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Itacitinib for the Prevention of Graft Versus Host Disease in Patients Undergoing Donor Stem Cell Transplantation

Primary Purpose

Allogeneic Stem Cell Transplant Recipient, Hematologic and Lymphocytic Disorder, Hematopoietic and Lymphoid Cell Neoplasm

Status
Withdrawn
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Allogeneic Hematopoietic Stem Cell Transplantation
Busulfan
Fludarabine
Itacitinib
Methotrexate
Tacrolimus
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Allogeneic Stem Cell Transplant Recipient

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Karnofsky performance status of at least 70
  • Patients with hematological disorders undergoing ASCT with conditioning regimen of timed sequential busulfan and fludarabine
  • Human leukocyte antigen (HLA)-identical sibling or 8/8 matched unrelated donor available
  • Life expectancy of at least 12 weeks (3 months)
  • Direct bilirubin not greater than 1 mg/dL
  • Alanine transaminase (ALT) less than or equal 3 x upper limit of normal range
  • Serum creatinine less than 1.5 x the upper limit of normal range and creatinine clearance greater than 50 ml/min
  • Diffusing capacity for carbon monoxide (DLCO) 65% of predicted corrected for hemoglobin
  • Left ventricle ejection fraction (LVEF) of at least 50%
  • Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test
  • Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent until at least 30 days after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate

Exclusion Criteria:

  • Patients with a comorbidity score > 3. The principal investigator is the final arbiter of eligibility and enrollment of patients with comorbidity score > 3 and may permit enrollment of these patients on individual basis

    • Active or clinically significant cardiac disease including:

      • Congestive heart failure New York Heart Association (NYHA) > class II
      • Active coronary artery disease
      • Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin
      • Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before transplant, or myocardial infarction within 6 months before transplant
  • Patients with uncontrolled infections
  • Patients with active hepatitis B and C

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Prevention (itacitinib, busulfan, fludarabine, ASCT)

Arm Description

CONDITIONING CHEMOTHERAPY: Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC STEM CELL TRANSPLANTATION: Patients undergo ASCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD on days -21 to 80. Patients with no evidence of GVHD at day 80 receive a tapered dose of itacitinib until day 90. Patients also receive tacrolimus IV then PO BID for 3 months when able, and methotrexate IV over 30 minutes on days 1, 3, and 6 (day 11 also for patients with a matched unrelated donor).

Outcomes

Primary Outcome Measures

Graft versus host disease (GVHD)-free/relapse free survival rate
The proportion of patients who are alive without disease relapse of GVHD at one year will be reported, along with the corresponding 95% confidence interval. Logistic regression will be used to assess the association between success and clinical and treatment covariates of interest.

Secondary Outcome Measures

Time to neutrophil engraftment
Will be calculated from the time of transplant and estimated by the Kaplan-Meier method. Distributions will be compared between patients with matched and mismatched donors via the long-rank test.
Time to platelet engraftment
Will be calculated from the time of transplant and estimated by the Kaplan-Meier method. Distributions will be compared between patients with matched and mismatched donors via the long-rank test.
To assess the incidence of non-relapse mortality
To assess the toxicity profile associated with this regimen
To assess the incidence of acute and chronic GVHD.
Time to disease relapse
Will be modeled using Cox proportional hazards regression models, considering clinical, demographic, and treatment covariates of interest.
Incidence of non-relapse mortality
Will be modeled using Cox proportional hazards regression models, considering clinical, demographic, and treatment covariates of interest. Will be assessed in a competing risks framework, with similar analyses performed.
To assess overall survival and progression-free survival.
Incidence of withdrawal syndrome in patients with myelofibrosis

Full Information

First Posted
September 30, 2019
Last Updated
October 27, 2020
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT04127721
Brief Title
Itacitinib for the Prevention of Graft Versus Host Disease in Patients Undergoing Donor Stem Cell Transplantation
Official Title
Itacitinib to Prevent Graft Versus Host Disease
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Withdrawn
Why Stopped
0 ACTUAL Enrollment must have Overall Recruitment Status
Study Start Date
September 22, 2020 (Actual)
Primary Completion Date
September 22, 2020 (Actual)
Study Completion Date
September 22, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This phase II trial studies how well itacitinib works in preventing graft versus host disease in patients with blood disorders undergoing donor stem cell transplantation. A donor transplantation uses blood-making cells from a family member or unrelated donor to remove and replace abnormal blood cells. Graft versus host disease is a reaction of the donor's immune cells against the patient's body. Itacitinib plus standard treatment may help prevent graft versus host disease in patients who have received a donor stem cell transplantation.
Detailed Description
PRIMARY OBJECTIVE: I. To estimate the graft-versus (vs.) host disease-free/relapse free survival (GRFS) rate of itacitinib used as prophylaxis to prevent graft versus host disease (GVHD) after allogeneic stem cell transplantation (ASCT) at one year. SECONDARY OBJECTIVES: I. To assess the time to neutrophil and platelet engraftment and compare between matched and unmatched donors. II. To assess safety of itacitinib as measured by non-relapse mortality (NRM) at day 100. III. To assess the toxicity profile associated with this regimen. IV. To assess the incidence of acute and chronic GVHD. V. To assess the incidence of disease relapse. VI. To assess the incidence of non-relapse mortality. VII. To assess overall survival and progression-free survival. VIII. To assess the incidence of withdrawal syndrome in patients with myelofibrosis. TERTIARY OBJECTIVES (CORRELATIVE STUDIES): I. To study immune recovery and cytokines at various time points pre and post-transplant. II. To study deoxyribonucleic acid (DNA) damage studies in various cells post-transplant. OUTLINE: CONDITIONING CHEMOTHERAPY: Patients receive busulfan intravenously (IV) over 3 hours on days -20, -13, and -6 to -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC STEM CELL TRANSPLANTATION: Patients undergo ASCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib orally (PO) once daily (QD) on days -21 to 80. Patients with no evidence of GVHD at day 80 receive a tapered dose of itacitinib until day 90. Patients also receive tacrolimus IV then PO twice daily (BID) for 3 months when able, and methotrexate IV over 30 minutes on days 1, 3, and 6 (day 11 also for patients with a matched unrelated donor). After completion of study treatment, patients are followed up at 100 days, 6 months, and 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Allogeneic Stem Cell Transplant Recipient, Hematologic and Lymphocytic Disorder, Hematopoietic and Lymphoid Cell Neoplasm

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prevention (itacitinib, busulfan, fludarabine, ASCT)
Arm Type
Experimental
Arm Description
CONDITIONING CHEMOTHERAPY: Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, and fludarabine IV over 1 hour on days -6 to -3 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC STEM CELL TRANSPLANTATION: Patients undergo ASCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD on days -21 to 80. Patients with no evidence of GVHD at day 80 receive a tapered dose of itacitinib until day 90. Patients also receive tacrolimus IV then PO BID for 3 months when able, and methotrexate IV over 30 minutes on days 1, 3, and 6 (day 11 also for patients with a matched unrelated donor).
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT
Intervention Description
Undergo ASCT
Intervention Type
Drug
Intervention Name(s)
Busulfan
Other Intervention Name(s)
1, 4-Bis[methanesulfonoxy]butane, BUS, Bussulfam, Busulfanum, Busulfex, Busulphan, CB 2041, CB-2041, Glyzophrol, GT 41, GT-41, Joacamine, Methanesulfonic Acid Tetramethylene Ester, Methanesulfonic acid, tetramethylene ester, Mielucin, Misulban, Misulfan, Mitosan, Myeleukon, Myeloleukon, Myelosan, Mylecytan, Myleran, Sulfabutin, Tetramethylene Bis(methanesulfonate), Tetramethylene bis[methanesulfonate], WR-19508
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fluradosa
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Itacitinib
Other Intervention Name(s)
INCB 039110, INCB-039110, INCB039110
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Methotrexate
Other Intervention Name(s)
Abitrexate, Alpha-Methopterin, Amethopterin, Brimexate, CL 14377, CL-14377, Emtexate, Emthexat, Emthexate, Farmitrexat, Fauldexato, Folex, Folex PFS, Lantarel, Ledertrexate, Lumexon, Maxtrex, Medsatrexate, Metex, Methoblastin, Methotrexate LPF, Methotrexate Methylaminopterin, Methotrexatum, Metotrexato, Metrotex, Mexate, Mexate-AQ, MTX, Novatrex, Rheumatrex, Texate, Tremetex, Trexeron, Trixilem, WR-19039
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK 506, Fujimycin, Hecoria, Prograf, Protopic
Intervention Description
Given IV and PO
Primary Outcome Measure Information:
Title
Graft versus host disease (GVHD)-free/relapse free survival rate
Description
The proportion of patients who are alive without disease relapse of GVHD at one year will be reported, along with the corresponding 95% confidence interval. Logistic regression will be used to assess the association between success and clinical and treatment covariates of interest.
Time Frame
At 1 year
Secondary Outcome Measure Information:
Title
Time to neutrophil engraftment
Description
Will be calculated from the time of transplant and estimated by the Kaplan-Meier method. Distributions will be compared between patients with matched and mismatched donors via the long-rank test.
Time Frame
Up to day 42
Title
Time to platelet engraftment
Description
Will be calculated from the time of transplant and estimated by the Kaplan-Meier method. Distributions will be compared between patients with matched and mismatched donors via the long-rank test.
Time Frame
Up to day 42
Title
To assess the incidence of non-relapse mortality
Time Frame
At day 100
Title
To assess the toxicity profile associated with this regimen
Time Frame
Up to 1 year
Title
To assess the incidence of acute and chronic GVHD.
Time Frame
Up to 1 year
Title
Time to disease relapse
Description
Will be modeled using Cox proportional hazards regression models, considering clinical, demographic, and treatment covariates of interest.
Time Frame
Up to 1 year
Title
Incidence of non-relapse mortality
Description
Will be modeled using Cox proportional hazards regression models, considering clinical, demographic, and treatment covariates of interest. Will be assessed in a competing risks framework, with similar analyses performed.
Time Frame
Up to 1 year
Title
To assess overall survival and progression-free survival.
Time Frame
From day of transplant until day of death, assessed up to 1 year
Title
Incidence of withdrawal syndrome in patients with myelofibrosis
Time Frame
Up to 1 year
Other Pre-specified Outcome Measures:
Title
Immune recovery and cytokines
Description
Generalized linear mixed models will be used to assess the association between cytokines over time and treatment and other factors.
Time Frame
Up to 1 year
Title
Deoxyribonucleic acid (DNA) damage studies
Description
The proportion of patients with DNA damage will be reported, and generalized logistic mixed models may be used to assess the association with similar covariates.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Karnofsky performance status of at least 70 Patients with hematological disorders undergoing ASCT with conditioning regimen of timed sequential busulfan and fludarabine Human leukocyte antigen (HLA)-identical sibling or 8/8 matched unrelated donor available Life expectancy of at least 12 weeks (3 months) Direct bilirubin not greater than 1 mg/dL Alanine transaminase (ALT) less than or equal 3 x upper limit of normal range Serum creatinine less than 1.5 x the upper limit of normal range and creatinine clearance greater than 50 ml/min Diffusing capacity for carbon monoxide (DLCO) 65% of predicted corrected for hemoglobin Left ventricle ejection fraction (LVEF) of at least 50% Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of study drug. Post-menopausal women (defined as no menses for at least 1 year) and surgically sterilized women are not required to undergo a pregnancy test Subjects (men and women) of childbearing potential must agree to use adequate contraception beginning at the signing of the informed consent until at least 30 days after the last dose of study drug. The definition of adequate contraception will be based on the judgment of the principal investigator or a designated associate Exclusion Criteria: Patients with a comorbidity score > 3. The principal investigator is the final arbiter of eligibility and enrollment of patients with comorbidity score > 3 and may permit enrollment of these patients on individual basis Active or clinically significant cardiac disease including: Congestive heart failure New York Heart Association (NYHA) > class II Active coronary artery disease Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin Unstable angina (anginal symptoms at rest), new-onset angina within 3 months before transplant, or myocardial infarction within 6 months before transplant Patients with uncontrolled infections Patients with active hepatitis B and C
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Uday R Popat
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Itacitinib for the Prevention of Graft Versus Host Disease in Patients Undergoing Donor Stem Cell Transplantation

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