Cytokine Release Syndrome
Conditions
Keywords
Cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, Janus kinase inhibitor, immune effector cell therapy
Brief summary
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.
Interventions
DRUGItacitinib
Part 1: Itacitinib 200 mg once daily for 30 days. Part 2: Itacitinib 200 mg twice daily for 30 days.
DRUGImmune 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.
DRUGPlacebo
Participants will receive placebo twice daily.
BIOLOGICALYescarta
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.
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Part 1 is not masked (open label). Part 2 is double blinded (participant, investigator)
Intervention model description
Part 1: Singe Group Assignment Part 2: Parallel Assignment
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 (excluding vasopressin), and/or; hypoxia requiring positive pressure (e.g., continuous positive airway pressure \[CPAP\], bilevel intermittent positive air pressure \[BiPAP\], intubation, mechanical ventilation). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading | 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 impairment; score 7-9: Grade 1 ICANS; score 3-6: Grade 2 ICANS; score 0-2: Grade 3 ICANS. |
| Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy | 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 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 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS | 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 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. |
| Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 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 vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation). |
| Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 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 vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation). |
| Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 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 vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation). |
| Percentage of Participants Who Were Treated With Tocilizumab for CRS | 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. |
| Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS | up to Day 30 of Parts 1 and 2 | Dexamethasone use as rescue medication for ICANS was assessed. |
| Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 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 vasopressin), and/or; hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, mechanical ventilation). |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS | 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. |
| Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Hospital Admissions for Participants With CRS and/or ICANS by the End of the Study | up to Day 180 of Parts 1 and 2 | The number of hospital admissions was assessed through study completion. |
| Duration of Hospital Stay for Participants With CRS and/or ICANS by End of Study | up to Day 180 of Parts 1 and 2 | The duration of hospital stays was assessed through study completion. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah Participants being treated with Kymriah (Day 0; per prescribing information), an immune effector cell (IEC) therapy for hematologic malignancies, received itacitinib 200 mg once daily (QD) for 30 days (Day -3 to Day 26). | 16 |
| Part 1: Itacitinib 200 mg QD + Tecartus Participants being treated with Tecartus (Day 0; per prescribing information), an IEC therapy for hematologic malignancies, received itacitinib 200 mg QD for 30 days (Day -3 to Day 26). | 12 |
| Part 1: Itacitinib 200 mg QD + Yescarta Participants being treated with Yescarta (Day 0; per prescribing information), an IEC therapy for hematologic malignancies, received itacitinib 200 mg QD for 30 days (Day -3 to Day 26). | 35 |
| Part 2: Itacitinib 200 mg BID + Yescarta Participants being treated with Yescarta (Day 0; per prescribing information) for relapsed or refractory large B-cell lymphoma or follicular lymphoma received itacitinib 200 mg twice daily (BID) for 30 days (Day -3 to Day 26). | 23 |
| Part 2: Placebo BID + Yescarta Participants being treated with Yescarta (Day 0; per prescribing information) for relapsed or refractory large B-cell lymphoma or follicular lymphoma BID for 30 days (Day -3 to Day 26). | 24 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Part 1: Open-label (29 Days) | Death | 4 | 2 | 8 | 0 | 0 |
| Part 1: Open-label (29 Days) | Progressive Disease | 0 | 0 | 4 | 0 | 0 |
| Part 1: Open-label (29 Days) | Withdrawal by Subject | 1 | 0 | 1 | 0 | 0 |
| Part 2: Randomized (29 Days) | Death | 0 | 0 | 0 | 2 | 2 |
| Part 2: Randomized (29 Days) | Declined Further Treatment; Entered Hospice | 0 | 0 | 0 | 1 | 0 |
| Part 2: Randomized (29 Days) | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Part 2: Randomized (29 Days) | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Part 2: Randomized (29 Days) | Progressive Disease | 0 | 0 | 0 | 2 | 4 |
| Part 2: Randomized (29 Days) | Protocol Violation | 0 | 0 | 0 | 0 | 1 |
| Part 2: Randomized (29 Days) | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Part 2: Placebo BID + Yescarta | Part 2: Itacitinib 200 mg BID + Yescarta | Part 1: Itacitinib 200 mg QD + Yescarta | Part 1: Itacitinib 200 mg QD + Tecartus | Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.18 years STANDARD_DEVIATION 11.87 | 62.0 years STANDARD_DEVIATION 9.93 | 63.2 years STANDARD_DEVIATION 13.37 | 63.5 years STANDARD_DEVIATION 10.21 | 66.2 years STANDARD_DEVIATION 12.08 | 68.8 years STANDARD_DEVIATION 15.22 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 100 Participants | 23 Participants | 20 Participants | 32 Participants | 10 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized American-Indian/Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black/African-American | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Captured as Other in Database | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White/Caucasian | 98 Participants | 21 Participants | 21 Participants | 31 Participants | 12 Participants | 13 Participants |
| Sex: Female, Male Female | 32 Participants | 7 Participants | 8 Participants | 12 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 78 Participants | 17 Participants | 15 Participants | 23 Participants | 11 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 16 | 2 / 12 | 9 / 35 | 15 / 63 | 2 / 23 | 2 / 24 |
| other Total, other adverse events | 16 / 16 | 12 / 12 | 35 / 35 | 63 / 63 | 22 / 23 | 24 / 24 |
| serious Total, serious adverse events | 2 / 16 | 1 / 12 | 9 / 35 | 12 / 63 | 3 / 23 | 6 / 24 |
Outcome results
Primary
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).
Time frame: up to Day 14 of Parts 1 and 2
Population: Efficacy Evaluable Analysis Set (EAS): all participants who received at least 1 dose of study drug and received IEC therapy. The exact 95% confidence interval (2-sided) was calculated using the Clopper-Pearson method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | 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 | 12.5 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | 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 | 41.7 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | 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 | 20.0 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | 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 | 17.4 percentage of participants |
| Part 2: Placebo BID + Yescarta | 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 | 56.5 percentage of participants |
p-value: 0.00395% CI: [-0.6463, -0.1363]One-sided Z-test
95% CI: [-0.6073, -0.1231]
95% CI: [-0.1778, 0.2299]
Secondary
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).
Time frame: up to Day 56 of Parts 1 and 2
Population: EAS. Only participants with CRS onset by Day 28 were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 5.0 days |
| Part 1: Itacitinib 200 mg QD + Tecartus | Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 4.0 days |
| Part 1: Itacitinib 200 mg QD + Yescarta | Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 5.0 days |
| Part 2: Itacitinib 200 mg BID + Yescarta | Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 5.0 days |
| Part 2: Placebo BID + Yescarta | Duration of All Grades of CRS Occurring by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 4.0 days |
Secondary
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.
Time frame: up to Day 28 of Parts 1 and 2
Population: EAS. Only participants with ICANS onset by Day 28 were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Duration of ICANS Occurring by Day 28 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS | 3.0 days |
| Part 1: Itacitinib 200 mg QD + Tecartus | Duration of ICANS Occurring by Day 28 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS | 5.0 days |
| Part 1: Itacitinib 200 mg QD + Yescarta | Duration of ICANS Occurring by Day 28 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS | 1.5 days |
| Part 2: Itacitinib 200 mg BID + Yescarta | Duration of ICANS Occurring by Day 28 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS | 2.0 days |
| Part 2: Placebo BID + Yescarta | Duration of ICANS Occurring by Day 28 After IEC Therapy Using the ICANS Consensus Grading, Regardless of CRS | 3.5 days |
Secondary
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.
Time frame: from at Day -3 through the duration of safety follow-up (up to Day 56) for Parts 1 and 2
Population: Safety Evaluable Set: all enrolled participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS | 16 participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS | 12 participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS | 35 participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS | 22 participants |
| Part 2: Placebo BID + Yescarta | Number of Participants With Any Treatment-emergent Adverse Event (TEAE) Except CRS and ICANS | 24 participants |
Secondary
Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS
Dexamethasone use as rescue medication for ICANS was assessed.
Time frame: up to Day 30 of Parts 1 and 2
Population: EAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS | 12.5 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS | 25.0 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS | 22.9 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS | 4.3 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants Requiring More Than 1 Dose of Dexamethasone (or Equivalent) for ICANS | 30.4 percentage of participants |
Secondary
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.
Time frame: up to Day 56 of Parts 1 and 2
Population: EAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants Who Were Treated With Tocilizumab for CRS | 18.8 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants Who Were Treated With Tocilizumab for CRS | 41.7 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants Who Were Treated With Tocilizumab for CRS | 20.0 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants Who Were Treated With Tocilizumab for CRS | 17.4 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants Who Were Treated With Tocilizumab for CRS | 65.2 percentage of participants |
Secondary
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.
Time frame: Day 28 of Parts 1 and 2
Population: EAS. Only participants with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Neutrophils | 8.3 percentage of participants |
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Hemoglobin | 0.0 percentage of participants |
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Platelets | 25.0 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Hemoglobin | 20.0 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Neutrophils | 22.2 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Platelets | 50.0 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Neutrophils | 26.6 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Hemoglobin | 16.7 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Platelets | 26.7 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Platelets | 36.4 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Hemoglobin | 9.1 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Neutrophils | 31.8 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Hemoglobin | 4.5 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Neutrophils | 13.6 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants With Any ≥Grade 3 Cytopenias Ongoing at Day 28 | Platelets | 18.2 percentage of participants |
Secondary
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).
Time frame: up to Day 2 of Parts 1 and 2
Population: EAS. The exact 95% confidence interval (2-sided) was calculated using the Clopper-Pearson method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 37.5 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 33.3 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 48.6 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 26.1 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants With Any Grade of CRS at 48 Hours After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 30.4 percentage of participants |
Secondary
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).
Time frame: up to Day 28 of Parts 1 and 2
Population: EAS. The exact 95% confidence interval (2-sided) was calculated using the Clopper-Pearson method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 12.5 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 41.7 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 20.0 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 21.7 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants With ≥Grade 2 CRS by Day 28 After First IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 56.5 percentage of participants |
Secondary
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.
Time frame: up to Day 28 of Parts 1 and 2
Population: EAS. The exact 95% confidence interval (2-sided) was calculated using the Clopper-Pearson method.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading | 31.3 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Tecartus | Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading | 41.7 percentage of participants |
| Part 1: Itacitinib 200 mg QD + Yescarta | Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading | 45.7 percentage of participants |
| Part 2: Itacitinib 200 mg BID + Yescarta | Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading | 13.0 percentage of participants |
| Part 2: Placebo BID + Yescarta | Percentage of Participants With Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) by Day 28 After IEC Therapy, Assessed by Using the ICANS Consensus Grading | 34.8 percentage of participants |
Secondary
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).
Time frame: up to Day 28 of Parts 1 and 2
Population: EAS. Only participants with CRS onset by Day 28 were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 2.0 days |
| Part 1: Itacitinib 200 mg QD + Tecartus | Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 2.5 days |
| Part 1: Itacitinib 200 mg QD + Yescarta | Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 1.0 days |
| Part 2: Itacitinib 200 mg BID + Yescarta | Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 2.0 days |
| Part 2: Placebo BID + Yescarta | Time to Onset of All Grades of CRS by Day 28 After IEC Therapy, Assessed by Using ASBMT CRS Consensus Grading | 3.0 days |
Secondary
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.
Time frame: up to Day 28 of Parts 1 and 2
Population: EAS. Only participants with ICANS onset by Day 28 were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Itacitinib 200 Milligrams (mg) QD + Kymriah | Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy | 4.0 days |
| Part 1: Itacitinib 200 mg QD + Tecartus | Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy | 4.0 days |
| Part 1: Itacitinib 200 mg QD + Yescarta | Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy | 5.0 days |
| Part 2: Itacitinib 200 mg BID + Yescarta | Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy | 5.0 days |
| Part 2: Placebo BID + Yescarta | Time to Onset of ICANS Using the ICANS Consensus Grading, Regardless of CRS, by Day 28 After IEC Therapy | 6.5 days |
Other Pre-specified
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.
Time frame: up to Day 180 of Parts 1 and 2
Population: Data have not been reported as the outcome measure is exploratory.
Other Pre-specified
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.
Time frame: up to Day 180 of Parts 1 and 2
Population: Data have not been reported, as the outcome measure is exploratory.