Itacitinib, Tacrolimus, and Sirolimus for the Prevention of GVHD in Patients With Acute Leukemia, Myelodysplastic Syndrome, or Myelofibrosis Undergoing Reduced Intensity Conditioning Donor Stem Cell Transplantation

Sponsor

City of Hope Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT04339101

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Arm

36.9

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase IIa trial studies the side effects of itacitinib when given together with standard treatment (tacrolimus and sirolimus), and to see how well it works in preventing graft-versus-host-disease (GVHD) in patients with acute leukemia, myelodysplastic syndrome or myelofibrosis who are undergoing reduced intensity conditioning donor stem cell transplantation. GVHD is a common complication after donor stem cell transplantation, resulting from donor immune cells recognizing recipients' cells and attacking them. Adding itacitinib to tacrolimus and sirolimus may reduce the risk GVHD and ultimately improve overall outcome and survival after donor stem cell transplantation.

Condition or Disease	Intervention/Treatment	Phase
Acute Leukemia Hematologic and Lymphocytic Disorder Myelodysplastic Syndrome Primary Myelofibrosis Secondary Myelofibrosis	Drug: Fludarabine Drug: Itacitinib Adipate Drug: Melphalan Other: Quality-of-Life Assessment Other: Questionnaire Administration Drug: Sirolimus Drug: Tacrolimus	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

Following a patient safety lead-in, estimate graft-versus-host disease free relapse free (GRFS) survival at 1- year post allogeneic stem cell transplantation (alloHCT).

SECONDARY OBJECTIVES:

Estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and non-relapse mortality (NRM) at 100-days post-transplant.
Estimate the cumulative incidence of chronic GVHD at 1- and 2-years post-transplant.
Estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years post-transplant.
Estimate rate of infection and development of second malignancies including lymphoproliferative disorders at 1- and 2-years post-transplant.
Assess patients' quality of life (QOL) at day 100 and 1 year post alloHCT.

EXPLORATORY OBJECTIVES:

Characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by cell count and flow cytometry of lymphocyte subsets.
Characterize changes in aGVHD biomarkers (Reg-3alpha, TNF-RI, and ST2) and a composite biomarker panel (IL2Ralpha, TNF-R1, IL-8, and hepatocyte growth factor), JAK-regulated pro-inflammatory cytokines (i.e., IL-6, TNFalpha, CRP, Beta2 Microglobulin, and IFNgamma) and STAT3 phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade.

OUTLINE:

REDUCED INTENSITY CONDITIONING (RIC): Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT (HSCT): Patients undergo HSCT on day 0.

GVHD PROPHYLAXIS: Patients receive itacitinib orally (PO) once daily (QD) beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus intravenously (IV) or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, then periodically for up to 2 years post- transplantation.

Study Design

Study Type:

Interventional

Actual Enrollment :

59 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase IIa Study of Addition of Itacitinib With Tacrolimus/Sirolimus Regimen for GVHD Prophylaxis in Fludarabine and Melphalan Non-Myeloablative Conditioning Hematopoietic Cell Transplantation for Acute Leukemias, MDS or MF

Actual Study Start Date :

Nov 11, 2020

Anticipated Primary Completion Date :

Dec 9, 2022

Anticipated Study Completion Date :

Dec 9, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (itacitinib adipate, tacrolimus, sirolimus) RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.	Drug: Fludarabine Given via infusion Other Names: Fluradosa Drug: Itacitinib Adipate Given PO Other Names: INCB-039110 Adipate INCB039110 Adipate Drug: Melphalan Given IV Other Names: Alanine Nitrogen Mustard CB-3025 L-PAM L-Phenylalanine mustard L-Sarcolysin L-Sarcolysin Phenylalanine mustard L-Sarcolysine Melphalanum Phenylalanine Mustard Phenylalanine nitrogen mustard Sarcoclorin Sarkolysin WR-19813 Other: Quality-of-Life Assessment Ancillary studies Other Names: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies Drug: Sirolimus Given PO Other Names: AY 22989 RAPA Rapamune rapamycin SILA 9268A WY-090217 Drug: Tacrolimus Given IV or PO Other Names: FK 506 Fujimycin Hecoria Prograf Protopic

Arm

Intervention/Treatment

Experimental: Treatment (itacitinib adipate, tacrolimus, sirolimus)

RIC: Patients receive fludarabine via infusion on days -9 to -5 and melphalan on day -4 in the absence of disease progression or unacceptable toxicity. ALLOGENEIC HSCT: Patients undergo HSCT on day 0. GVHD PROPHYLAXIS: Patients receive itacitinib PO QD beginning on day -3 and continuing until day 100 in the absence of disease progression or unacceptable toxicity. Patients also receive tacrolimus IV or PO and sirolimus PO beginning day -3 and continuing until day 100 with a taper in the absence of disease progression or unacceptable toxicity.

Drug: Fludarabine

Given via infusion

Other Names:

Fluradosa

Drug: Itacitinib Adipate

Given PO

Other Names:

INCB-039110 Adipate

INCB039110 Adipate

Drug: Melphalan

Given IV

Other Names:

Alanine Nitrogen Mustard

CB-3025

L-PAM

L-Phenylalanine mustard

L-Sarcolysin

L-Sarcolysin Phenylalanine mustard

L-Sarcolysine

Melphalanum

Phenylalanine Mustard

Phenylalanine nitrogen mustard

Sarcoclorin

Sarkolysin

WR-19813

Other: Quality-of-Life Assessment

Ancillary studies

Other Names:

Quality of Life Assessment

Other: Questionnaire Administration

Ancillary studies

Drug: Sirolimus

Given PO

Other Names:

AY 22989

RAPA

Rapamune

rapamycin

SILA 9268A

WY-090217

Drug: Tacrolimus

Given IV or PO

Other Names:

FK 506

Fujimycin

Hecoria

Prograf

Protopic

Outcome Measures

Primary Outcome Measures

Incidence of adverse events (Safety Lead-In) [Up to 30 days post transplant]
Toxicity will be scored on both the Bearman Scale and National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 scale.
Graft-versus-host disease free relapse free (GRFS) [From the date of transplantation to the first time of observing following events: grade 3-4 acute graft versus host disease (GVHD), chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first, assessed at 1 year post transplant]
Kaplan-Meier curve will be generated for GRFS.

Secondary Outcome Measures

Cumulative incidence of acute GVHD [From day 0 (date of stem cell infusion) through 100 days post-transplant]
Acute GVHD will be graded and staged according to the Consensus Grading.
Cumulative incidence of non-relapse mortality (NRM) [From date of stem cell infusion until non-disease related death, or last follow-up, whichever comes first, assessed at 100 days post-transplant]
NRM is defined as death occurring in a patient from causes other than relapse or progression.
Cumulative incidence of chronic GvHD [At 1 year post transplant]
Chronic graft versus host disease will be evaluated and scored according to National Institute of Health (NIH) Consensus Staging.
Cumulative incidence of chronic GvHD [At 2 years post-transplant]
Chronic graft versus host disease will be evaluated and scored according to NIH Consensus Staging.
Infection and development of second malignancies including lymphoproliferative disorders [At 1 year post-transplant]
Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. This data will be captured via case report form and will be collected from day -9 to day 100 post-transplant and will follow the same data collection intervals as the toxicity and adverse event data.
Infection and development of second malignancies including lymphoproliferative disorders [At 2 years post-transplant]
Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. This data will be captured via case report form and will be collected from day -9 to day 100 post-transplant and will follow the same data collection intervals as the toxicity and adverse event data.
Progression free survival (PFS) [From the date of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, whichever occurs first, assessed at 1 year post transplant]
Kaplan-Meier curve will be generated for PFS.
PFS [From the date of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, whichever occurs first, assessed at 2 year post transplant]
Kaplan-Meier curve will be generated for PFS.
Overall survival (OS) [From the day of stem cell infusion until death, or last follow-up, whichever comes first, assessed at 1 year post transplant]
Kaplan-Meier curve will be generated for OS.
OS [From the day of stem cell infusion until death, or last follow-up, whichever comes first, assessed at 2 years post transplant]
Kaplan-Meier curve will be generated for OS.
Relapse/progression [From day of stem cell infusion (day 0) assessed up to 2 years post transplant]
Deaths without relapse/progression are considered a competing risk. Surviving patients with no history of relapse/progression are censored at time of last follow-up.
Quality of life Questionnaires [Up to 2 years post transplant]
Will be assessed using self-reported patient questionnaires.

Other Outcome Measures

Hematologic recovery, donor cell engraftment and immune reconstitution [Up to 2 years post transplant]
Immune reconstitution studies will be done by flow cytometry.
Biomarker analysis [Up to 2 years post transplant]
Will assess acute GVHD biomarkers, JAK-regulated pro-inflammatory cytokines, and STAT3 phosphorylation.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Documented informed consent of the participant and/or legally authorized representative
Assent, when appropriate, will be obtained per institutional guidelines
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
If unavailable, exceptions may be granted with study principal investigator (PI) approval
Performance status: Karnofsky >= 70%
Patients with neoplastic hematologic disorders with indication of allogeneic transplant according to the standard guidelines as follows:
Acute leukemia (AL) in first complete response (CR1) or subsequent complete response (CR) or active disease with bone marrow (BM) blast of < 5%
Myelodysplastic syndrome (MDS) with intermediate-2 or high risk per International Prognostic Scoring System (IPSS) or
Myelofibrosis; primary or secondary if intermediate-2 or high risk per Dynamic International Prognostic Scoring System (DIPPS)
All candidates for this study must have a matched related donor (MRD) who is willing to donate BM or peripheral blood stem cells or an 8/8 allele matched unrelated donor (MUD)
Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
Aspartate aminotransferase (AST) =< 2.5 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
Alanine aminotransferase (ALT) =< 2.5 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
Creatinine clearance of >= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated. In case of active disease, evaluation should be done within 15 days)
Left ventricular ejection fraction (LVEF) >= 50%
Note: To be performed within 28 days prior to day 1 of protocol therapy
If able to perform pulmonary function tests: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusion capacity of the lung for carbon monoxide (DLCO) (diffusion capacity) >= 50% of predicted (corrected for hemoglobin). If unable to perform pulmonary function tests: oxygen (O2) saturation > 92% on room air.
Note To be performed within 28 days prior to day 1 of protocol therapy
Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combination (combo), hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin measurement [RPR])
If HCV positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed
Meets other institutional and federal requirements for infectious disease titer requirements
Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy
Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of protocol therapy
Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

Chemotherapy, radiation therapy, biological therapy, and/or immunotherapy within 21 days prior to day 1 of protocol therapy
Note: Conditioning regimen within 21 days prior to day 1 of protocol therapy is not considered as an exclusion criterion
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
Psychological issues, no appropriate caregivers identified, or non-compliant to medication
Uncontrolled medical or psychiatric disorders which may preclude patients to undergo clinical studies (Discretion of the attending physician)
Active diarrhea due to inflammatory bowel disease or malabsorption syndrome
Clinically significant uncontrolled illness
Active, uncontrolled systemic infection (bacterial, viral, or fungal) requiring antibiotics
Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection
Diagnosis of Gilbert's disease
Other active malignancy
Females only: Pregnant or breastfeeding
Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)