NCT04071366

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

Completed Phase 2 Results posted Last updated 26 March 2024

What this trial tests

Phase 2 trial testing Itacitinib in Cytokine Release Syndrome in 112 participants. Completed in 22 August 2023.

Timeline

7 February 2020

Primary endpoint
23 February 2023

22 August 2023

Quick facts

Lead sponsor	Incyte Corporation
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	prevention
Enrollment	112
Start date	7 February 2020
Primary completion	23 February 2023
Estimated completion	22 August 2023
Sites	10 locations across United States

Drugs / interventions tested

• Itacitinib — full drug profile →
• Immune effector cell therapy — full drug profile →
• Placebo
• Yescarta — full drug profile →

Conditions studied

• Cytokine Release Syndrome — all drugs for Cytokine Release Syndrome →

Sponsor

Incyte Corporation — full company profile →

Who can join

12 and older, any sex, with Cytokine Release Syndrome. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · up to Day 14 of Parts 1 and 2

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 (ex

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	12.5	1.6 – 38.3
Part 1: Itacitinib 200 mg QD + Tecartus	41.7	15.2 – 72.3
Part 1: Itacitinib 200 mg QD + Yescarta	20.0	8.4 – 36.9
Part 2: Itacitinib 200 mg BID + Yescarta	17.4	5.0 – 38.8
Part 2: Placebo BID + Yescarta	56.5	34.5 – 76.8

Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading Secondary · up to Day 28 of Parts 1 and 2

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 impair

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	31.3	11.0 – 58.7
Part 1: Itacitinib 200 mg QD + Tecartus	41.7	15.2 – 72.3
Part 1: Itacitinib 200 mg QD + Yescarta	45.7	28.8 – 63.4
Part 2: Itacitinib 200 mg BID + Yescarta	13.0	2.8 – 33.6
Part 2: Placebo BID + Yescarta	34.8	16.4 – 57.3

Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy Secondary · up to Day 28 of Parts 1 and 2

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 impair

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	4.0	0 – 11
Part 1: Itacitinib 200 mg QD + Tecartus	4.0	0 – 6
Part 1: Itacitinib 200 mg QD + Yescarta	5.0	1 – 9
Part 2: Itacitinib 200 mg BID + Yescarta	5.0	4 – 9
Part 2: Placebo BID + Yescarta	6.5	2 – 11

Duration of ICANS Occurring by Day 28 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS Secondary · up to Day 28 of Parts 1 and 2

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 impair

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	3.0	1 – 4
Part 1: Itacitinib 200 mg QD + Tecartus	5.0	1 – 17
Part 1: Itacitinib 200 mg QD + Yescarta	1.5	1 – 16
Part 2: Itacitinib 200 mg BID + Yescarta	2.0	2 – 11
Part 2: Placebo BID + Yescarta	3.5	2 – 13

Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading Secondary · up to Day 28 of Parts 1 and 2

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

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	2.0	1 – 6
Part 1: Itacitinib 200 mg QD + Tecartus	2.5	0 – 7
Part 1: Itacitinib 200 mg QD + Yescarta	1.0	1 – 8
Part 2: Itacitinib 200 mg BID + Yescarta	2.0	0 – 8
Part 2: Placebo BID + Yescarta	3.0	0 – 9

Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading Secondary · up to Day 56 of Parts 1 and 2

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

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	5.0	2 – 11
Part 1: Itacitinib 200 mg QD + Tecartus	4.0	2 – 11
Part 1: Itacitinib 200 mg QD + Yescarta	5.0	1 – 11
Part 2: Itacitinib 200 mg BID + Yescarta	5.0	3 – 12
Part 2: Placebo BID + Yescarta	4.0	1 – 8

Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading Secondary · up to Day 2 of Parts 1 and 2

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

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	37.5	15.2 – 64.6
Part 1: Itacitinib 200 mg QD + Tecartus	33.3	9.9 – 65.1
Part 1: Itacitinib 200 mg QD + Yescarta	48.6	31.4 – 66.0
Part 2: Itacitinib 200 mg BID + Yescarta	26.1	10.2 – 48.4
Part 2: Placebo BID + Yescarta	30.4	13.2 – 52.9

Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading Secondary · up to Day 28 of Parts 1 and 2

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

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	12.5	1.6 – 38.3
Part 1: Itacitinib 200 mg QD + Tecartus	41.7	15.2 – 72.3
Part 1: Itacitinib 200 mg QD + Yescarta	20.0	8.4 – 36.9
Part 2: Itacitinib 200 mg BID + Yescarta	21.7	7.5 – 43.7
Part 2: Placebo BID + Yescarta	56.5	34.5 – 76.8

Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS Secondary · from at Day -3 through the duration of safety follow-up (up to Day 56) for Parts 1 and 2

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.

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	16
Part 1: Itacitinib 200 mg QD + Tecartus	12
Part 1: Itacitinib 200 mg QD + Yescarta	35
Part 2: Itacitinib 200 mg BID + Yescarta	22
Part 2: Placebo BID + Yescarta	24

Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 Secondary · Day 28 of Parts 1 and 2

Cytopenia is characterized by low levels of white blood cells, red blood cells, or platelets. Analysis used laboratory counts at Day 28.

Neutrophils

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	8.3
Part 1: Itacitinib 200 mg QD + Tecartus	22.2
Part 1: Itacitinib 200 mg QD + Yescarta	26.6
Part 2: Itacitinib 200 mg BID + Yescarta	31.8
Part 2: Placebo BID + Yescarta	13.6

Hemoglobin

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	0.0
Part 1: Itacitinib 200 mg QD + Tecartus	20.0
Part 1: Itacitinib 200 mg QD + Yescarta	16.7
Part 2: Itacitinib 200 mg BID + Yescarta	9.1
Part 2: Placebo BID + Yescarta	4.5

Platelets

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	25.0
Part 1: Itacitinib 200 mg QD + Tecartus	50.0
Part 1: Itacitinib 200 mg QD + Yescarta	26.7
Part 2: Itacitinib 200 mg BID + Yescarta	36.4
Part 2: Placebo BID + Yescarta	18.2

Percentage of Participants Who Were Treated With Tocilizumab for CRS Secondary · up to Day 56 of Parts 1 and 2

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.

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	18.8
Part 1: Itacitinib 200 mg QD + Tecartus	41.7
Part 1: Itacitinib 200 mg QD + Yescarta	20.0
Part 2: Itacitinib 200 mg BID + Yescarta	17.4
Part 2: Placebo BID + Yescarta	65.2

Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS Secondary · up to Day 30 of Parts 1 and 2

Dexamethasone use as rescue medication for ICANS was assessed.

Group	Value	95% CI
Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah	12.5
Part 1: Itacitinib 200 mg QD + Tecartus	25.0
Part 1: Itacitinib 200 mg QD + Yescarta	22.9
Part 2: Itacitinib 200 mg BID + Yescarta	4.3
Part 2: Placebo BID + Yescarta	30.4

Adverse events — posted to ClinicalTrials.gov

Time frame: TEAEs collected from Day -3 through the duration of safety follow-up (up to Day 56) for Parts 1 and 2 have been reported. Deaths occurring up to the end of the study (Day 180) or until early study withdrawal have been reported.. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah

Serious: 2/16 (13%)

Deaths: 4/16

Part 1: Itacitinib 200 mg QD + Tecartus

Serious: 1/12 (8%)

Deaths: 2/12

Part 1: Itacitinib 200 mg QD + Yescarta

Serious: 9/35 (26%)

Deaths: 9/35

Part 1: Itacitinib 200 mg + Any IEC

Serious: 12/63 (19%)

Deaths: 15/63

Part 2: Itacitinib 200 mg BID + Yescarta

Serious: 3/23 (13%)

Deaths: 2/23

Part 2: Placebo BID + Yescarta

Serious: 6/24 (25%)

Deaths: 2/24

Serious adverse events (26 terms)

Reaction	System	Part 1: Itacitinib 200 Mil…	Part 1: Itacitinib 200 mg …	Part 1: Itacitinib 200 mg …	Part 1: Itacitinib 200 mg …	Part 2: Itacitinib 200 mg …	Part 2: Placebo BID + Yesc…
Pyrexia	General disorders	—	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—	—
Acute kidney injury	Renal and urinary disorders	—	—	—	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—	—	—	—
Adrenal insufficiency	Endocrine disorders	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—
Bronchopleural fistula	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Encephalopathy	Nervous system disorders	—	—	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Fusarium infection	Infections and infestations	—	—	—	—	—	—
Gastrointestinal haemorrhage	Gastrointestinal disorders	—	—	—	—	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Immune effector cell-associated neurotoxicity syndrome	Nervous system disorders	—	—	—	—	—	—
Intestinal ischaemia	Gastrointestinal disorders	—	—	—	—	—	—
Multiple organ dysfunction syndrome	General disorders	—	—	—	—	—	—
Neurotoxicity	Nervous system disorders	—	—	—	—	—	—
Orthostatic hypotension	Vascular disorders	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—
Pneumonia necrotising	Infections and infestations	—	—	—	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Seizure	Nervous system disorders	—	—	—	—	—	—
Sinusitis fungal	Infections and infestations	—	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—	—

Other adverse events (150 terms — click to expand)

Reaction	System	Part 1: Itacitinib 200 Mil…	Part 1: Itacitinib 200 mg …	Part 1: Itacitinib 200 mg …	Part 1: Itacitinib 200 mg …	Part 2: Itacitinib 200 mg …	Part 2: Placebo BID + Yesc…
Pyrexia	General disorders	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—	—
Hypotension	Vascular disorders	—	—	—	—	—	—
Chills	General disorders	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—	—	—
Hypophosphataemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—	—	—
Neutrophil count decreased	Investigations	—	—	—	—	—	—
Platelet count decreased	Investigations	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Lymphocyte count decreased	Investigations	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—	—	—
White blood cell count decreased	Investigations	—	—	—	—	—	—
Confusional state	Psychiatric disorders	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Hypomagnesaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Hyponatraemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Sinus tachycardia	Cardiac disorders	—	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—	—
Tremor	Nervous system disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Hypocalcaemia	Metabolism and nutrition disorders	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—	—
Blood alkaline phosphatase increased	Investigations	—	—	—	—	—	—
Blood lactate dehydrogenase increased	Investigations	—	—	—	—	—	—

Most-reported serious reactions: Pyrexia, Hypotension, Sepsis, Acute kidney injury, Acute myocardial infarction, Adrenal insufficiency, Anaemia, Atrial fibrillation.

Data from ClinicalTrials.gov NCT04071366 adverse events section.

Sponsor's own description

"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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. The JAK/STAT signaling pathway: from bench to clinic.
   Hu X, Li J, Fu M, Zhao X, et al · · 2021 · cited 1761× · PMID 34824210 · DOI 10.1038/s41392-021-00791-1
2. Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies.
   Siegler EL, Kenderian SS. · · 2020 · cited 204× · PMID 32983132 · DOI 10.3389/fimmu.2020.01973
3. JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens.
   Hu Q, Bian Q, Rong D, Wang L, et al · · 2023 · cited 190× · PMID 36911202 · DOI 10.3389/fbioe.2023.1110765
4. Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies.
   Xiao X, Huang S, Chen S, Wang Y, et al · · 2021 · cited 187× · PMID 34794490 · DOI 10.1186/s13046-021-02148-6
5. How I treat refractory CRS and ICANS after CAR T-cell therapy.
   Jain MD, Smith M, Shah NN. · · 2023 · cited 174× · PMID 36989488 · DOI 10.1182/blood.2022017414
6. Cytokine Release Syndrome: Current Perspectives.
   Murthy H, Iqbal M, Chavez JC, Kharfan-Dabaja MA. · · 2019 · cited 136× · PMID 31754614 · DOI 10.2147/itt.s202015
7. JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition.
   Luo Y, Alexander M, Gadina M, O'Shea JJ, et al · · 2021 · cited 92× · PMID 34625141 · DOI 10.1016/j.jaci.2021.08.004
8. Macrophage, the potential key mediator in CAR-T related CRS.
   Hao Z, Li R, Li R, Meng L, et al · · 2020 · cited 83× · PMID 32665874 · DOI 10.1186/s40164-020-00171-5