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GRAVITAS-301 Studie (INCB39110-301)

AcronymISRCTNEudraCTClinicaltrials.govDRKS
113.4282017-000538-78NCT03139604

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

Status: Active (Recruitment Closed)

Purpose / Objectives

Primary Outcome

  • ORR at Day 28, defined as the proportion of subjects demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).

Secondary Outcomes

  • Nonrelapse mortality (NRM) at Month 6, defined as the proportion of subjects who died due to causes other than malignancy relapse at Month 6.
  • NRM at Months 9, 12, and 24.
  • ORR, defined as the proportion of subjects demonstrating a CR, VGPR, or PR at Days 14, 56, and 100.
  • Duration of response, defined as the interval from first response until graft-versus-host disease (GVHD) progression or death.
  • Time to response, defined as the interval from treatment initiation to first response.
  • Malignancy relapse rate, defined as the proportion of subjects whose underlying malignancy relapses.
  • Malignancy relapse-related mortality rate, defined as the proportion of subjects whose malignancy relapses and has a fatal outcome.
  • 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), at Month 6.
  • Overall survival (OS), defined as the interval from study enrollment to death due to any cause.

Diagnosis

Patient attributes

Age

18-99

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. Biopsies should be obtained to pathologically confirm aGVHD; in cases where a biopsy is negative, is unable to be obtained, or is clinically contraindicated, clinical suspicion of aGVHD by the treating physician is sufficient, provided that alternative diagnoses of drug effects or infection are adequately ruled out.
  • Evidence of myeloid engraftment (eg, ANC ≥ 0.5 × 109/L for 3 consecutive days if ablative therapy was previously used). 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.
  • [...]

Exclusion criteria

  • Has received more than 1 allo-HSCT.
  • Has received more than 2 days of systemic corticosteroids for acute-GVHD.
  • Presence of GVHD overlap syndrome.
  • Presence of an active uncontrolled infection. An active uncontrolled infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as an active uncontrolled infection.
  • Known human immunodeficiency virus infection.
  • Active HBV or HCV infection that requires treatment or at risk for HBV reactivation. HBV DNA and HCV RNA must be undetectable upon testing. At risk for HBV reactivation is defined as hepatitis B surface antigen positive or anti–hepatitis B core antibody positive. Prior test results obtained as part of standard of care that confirm a subject is immune and not at risk for reactivation (ie, hepatitis B surface antigen negative, surface antibody positive) may be used for purposes of eligibility and tests do not need to be repeated. Subjects with prior positive serology results must have negative polymerase chain reaction results. Subjects whose immune status is unknown or uncertain must have results confirming immune status before enrollment.
  • Subjects with evidence of relapsed primary disease, or subjects 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.
  • [...]

Trial design

  • Phase III
  • Multicenter
  • Prospective
  • Randomized
  • Two-arm
  • Double-blind

Intervention

  • Subjects will begin treatment with itacitinib at a dose level of 200 mg (2 × 100 mg tablets) taken by mouth (PO) QD. Subjects may have dose reductions and interruptions during the course of treatment based on safety and laboratory assessments. Tapering of itacitinib is permitted provided that the subject has reached the Day 180 visit, achieved a CR or VGPR, and discontinued corticosteroid therapy for at least 8 weeks. The dose of itacitinib may be escalated or re-started if GVHD flares during the course of a taper. Subjects who experience worsening GVHD during itacitinib escalation and require additional therapy will be considered as having progressive disease and be withdrawn from treatment.

Documents (password protected)

Responsibilities in overall trial

Incyte Corporation

National Coordinating Investigator

Prof. Dr. Robert Zeiser

Study Sites

Klinik I für Innere Medizin

Study office

  • Klinisches Studienzentrum der Klinik I für Innere Medizin Köln

Status

Active (Recruitment Closed)

Principal Investigator

Prof. Dr. med. Dr. h. c. Christoph Scheid

Deputy of Principal Investigator

  • PD Dr. Dr. med. Udo Holtick

Subinvestigator

  • Dr. med. Anja Lohneis
  • Dr. med. Lukas Frenzel
  • PD Dr. med. Marco Herling

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