Itacitinib for the Prevention of Graft Versus Host Disease

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04859946

Collaborator

Incyte Corporation (Industry)

Enrollment

Location

Arm

11.7

Anticipated Duration (Months)

2.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies if itacitinib plus standard of care treatment may help prevent graft-versus-host-disease (GVHD) in patients who have received an allogeneic (donor) stem cell transplant. An allogeneic transplant uses blood-making cells from a family member or unrelated donor to remove and replace a patient's abnormal blood cells. Sometimes the transplanted cells from a donor can attack the body's normal cells (called graft-versus-host disease). Giving itacitinib with standard of care treatment after the transplant may stop this from happening.

Condition or Disease	Intervention/Treatment	Phase
Hematologic and Lymphocytic Disorder	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Drug: Busulfan Drug: Cyclophosphamide Drug: Fludarabine Drug: Itacitinib Drug: Tacrolimus Drug: Thiotepa	Phase 1

Detailed Description

PRIMARY OBJECTIVE:

To compare the 100-day acute grade 2-4 GvHD rate to matched controls.

SECONDARY OBJECTIVES:

To compare the 1-year rate of GvHD-free, relapse-free survival to matched controls.
To assess the time to neutrophil and platelet engraftment. III. To assess the toxicity profile associated with this regimen. IV. To assess the incidence of severe grade 3-4 acute GVHD. V. To assess the incidence of limited, extensive, and moderate to severe chronic GVHD.
To assess the incidence of disease relapse. VII. To assess the incidence of non-relapse mortality. VIII. To assess overall survival and progression-free survival. IX. To assess immunosuppression discontinuation rate.

TERTIARY OBJECTIVE (CORRELATIVE STUDY):

Immune recovery and cytokines at various time points pre- and post- transplant

OUTLINE:

CONDITIONING: Patients receive busulfan intravenously (IV) over 3 hours on days -20, -13, and -6 to -3, thiotepa IV on day -7, and fludarabine IV over 1 hour on days -6 to -3.

STEM CELL TRANSPLANT: Patients undergo stem cell transplant on day 0.

GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4. Patients also receive itacitinib orally (PO) once daily (QD) on days 5-60 in the absence of disease progression or unacceptable toxicity. Beginning day 5 after stem cell transplant, patients also receive tacrolimus IV over 24 hours until able to tolerate oral tacrolimus, whereby patients then receive tacrolimus PO twice daily (BID).

After completion of study intervention, patients are followed up at days 100, 180, and 365 after stem cell transplant.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

Itacitinib to Prevent Graft Versus Host Disease

Actual Study Start Date :

Jan 11, 2022

Anticipated Primary Completion Date :

Jan 1, 2023

Anticipated Study Completion Date :

Jan 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Supportive care (itacitinib) CONDITIONING: Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, thiotepa IV on day -7, and fludarabine IV over 1 hour on days -6 to -3. STEM CELL TRANSPLANT: Patients undergo stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4. Patients also receive itacitinib PO QD on days 5-60 in the absence of disease progression or unacceptable toxicity. Beginning day 5 after stem cell transplant, patients also receive tacrolimus IV over 24 hours until able to tolerate oral tacrolimus, whereby patients then receive tacrolimus PO BID.	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation Undergo stem cell transplant Other Names: Allogeneic Allogeneic Hematopoietic Cell Transplantation Allogeneic Stem Cell Transplantation HSC HSCT Stem Cell Transplantation, Allogeneic Drug: Busulfan Given IV Other Names: 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 Drug: Cyclophosphamide Given IV Other Names: (-)-Cyclophosphamide 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate Carloxan Ciclofosfamida Ciclofosfamide Cicloxal Clafen Claphene CP monohydrate CTX CYCLO-cell Cycloblastin Cycloblastine Cyclophospham Cyclophosphamid monohydrate Cyclophosphamide Monohydrate Cyclophosphamidum Cyclophosphan Cyclophosphane Cyclophosphanum Cyclostin Cyclostine Cytophosphan Cytophosphane Cytoxan Fosfaseron Genoxal Genuxal Ledoxina Mitoxan Neosar Revimmune Syklofosfamid WR- 138719 Drug: Fludarabine Given IV Other Names: Fluradosa Drug: Itacitinib Given PO Other Names: INCB 039110 INCB-039110 INCB039110 Drug: Tacrolimus Given IV or PO Other Names: FK 506 Fujimycin Hecoria Prograf Protopic Drug: Thiotepa Given IV Other Names: 1,1'',1''''-Phosphinothioylidynetrisaziridine Girostan N,N'', N''''-Triethylenethiophosphoramide Oncotiotepa STEPA Tepadina TESPA Tespamin Tespamine Thio-Tepa Thiofosfamide Thiofozil Thiophosphamide Thiophosphoramide Thiotef Tifosyl TIO TEF Tio-tef Triethylene Thiophosphoramide Triethylenethiophosphoramide Tris(1-aziridinyl)phosphine sulfide TSPA WR 45312

Arm

Intervention/Treatment

Experimental: Supportive care (itacitinib)

CONDITIONING: Patients receive busulfan IV over 3 hours on days -20, -13, and -6 to -3, thiotepa IV on day -7, and fludarabine IV over 1 hour on days -6 to -3. STEM CELL TRANSPLANT: Patients undergo stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive cyclophosphamide IV over 3 hours on days 3 and 4. Patients also receive itacitinib PO QD on days 5-60 in the absence of disease progression or unacceptable toxicity. Beginning day 5 after stem cell transplant, patients also receive tacrolimus IV over 24 hours until able to tolerate oral tacrolimus, whereby patients then receive tacrolimus PO BID.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation

Undergo stem cell transplant

Other Names:

Allogeneic

Allogeneic Hematopoietic Cell Transplantation

Allogeneic Stem Cell Transplantation

HSC

HSCT

Stem Cell Transplantation, Allogeneic

Drug: Busulfan

Given IV

Other Names:

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

Drug: Cyclophosphamide

Given IV

Other Names:

(-)-Cyclophosphamide

2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate

Carloxan

Ciclofosfamida

Ciclofosfamide

Cicloxal

Clafen

Claphene

CP monohydrate

CTX

CYCLO-cell

Cycloblastin

Cycloblastine

Cyclophospham

Cyclophosphamid monohydrate

Cyclophosphamide Monohydrate

Cyclophosphamidum

Cyclophosphan

Cyclophosphane

Cyclophosphanum

Cyclostin

Cyclostine

Cytophosphan

Cytophosphane

Cytoxan

Fosfaseron

Genoxal

Genuxal

Ledoxina

Mitoxan

Neosar

Revimmune

Syklofosfamid

WR- 138719

Drug: Fludarabine

Given IV

Other Names:

Fluradosa

Drug: Itacitinib

Given PO

Other Names:

INCB 039110

INCB-039110

INCB039110

Drug: Tacrolimus

Given IV or PO

Other Names:

FK 506

Fujimycin

Hecoria

Prograf

Protopic

Drug: Thiotepa

Given IV

Other Names:

1,1'',1''''-Phosphinothioylidynetrisaziridine

Girostan

N,N'', N''''-Triethylenethiophosphoramide

Oncotiotepa

STEPA

Tepadina

TESPA

Tespamin

Tespamine

Thio-Tepa

Thiofosfamide

Thiofozil

Thiophosphamide

Thiophosphoramide

Thiotef

Tifosyl

TIO TEF

Tio-tef

Triethylene Thiophosphoramide

Triethylenethiophosphoramide

Tris(1-aziridinyl)phosphine sulfide

TSPA

WR 45312

Outcome Measures

Primary Outcome Measures

Incidence of acute grade 2-4 graft versus host disease (GVHD) [At 100 days after stem cell transplant]
The 100-day acute grade 2-4 GvHD rate will be compared between groups using Fisher's exact test. Matched logistic regression techniques will also be considered for this endpoint. The proportion of patients with acute grade 2-4 GVHD at 100 days will be reported, along with the corresponding 95% confidence interval.

Secondary Outcome Measures

GVHD-free relapse-free survival [From day of stem cell transplant to time of grade 3 or 4 acute GVHD or chronic GVHD needing systemic immunosuppression or relapse or death whichever occurs first, assessed at 1 year after stem cell transplant]
Will be compared between groups using the log-rank test. The method of Kaplan and Meier will be used to estimate the distribution of GVHD-free, relapse-free survival. The estimated probability will be reported at 1 year along with a corresponding 95% confidence interval. In addition, Cox proportional hazards regression models will be fit to this endpoint, considering clinical, demographic, and treatment covariates of interest.
Time to neutrophil and platelet engraftment [Up to 365 days after stem cell transplant]
Engraftment is defined as the presence of neutrophil recovery by day 28 post stem cell infusion. Neutrophil recovery is defined as a sustained absolute neutrophil count (ANC) > 0.5 x 10^9/L for three consecutive days. Initial platelet recovery is defined as the first date of three consecutive laboratory values obtained for platelet count was >= 20 x 10^9/L AND no platelet transfusions were administered for seven consecutive days immediately preceding this date. 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 log-rank test.
Overall survival [From day of stem cell transplant to day of death, assessed up to 365 days after stem cell transplant]
Will be calculated from the time of transplant by the method of Kaplan and Meier. Cox proportional hazards regression analysis will be used to assess the association between these survival parameters and clinical and treatment covariates of interest.
Progression-free survival [From day of transplant to day of death or disease progression, assessed up to 365 days after stem cell transplant]
Will be calculated from the time of transplant by the method of Kaplan and Meier. Cox proportional hazards regression analysis will be used to assess the association between these survival parameters and clinical and treatment covariates of interest.
Time to relapse [Up to 365 days after stem cell transplant]
Non-relapse mortality [Up to 365 days after stem cell transplant]
Defined as death from any cause other than relapse disease.
Cumulative incidence of limited, extensive, and moderate to severe chronic GVHD [Up to 365 days after stem cell transplant]
The cumulative incidence of acute and chronic GVHD with the competing risk of relapse and death without relapse will be estimated using the method of Gooley, and the method of Fine and Gray will be used to model the incidence by disease and clinical characteristics of interest.
Incidence of adverse events [Up to 365 days after stem cell transplant]
Descriptive statistics will be used to summarize adverse events. Frequency counts and percentages will also be presented of subjects with serious adverse events and adverse events leading to withdrawal. All other safety parameters will be summarized using descriptive statistics or frequency counts. Graphical summaries will be used where appropriate.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients 18 years to less than or equal to 70 years
Karnofsky performance status of at least 70
Patients with hematological disorders undergoing allogeneic stem cell transplant (ASCT) with conditioning regimen of fractionated busulfan, thiotepa and fludarabine
Human leukocyte antigen (HLA)-identical sibling or at least 7/8 matched unrelated donor, or a haploidentical related 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
Creatinine clearance >= 60 ml/ min
Diffusing capacity for carbon monoxide (DLCO) 50% of predicted corrected for hemoglobin
Left ventricular 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 form (ICF) until at least 30 days after the last dose of study drug. Recommended methods of birth control are:
Hormonal contraception (birth control pills, patches, or rings)
Intrauterine device (IUD)
Birth control injections
Double barrier methods (diaphragm with spermicidal gel or condoms with birth control foam)
Sterilization of patient or partner ("tubes tied" or vasectomy)

Exclusion Criteria:

Patients with toxicities (Grade > 1) unresolved from prior treatment (including chemotherapy, targeted therapy, immunotherapy, experimental agents, radiation, or surgery)
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 active hepatitis B and C