: End of Study, total particpation expected to average 24 months ]
    Defined as the interval from treatment initiation to first response

  9. Relapse Rate of Malignant and Nonmalignant Hematologic Disease [ Time Frame: Randomization through end of Study, study duration expected to average 24 months ]
    Defined as the proportion of subjects whose underlying hematologic disease relapses

  10. Malignancy Relapse-related Mortality Rate [ Time Frame: 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.

  11. Failure-free Survival [ Time Frame: 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)

  12. Overall Survival (OS) [ Time Frame: End of Study up to approximately 24 months ]
    Defined as the interval from study enrollment to death due to any cause.

  13. Number of Treatment-emergent Adverse Events With INCB39110 [ Time Frame: 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

  14. Incidence Rate of Secondary Graft Failure [ Time Frame: 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

  15. Proportion of Subjects Who Discontinue Corticosteroids [ Time Frame: Days 28, 56, 100, and 180 ]
    Average and cumulative corticosteroid dose usage will be calculated and proportion of subjects discontinuing corticosteroids will be tabulated

  16. Proportion of Subjects Who Discontinue Immunosuppressive Medications [ Time Frame: Days 56 and 100 ]
    Summary statistics of subjects discontinuing immunosuppressive medications will be calculated

  17. Incidence Rate of aGVHD Flares [ Time Frame: up to day 100 ]
  18. Incidence Rate of cGVHD [ Time Frame: Days 180 and 365 ]
  19. Objective Response Rate [ Time Frame: Days 14, 56 and 100 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03139604


Locations
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Sponsors and Collaborators
Incyte Corporation
Investigators
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Study Director: Rodica Morariu-Zamfir, MD Incyte Corporation
  Study Documents (Full-Text)

Documents provided by Incyte Corporation:
Study Protocol  [PDF] August 13, 2018
Statistical Analysis Plan  [PDF] July 23, 2019

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Incyte Corporation
ClinicalTrials.gov Identifier: NCT03139604    
Other Study ID Numbers: INCB 39110-301
First Posted: May 4, 2017    Key Record Dates
Results First Posted: May 15, 2020
Last Update Posted: August 11, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Incyte Corporation:
Acute graft-versus-host disease
Janus kinase (JAK) inhibitor
itacitinib
corticosteroids
allogeneic hematopoietic stem cell transplant (allo-HSCT)
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Prednisone
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Inflammatory Agents
Glucocorticoids
 Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Neuroprotective Agents
Protective Agents