A Study of Itacitinib for the Prevention of Cytokine Release Syndrome Induced by Immune Effector Cell Therapy

A Phase 2 Study of Itacitinib, for the Prevention of Cytokine Release Syndrome Induced by Immune Effector Cell Therapy

"The purpose of this study is to assess the safety and efficacy of oral administration of itacitinib for the prevention of cytokine release syndrome (CRS) in male or female participants aged 12 years or older and who are planning to receive an approved immune effector cell (IEC) therapy for hematologic malignancies.

Study Overview

• Status: Completed
• Conditions: Cytokine Release Syndrome
• Intervention / Treatment: Drug: Itacitinib; Drug: Immune effector cell therapy; Drug: Placebo; Biological: Yescarta

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center
    • Tampa, Florida, United States, 33612
      • Moffitt Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Childrens Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Part 1: Eligible to receive any IEC therapy for any approved indication.
• Part 2: Eligible to receive Yescarta for relapsed or refractory large B-cell lymphoma or follicular lymphoma.
• Eastern Cooperative Oncology Group performance status 0 to 1.
• Willingness to avoid pregnancy or fathering children

Exclusion Criteria:

• Evidence of active uncontrolled/untreated infection (viral, bacterial, fungal, opportunistic) of any origin.
• Evidence of active hepatitis B virus or hepatitis C virus infection.
• Known human immunodeficiency virus.
• Active acute or chronic graft-versus-host disease requiring systemic therapy.
• Concurrent use of chronic systemic steroids or immunosuppressant medications.
• Any unresolved toxicity ≥ Grade 2 (except stable Grade 2 peripheral neuropathy or alopecia) from previous anticancer therapy.
• Known history or prior diagnosis of immunologic or inflammatory/autoimmune disease affecting the central nervous system (CNS) and unrelated to their disease under study or previous treatment.
• Clinically significant or uncontrolled cardiac disease.
• Acute lymphoblastic leukemia participants with protocol-defined CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia.
• Diffuse large B-cell lymphoma participants must have no signs or symptoms of CNS disease or detectable evidence of CNS disease; participants who have been previously treated for CNS disease but have no evidence of disease at screening are eligible.
• Laboratory values at screening outside the protocol-defined ranges.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Open Label Itacitinib Once Daily; During Part 1, all participants receive itacitinib 200mg once daily (open label) for 30 days. The study population will include participants receiving any approved IEC for an approved indication.	Drug: Itacitinib; Part 1: Itacitinib 200 mg once daily for 30 days. Part 2: Itacitinib 200 mg twice daily for 30 days.; Other Names: INCB039110; Drug: Immune effector cell therapy; Participants will receive IEC therapy that is approved by the health authority in the country where the study is being conducted for any approved hematologic indication.; Other Names: CAR-T cell therapy
Experimental: Part 2: Double-Blind Itacitinib Twice Daily; During Part 2, participants will be randomized to receive itacitinib 200mg or placebo twice daily for 30 days. The study population also includes participants who are receiving Yescarta for relapsed or refractory large B-cell lymphoma or follicular lymphoma.	Drug: Itacitinib; Part 1: Itacitinib 200 mg once daily for 30 days. Part 2: Itacitinib 200 mg twice daily for 30 days.; Other Names: INCB039110; Drug: Placebo; Participants will receive placebo twice daily.; Biological: Yescarta; Eligible participants are receiving Yescarta (An infusion of chimeric antigen receptor (CAR)-transduced autologous T cells) for relapsed or refractory larbe B-cell lymphoma or follicular lymphoma intravenously.; Other Names: axicabtagene ciloleucel KTE-C19

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Developed ≥Grade 2 Cytokine Release Syndrome (CRS) by Day 14 After Immune Effector Cell (IEC) Therapy, Assessed by Using American Society for Blood and Marrow Transplantation (ASBMT) CRS Consensus Grading	The ASBMT CRS Consensus Grading Criteria was used to assess the severity of CRS. Grade 2 CRS: temperature ≥38°C not attributable to any other cause, defined as fever; hypotension not requiring vasopressors, and/or; hypoxia requiring low-flow nasal cannula (oxygen delivered at ≤6 liters/minute) or blow-by. Grade 3 CRS: fever; hypotension requiring one vasopressor with or without vasopressin, and/or; hypoxyia requiring high-flow nasal cannula (oxygen delivered at >6 liters/minute), facemask, nonrebreather mask, or Venturi mask. Grade 4 CRS: fever; hypotension requiring multiple vasopressors (excluding vasopressin), and/or; hypoxia requiring positive pressure (e.g., continuous positive airway pressure [CPAP], bilevel intermittent positive air pressure [BiPAP], intubation, mechanical ventilation).	up to Day 14 of Parts 1 and 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading	Participants were monitored for signs and symptoms of ICANS, if symptoms developed at any point after IEC. ICANS Consensus Grading Criteria were used to assess 5 domains of neurotoxicity: orientation (orient to year, month, city, and hospital), naming (naming 3 objects), following commands (follow commands such as: show me 2 fingers or close your eyes and stick out your tongue), writing (ability to write a standard sentence), and attention (count backwards from 100 by 10). Each domain is associated with a certain number of points, which are summed to generate a total score. Score 10: no impairment; score 7-9: Grade 1 ICANS; score 3-6: Grade 2 ICANS; score 0-2: Grade 3 ICANS.	up to Day 28 of Parts 1 and 2
Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy	Participants were monitored for signs and symptoms of ICANS, if symptoms developed at any point after IEC. ICANS Consensus Grading Criteria were used to assess 5 domains of neurotoxicity: orientation (orient to year, month, city, and hospital), naming (naming 3 objects), following commands (follow commands such as: show me 2 fingers or close your eyes and stick out your tongue), writing (ability to write a standard sentence), and attention (count backwards from 100 by 10). Each domain is associated with a certain number of points, which are summed to generate a total score. Score 10: no impairment; score 7-9: Grade 1 ICANS; score 3-6: Grade 2 ICANS; score 0-2: Grade 3 ICANS.	up to Day 28 of Parts 1 and 2
Duration of ICANS Occurring by Day 28 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS	Participants were monitored for signs and symptoms of ICANS, if symptoms developed at any point after IEC. ICANS Consensus Grading Criteria were used to assess 5 domains of neurotoxicity: orientation (orient to year, month, city, and hospital), naming (naming 3 objects), following commands (follow commands such as: show me 2 fingers or close your eyes and stick out your tongue), writing (ability to write a standard sentence), and attention (count backwards from 100 by 10). Each domain is associated with a certain number of points, which are summed to generate a total score. Score 10: no impairment; score 7-9: Grade 1 ICANS; score 3-6: Grade 2 ICANS; score 0-2: Grade 3 ICANS. Duration of ICANS occurring by Day 28 corresponds to the sum of days with non-zero grade ICANS by Day 28.	up to Day 28 of Parts 1 and 2
Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading	The ASBMT CRS Consensus Grading Criteria was used to assess the severity of CRS. Grade 1: fever; either no hypotention and/or no hypoxia. Grade 2 CRS: fever; hypotension not requiring vasopressors, and/or; hypoxia requiring low-flow nasal cannula (oxygen delivered at ≤6 liters/minute) or blow-by. Grade 3 CRS: fever; hypotension requiring one vasopressor with or without vasopressinc, and/or; hypoxyia requiring high-flow nasal cannula (oxygen delivered at >6 liters/minute), facemask, nonrebreather mask, or Venturi mask. Grade 4 CRS: fever; hypotension requiring multiple vasopressors (excluding vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation).	up to Day 28 of Parts 1 and 2
Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading	The ASBMT CRS Consensus Grading Criteria was used to assess the severity of CRS. Grade 1: fever; either no hypotention and/or no hypoxia. Grade 2 CRS: fever; hypotension not requiring vasopressors, and/or; hypoxia requiring low-flow nasal cannula (oxygen delivered at ≤6 liters/minute) or blow-by. Grade 3 CRS: fever; hypotension requiring one vasopressor with or without vasopressinc, and/or; hypoxyia requiring high-flow nasal cannula (oxygen delivered at >6 liters/minute), facemask, nonrebreather mask, or Venturi mask. Grade 4 CRS: fever; hypotension requiring multiple vasopressors (excluding vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation).	up to Day 56 of Parts 1 and 2
Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading	The ASBMT CRS Consensus Grading Criteria was used to assess the severity of CRS. Grade 1: fever; either no hypotention and/or no hypoxia. Grade 2 CRS: fever; hypotension not requiring vasopressors, and/or; hypoxia requiring low-flow nasal cannula (oxygen delivered at ≤6 liters/minute) or blow-by. Grade 3 CRS: fever; hypotension requiring one vasopressor with or without vasopressinc, and/or; hypoxyia requiring high-flow nasal cannula (oxygen delivered at >6 liters/minute), facemask, nonrebreather mask, or Venturi mask. Grade 4 CRS: fever; hypotension requiring multiple vasopressors (excluding vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation).	up to Day 2 of Parts 1 and 2
Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading	The ASBMT CRS Consensus Grading Criteria was used to assess the severity of CRS. Grade 1: fever; either no hypotention and/or no hypoxia. Grade 2 CRS: fever; hypotension not requiring vasopressors, and/or; hypoxia requiring low-flow nasal cannula (oxygen delivered at ≤6 liters/minute) or blow-by. Grade 3 CRS: fever; hypotension requiring one vasopressor with or without vasopressinc, and/or; hypoxyia requiring high-flow nasal cannula (oxygen delivered at >6 liters/minute), facemask, nonrebreather mask, or Venturi mask. Grade 4 CRS: fever; hypotension requiring multiple vasopressors (excluding vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation).	up to Day 28 of Parts 1 and 2
Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS	An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. For purposes of analysis, all AEs were considered TEAEs unless the AE could unequivocally be defined as not treatment emergent.	from at Day -3 through the duration of safety follow-up (up to Day 56) for Parts 1 and 2
Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28	Cytopenia is characterized by low levels of white blood cells, red blood cells, or platelets. Analysis used laboratory counts at Day 28.	Day 28 of Parts 1 and 2
Percentage of Participants Who Were Treated With Tocilizumab for CRS	Tocilizumab and/or corticosteroids for CRS Grade 1 was not allowed per the protocol. However, tocilizumab may have been given as rescue medication for CRS Grade 1 if no improvement was observed within 72 hours from onset, and the participant's medical condition required intervention per investigator judgment.	up to Day 56 of Parts 1 and 2
Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS	Dexamethasone use as rescue medication for ICANS was assessed.	up to Day 30 of Parts 1 and 2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Hospital Admissions for Participants With CRS and/or ICANS by the End of the Study	The number of hospital admissions was assessed through study completion.	up to Day 180 of Parts 1 and 2
Duration of Hospital Stay for Participants With CRS and/or ICANS by End of Study	The duration of hospital stays was assessed through study completion.	up to Day 180 of Parts 1 and 2

Collaborators and Investigators

• Sponsor: Incyte Corporation
• Investigators: Study Director: Peter Langmuir, MD, Incyte Corporation

Publications and helpful links

General Publications

• Huarte E, O'Connor RS, Peel MT, Nunez-Cruz S, Leferovich J, Juvekar A, Yang YO, Truong L, Huang T, Naim A, Milone MC, Smith PA. Itacitinib (INCB039110), a JAK1 Inhibitor, Reduces Cytokines Associated with Cytokine Release Syndrome Induced by CAR T-cell Therapy. Clin Cancer Res. 2020 Dec 1;26(23):6299-6309. doi: 10.1158/1078-0432.CCR-20-1739. Epub 2020 Sep 30.

Study record dates

Study Major Dates

• Study Start (Actual): February 7, 2020
• Primary Completion (Actual): February 23, 2023
• Study Completion (Actual): August 22, 2023

Study Registration Dates

• First Submitted: August 26, 2019
• First Submitted That Met QC Criteria: August 26, 2019
• First Posted (Actual): August 28, 2019

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: February 26, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Janus kinase inhibitor; Cytokine release syndrome; immune effector cell-associated neurotoxicity syndrome; immune effector cell therapy
• Additional Relevant MeSH Terms: Pathologic Processes; Systemic Inflammatory Response Syndrome; Inflammation; Disease; Shock; Syndrome; Cytokine Release Syndrome; Antineoplastic Agents; Antineoplastic Agents, Immunological; Axicabtagene ciloleucel
• Other Study ID Numbers: INCB 39110-211

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No