1 INDICATIONS AND USAGE TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of: Adult patients with relapsed or refractory mantle cell lymphoma (MCL).

Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

1.1 Mantle Cell Lymphoma TECARTUS is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).

1.2 Acute Lymphoblastic Leukemia TECARTUS is indicated for the treatment of adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

6 ADVERSE REACTIONS The most common non-laboratory adverse reactions (incidence greater than or equal to 20%) are: MCL: CRS, fever, encephalopathy, hypotension, infection with pathogen unspecified, viral infections, fatigue, tachycardias, chills, hypoxia, tremor, cough, musculoskeletal pain, nausea, edema, headache, constipation, diarrhea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, aphasia, motor dysfunction.

ALL: fever, CRS, hypotension, encephalopathy, tachycardia, nausea, chills, headache, fatigue, febrile neutropenia, diarrhea, musculoskeletal pain, hypoxia, rash, edema, tremor, infection with pathogen unspecified, constipation, decreased appetite, and vomiting.

( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Kite at 1-844-454-KITE (5483) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Study 1 (Relapsed/Refractory Mantle Cell Lymphoma) Cohort 1 and 2 The safety of TECARTUS in patients with relapsed/refractory Mantle cell lymphoma (MCL) was evaluated in a single-arm study (Study 1; Cohorts 1 and 2) in which a total of 82 patients received a single dose of TECARTUS (2 × 10 6 or 0.5 × 10 6 anti-CD19 CAR T cells/kg) [see Clinical Studies (14.1) ] .

The most common serious adverse reactions (> 2%) were encephalopathy, fever, infection with pathogen unspecified, CRS, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnea, fatigue, arrhythmia, tachycardia, and viral infections.

Table 3 summarizes the adverse reactions that occurred in at least 10% of patients in Study 1 Cohorts 1 and 2 and Table 4 lists the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients in Study 1 Cohorts 1 and 2.

Table 3.

Adverse Reactions Observed in at Least 10% of Patients in Study 1 (Cohorts 1 and 2) (N=82) Adverse Reaction Any Grade (%) Grade ≥3 (%) Blood and Lymphatic System Disorders Coagulopathy Includes multiple related terms.

10 2 Cardiac Disorders Tachycardias 45 0 Bradycardias 10 0 Non-ventricular Arrhythmias 10 4 Gastrointestinal Disorders Nausea 35 1 Constipation 29 0 Diarrhea 28 5 Abdominal pain 17 0 Oral pain 16 0 Vomiting 13 0 Dysphagia 10 2 General Disorders and Administration Site Conditions Fever 94 15 Fatigue 48 1 Chills 41 0 Edema 35 2 Pain 17 2 Immune System Disorders Cytokine release syndrome 91 18 Hypogammaglobulinemia 16 1 Infections and Infestations Infection with pathogen unspecified 43 24 Viral infections 18 4 Bacterial infections 13 6 Metabolism and Nutrition Disorders Decreased appetite 26 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 37 2 Motor dysfunction Motor dysfunction includes asthenia, intensive care acquired weakness, mobility decreased, muscle twitching, muscular weakness, myopathy.

17 4 Nervous System Disorders Encephalopathy Encephalopathy includes encephalopathy, altered state of consciousness, amnesia, balance disorder, cognitive disorder, confusional state, disturbance in attention, dysgraphia, dyskinesia, memory impairment, mental status changes, neurotoxicity, somnolence.

51 24 Tremor 38 2 Headache 35 1 Aphasia 20 7 Dizziness Dizziness includes dizziness, presyncope, syncope.

18 6 Neuropathy Neuropathy includes hyperaesthesia, neuropathy peripheral, paraesthesia, paraesthesia oral.

13 2 Psychiatric Disorders Insomnia 21 0 Delirium Delirium includes delirium, agitation, disorientation, hallucination, hypomania, irritability, nervousness, personality change.

18 5 Anxiety 16 0 Renal and Urinary Disorders Renal insufficiency 18 9 Urine output decreased 11 1 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 40 20 Cough 38 0 Dyspnea 24 6 Pleural effusion 21 5 Skin and Subcutaneous Tissue Disorders Rash 22 4 Vascular Disorders Hypotension 57 27 Hypertension 18 11 Thrombosis Thrombosis includes thrombosis, deep vein thrombosis, embolism, pulmonary embolism.

17 4 Other clinically important adverse reactions that occurred in less than 10% of patients include the following: Gastrointestinal disorders: dry mouth (7%) Infections and infestations disorders: fungal infections (9%) Metabolism and nutrition disorders: dehydration (6%) Nervous system disorders: ataxia (7%), seizure (5%), increased intracranial pressure (2%) Respiratory, thoracic and mediastinal disorders: respiratory failure (6%), pulmonary edema (4%) Skin and subcutaneous tissue disorders: rash (9%) Vascular disorders: hemorrhage (7%) Table 4.

Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in Study 1 (Cohorts 1 and 2) Following TECARTUS Infusion (N = 82) Grades 3 or 4 (%) Leukopenia 95 Neutropenia 95 Lymphopenia 86 Thrombocytopenia 63 Anemia 55 Hypophosphatemia 30 Hypocalcemia 21 Blood uric acid increased 17 Hyponatremia 16 Aspartate Aminotransferase increased 15 Alanine Aminotransferase increased 15 Hypokalemia 10 Cohort 3 The safety of TECARTUS in patients with relapsed/refractory MCL who had been treated with up to 5 prior treatment regimens but had not received prior therapy with a Bruton tyrosine kinase inhibitor (BTKi) was evaluated in Study 1 Cohort 3.

A total of 86 patients were treated with a single dose of TECARTUS (2 × 10 6 or 0.5 × 10 6 anti-CD19 CAR T cells/kg) [see Clinical Studies (14.1) ].

Serious adverse reactions occurred in 65% of patients.

The most common serious adverse reactions (>2%) were non-ventricular arrhythmias, tachycardias, pyrexia, cytokine release syndrome, unspecified pathogen infections, viral infections, bacterial infections, fungal infections, musculoskeletal pain, motor dysfunction, encephalopathy, aphasia, tremor, seizure, delirium, hypoxia, hypotension, hemorrhage, and thrombosis.

Table 5 summarizes the adverse reactions that occurred in at least 10% of patients in Study 1 Cohort 3 and Table 6 lists the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients in Study 1 Cohort 3.

Table 5.

Adverse Reactions Observed in at Least 10% of Patients in Study 1 (Cohort 3) (N=86) Adverse Reaction Any Grade (%) Grade ≥3 Cardiac Disorders Tachycardias Includes multiple related terms 20 1 Non-ventricular Arrhythmias 13 3 Gastrointestinal Disorders Nausea 33 1 Constipation 28 0 Diarrhea 24 0 Abdominal pain 19 1 Vomiting 15 0 Oral pain 14 1 General Disorders and Administration Site Conditions Fever 94 17 Fatigue 43 2 Edema 21 0 Chills 19 0 Immune System Disorders Cytokine release syndrome 95 6 Infections and Infestations Infection with pathogen unspecified 49 23 Viral infections 49 16 Bacterial infections 14 7 Fungal infections 14 2 Metabolism and Nutrition Disorders Decreased appetite 24 9 Weight decreased 12 1 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 24 0 Motor dysfunction Motor dysfunction includes Asthenia, Facial paresis, Fine motor skill dysfunction, Monoparesis, Motor dysfunction, Muscular weakness, Muscle spasms, Myoclonus, Myopathy, Paraparesis, Peroneal nerve palsy 20 3 Nervous System Disorders Encephalopathy Encephalopathy includes Agnosia, Agraphia, Altered state of consciousness, Amnesia, Anal incontinence, Aphasia, Balance disorder, Bradyphrenia, Cerebellar syndrome, Cognitive disorder, Confusional state, Depressed level of consciousness, Disturbance in attention, Dysarthria, Dysgeusia, Dysgraphia, Dysmetria, Dysphagia, Encephalopathy, Lethargy, Loss of consciousness, Memory impairment, Mental status changes, Neurological decompensation, Somnolence, Speech disorder, Toxic encephalopathy 66 24 Tremor Tremor includes Action tremor, Postural tremor, Tremor 30 2 Headache 29 0 Dizziness Dizziness includes Dizziness, Syncope 16 5 Peripheral neuropathy Peripheral Neuropathy includes Hypoesthesia, Neuropathy peripheral, Paresthesia, Paresthesia oral, Peripheral motor neuropathy, Peripheral sensory neuropathy, Polyneuropathy 12 1 Psychiatric Disorders Delirium Delirium includes Agitation, Delirium, Disorientation, Hallucination, Hallucinations, mixed, Nervousness 17 1 Insomnia 12 0 Renal and Urinary Disorders Renal insufficiency 19 2 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 24 10 Cough 14 0 Dyspnea 14 5 Skin and Subcutaneous Tissue Disorders Rash 16 0 Vascular Disorders Hypotension 52 8 Hemorrhage 16 5 Thrombosis Thrombosis includes Deep vein thrombosis, Embolism, Jugular vein thrombosis, Peripheral vein thrombosis, Pulmonary embolism, Venous thrombosis 13 3 Hypertension 10 2 Other clinically important adverse reactions that occurred in less than 10% of patients include the following: Blood and lymphatic system disorders: coagulopathy (5%), febrile neutropenia (1%) Cardiac disorders: Bradycardia (1%) Eye disorders: Visual impairment (6%) Gastrointestinal disorders: dry mouth (7%), dysphagia (1%) General disorders and administration site conditions: Pain (9%) Immune system disorders: hypersensitivity (1%), hypogammaglobulinemia (9%) Metabolism and nutrition disorders: dehydration (6%) Nervous system disorders: ataxia (9%), increased intracranial pressure (1%), seizure (5%) Psychiatric disorders: anxiety (8%) Renal and urinary disorders: urine output decreased (1%) Respiratory, thoracic and mediastinal disorders: pleural effusion (1%), pulmonary edema (3%), respiratory failure (6%) Table 6.

Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in Study 1 (Cohort 3) Following TECARTUS Infusion (N=86) Grades 3 or 4 (%) Leukopenia 97 Lymphopenia 96 Neutropenia 91 Thrombocytopenia 44 Hypophosphatemia 40 Anemia 31 Hyperglycemia 29 Blood uric acid increased 28 Alanine Aminotransferase increased 27 Hyponatremia 22 Calcium increased 12 Creatinine increased 12 Direct bilirubin increased 12 Magnesium increased 12 Aspartate Aminotransferase increased 10 Hypocalcemia 10 Study 2 (Relapsed/Refractory B-cell precursor Acute Lymphoblastic Leukemia) The safety of TECARTUS in patients with relapsed/refractory ALL was evaluated in an open-label, multicenter study in which a total of 78 patients received a single dose of CAR-positive T cells (1 x 10 6 anti-CD19 CAR T cells/kg) [see Clinical Studies (14.2) ] .

The most common serious adverse reactions (≥ 2%) were cytokine release syndrome, febrile neutropenia, hypotension, encephalopathy, fever, infection with pathogen unspecified, hypoxia, tachycardia, bacterial infections, respiratory failure, seizure, diarrhea, dyspnea, fungal infections, viral infections, coagulopathy, delirium, fatigue, hemophagocytic lymphohistiocytosis, musculoskeletal pain, edema, and paraparesis.

Fatal adverse reactions occurred in 5% (4/78) of patients including cerebral edema, sepsis, and fungal pneumonia.

Of the 4 patients who had fatal adverse reactions: 1 patient with fatal pneumonia had pre-existing pneumonia prior to study enrollment, and 1 patient with fatal sepsis had prolonged cytopenia and immunosuppression from prior therapies and underlying disease.

Table 7 summarizes the adverse reactions that occurred in at least 10% of patients in Study 2 and Table 8 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients in Study 2.

Table 7.

Adverse Reactions Observed in at Least 10% of Patients in Study 2 (N=78) Adverse Reaction Any Grade (%) Grade ≥3 (%) Blood and Lymphatic System Disorders Febrile Neutropenia Febrile neutropenia includes febrile neutropenia (11 (14%)) and fever occurring concurrently with neutropenia events (16 (21%)) 35 35 Coagulopathy Represents a composite of multiple, related preferred terms 17 5 Cardiac Disorders Tachycardias 63 6 Arrhythmia Arrhythmia includes cardiac arrest, .

15 1 Gastrointestinal Disorders Nausea 41 1 Diarrhea 32 6 Abdominal pain 19 0 Constipation 24 0 Vomiting 21 3 General Disorders and Administration Site Conditions Fever 96 38 Chills 40 0 Edema 29 5 Fatigue 37 1 Pain 13 1 Immune System Disorders Cytokine release syndrome 92 26 Infections and Infestations Infection with pathogen unspecified 28 22 Bacterial infections 15 8 Fungal infections 13 5 Metabolism and Nutrition Disorders Decreased appetite 22 1 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 32 5 Muscular weakness 14 1 Nervous System Disorders Encephalopathy Encephalopathy includes altered state of consciousness, aphasia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, encephalopathy, immune effector cell-associated neurotoxicity syndrome, memory impairment, mental status changes, slow response to stimuli, slow speech, somnolence, speech disorder.

63 27 Headache 38 1 Tremor 29 1 Dizziness Dizziness includes dizziness, syncope.

13 1 Psychiatric Disorders Delirium Delirium includes agitation, delirium, delusion, disorientation, hallucination.

18 5 Anxiety 12 0 Insomnia 13 0 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 31 23 Cough 12 0 Dyspnea 12 1 Skin and Subcutaneous Tissue Disorders Rash 31 0 Vascular Disorders Hypotension 69 33 Hemorrhage Hemorrhage includes conjunctival hemorrhage, contusion, epistaxis, gastric hemorrhage, hematoma, hematoma muscle, hemorrhage intracranial, hemorrhoidal hemorrhage, menorrhagia, petechiae, pulmonary alveolar hemorrhage, retinal hemorrhage, vaginal hemorrhage, vitreous hemorrhage.

13 4 Hypertension 13 6 Other clinically important adverse reactions that occurred in less than 10% of patients include the following: Cardiac disorder: cardiac failure (4%), palpitations (3%) Eye disorders: visual impairment (9%) Gastrointestinal disorders: dry mouth (6%), dysphagia (4%), oral pain (1%) Immune system disorders: hypogammaglobulinemia (9%), hemophagocytic lymphohistiocytosis (4%), drug hypersensitivity (1%) Infections and infestations: viral infections (6%) Metabolism and nutrition disorders: dehydration (5%), tumor lysis syndrome (1%) Musculoskeletal and connective tissue disorders: muscle spasms (4%), musculoskeletal stiffness (3%) Nervous system disorders: seizure (8%), ataxia (5%), peripheral neuropathy (4%), myoclonus (3%), paraparesis (3%), brain edema (1%), brain herniation (1%), cauda equina syndrome (1%), monoplegia (1%) Renal and urinary disorders: renal impairment (6%) Respiratory, thoracic and mediastinal disorders: respiratory failure (9%), pulmonary edema (6%), pleural effusion (4%), pneumonitis (4%) Skin and subcutaneous tissue disorders: skin lesion (4%), decubitus ulcer (3%), dry skin (3%), skin ulcer (3%), alopecia (1%), hyperhidrosis (1%), skin hyperpigmentation (1%) Vascular disorders: thrombosis (4%) Table 8.

Grade 3 or 4 Laboratory Abnormalities Occurring in ≥ 10% of Patients in Study 2 Following TECARTUS Infusion (N = 78) Grades 3 or 4 (%) Leukopenia 99 Neutropenia 97 Lymphopenia 96 Thrombocytopenia 87 Anemia 77 Hypophosphatemia 47 Alanine aminotransferase increased 31 Aspartate aminotransferase increased 23 Hyperglycemia 22 Hypocalcemia 22 Blood uric acid increased 19 Direct bilirubin increased 19 Hyponatremia 19 Hypokalemia 13 Hyperbilirubinemia 10 6.2 Postmarketing Experience Because adverse events to marketed products are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure.

The following adverse event has been identified during postmarketing use of TECARTUS: Immune System Disorders : Infusion related reaction The following adverse event has been identified during postmarketing use of BCMA- or CD19-directed genetically modified autologous T cell immunotherapies: Neoplasms : T cell malignancies