WARNING: CYTOKINE RELEASE SYNDROME Cytokine Release Syndrome (CRS), which may be severe or life-threatening, occurred in patients receiving TECELRA. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care. Ensure that healthcare providers administering TECELRA have immediate access to medications and resuscitative equipment to manage CRS [see Preparation and Administration (2.2) , and Warnings and Precautions (5.1) ] . WARNING: CYTOKINE RELEASE SYNDROME See full prescribing information for complete boxed warning. Cytokine Release Syndrome (CRS), which may be severe or life-threatening, occurred in patients receiving TECELRA. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care. Ensure that healthcare providers administering TECELRA have immediate access to medications and resuscitative equipment to manage CRS ( 2.2 , 5.1 ).
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warnings and cautions
5 WARNINGS AND PRECAUTIONS Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Monitor for ICANS events for at least 2 weeks after treatment with TECELRA. Effects on Ability to Drive and Use Machines: Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 2 weeks after receiving TECELRA ( 5.2 ). Prolonged Severe Cytopenia: Patients may exhibit severe cytopenia (hemoglobin < 8.0 g/dL, neutrophils < 1,000/mm 3 , platelets < 50,000/mm 3 ) for several weeks following lymphodepleting chemotherapy and TECELRA infusion. Monitor blood counts prior to and after TECELRA infusion ( 5.3 ). Infections: Monitor patients for signs and symptoms of infection; treat appropriately ( 5.4 ). Secondary Malignancies: In the event that a secondary malignancy occurs after treatment with TECELRA, contact 1-855-246-9232 ( 5.5 ). Hypersensitivity Reactions: Monitor for hypersensitivity reactions during infusion ( 5.6 ). 5.1 Cytokine Release Syndrome Cytokine release syndrome (CRS), including potentially life-threatening reaction has been observed following administration of TECELRA. CRS occurred in 72% of patients, including Grade ≥ 3 CRS in 2% patients. The median time to onset was 2 days (range: 1 to 7 days) and the median time to resolution was 3 days (range: 1 to 14 days). The most common symptoms were fever (97%), tachycardia (58%), hypotension (31%), nausea/vomiting (26%) and headache (21%) [see Adverse Reactions (6) ] . Management for CRS (including Grade 1) was tocilizumab (40%) and siltuximab (1 patient). Eight participants also required corticosteroids for CRS management. Ensure that healthcare providers administering TECELRA have immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. During and following TECELRA administration, closely monitor patients for signs and symptoms of CRS. Following treatment with TECELRA, monitor patients for at least 7 days at the healthcare facility for CRS. Continue to monitor patients for CRS for at least 2 weeks following treatment with TECELRA. Counsel patients to seek medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment with supportive care based on severity and consider further management per current practice guidelines. 5.2 Immune Effector Cell-associated Neurotoxicity Syndrome Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) has been observed following administration of TECELRA. Six patients (4%) had ICANS; five Grade 1 and one Grade 2. Time to onset was 2 to 8 days and time to resolution was 1 to 7 days. Symptoms included mild mental status changes. Other symptoms may include disorientation to time and place, mild drowsiness, mild inattention. Severe symptoms may include altered level of consciousness, seizures, cerebral edema, impairment of cognitive skills, progressive aphasia, motor weakness. Ensure that healthcare providers administering TECELRA have immediate access to medications and resuscitative equipment to manage ICANS. During and following TECELRA administration, closely monitor patients for signs and symptoms of ICANS. Following treatment with TECELRA, monitor patients for at least 7 days at the healthcare facility for ICANS. Continue to monitor patients for ICANS for at least 2 weeks following treatment with TECELRA. Counsel patients to seek medical attention should signs or symptoms of ICANS occur. At the first sign of ICANS, immediately evaluate patients for hospitalization and institute treatment with supportive care based on severity and consider further management per current practice guidelines. Effect on Ability to Drive and Use Machines Due to the potential for neurologic events, including dizziness and presyncope, patients receiving TECELRA are at risk for altered or decreased coordination in the 2 weeks following infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period. 5.3 Prolonged Severe Cytopenia Patients may exhibit severe cytopenias, including neutropenia and thrombocytopenia [see Adverse Reactions (6) ] . Patients exhibited anemia, neutropenia, and/or thrombocytopenia for several weeks following lymphodepleting chemotherapy and TECELRA infusion. Patients with Grade ≥ 3 cytopenia not resolved by week 4 included neutropenia (11%), anemia (6%), and thrombocytopenia (5%). The median time to resolution was 7.0 weeks (range: 6.1 to 12.4 weeks) for neutropenia, 6.4 weeks (range: 5.3 to 12.1 weeks) for anemia, and 9 weeks (range: 5.3 to 12.1 weeks) for thrombocytopenia. Monitor blood counts after TECELRA infusion. Manage cytopenia with growth factor and blood product transfusion according to local institutional guidelines/clinical practice. 5.4 Infections Infections may occur following lymphodepleting chemotherapy and TECELRA infusion. Infections (all grades) occurred in 35% of patients with synovial sarcoma. Grade 3 or higher infections occurred in 12% of patients. Do not administer TECELRA to patients with active infections and/or inflammatory disorders. Monitor patients for signs and symptoms of infection before and after TECELRA infusion and treat patients appropriately. Febrile neutropenia was observed in 10% of patients after TECELRA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated. Viral reactivation has occurred in patients following treatment with TECELRA. Perform screening for Epstein-Barr Virus, Cytomegalovirus, Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency Virus, and any other infectious agents if clinically indicated. Consider antiviral therapy to prevent viral reactivation per local guidelines. 5.5 Secondary Malignancies Patients treated with TECELRA may develop secondary malignancies or recurrence of their cancer. Monitor for secondary malignancies. In the event that a secondary malignancy occurs, contact 1-855-246-9232 to obtain instructions on patient samples to collect for testing. 5.6 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) in TECELRA. Observe patients for hypersensitivity reactions during infusion. 5.7 Potential for HIV Nucleic Acid Test False-Positive Results The lentiviral vector used to make TECELRA has limited, short spans of genetic material which are identical to HIV. Therefore, some commercial HIV nucleic acid tests may yield false-positive results in patients who have received TECELRA.
6 ADVERSE REACTIONS Most common adverse reactions (≥ 20%) were, cytokine release syndrome, nausea, fatigue, musculoskeletal pain, infections, pyrexia, constipation, vomiting, headache, diarrhea, cough, tachycardia, edema, dyspnea, and rash. ( 6.1 ) Grade 3 or 4 laboratory abnormalities (≥20%) were lymphocyte count decreased, white blood cell count decreased, neutrophil count decreased and red blood cell count decreased ( 6.1 ). The most common serious adverse reactions (≥ 5%) were cytokine release syndrome and infections ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact USWM CT, LLC at 1-855-246-9232 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. The safety of TECELRA was evaluated in the SPEARHEAD-1 study (Cohorts 1, 2, 3) in which 137 patients with advanced synovial sarcoma received TECELRA across a dose of 1.01 × 10 9 to 10 × 10 9 MAGE-A4 TCR positive T cells [see Clinical Studies (14) ]. Serious adverse reactions occurred in 35% of patients with synovial sarcoma. The most common serious adverse reactions (occurring in ≥ 5%) were CRS (7%) and infections (8%). Table 1 summarizes adverse reactions that occurred in at least 10% of patients. Table 1. Adverse Reactions Occurring in ≥10% of Patients in SPEARHEAD-1 (Cohorts 1, 2, 3) SOC Grouped Term (N=137) All Grades n (%) Grade ≥ 3 n (%) a Includes all adverse reactions reported following lymphodepleting chemotherapy and TECELRA, regardless of attribution to TECELRA Gastrointestinal disorders Nausea 88 (64) 5 (4) Vomiting 38 (28) 2 (2) Constipation 40 (29) 1 (1) Diarrhea 34 (25) 0 (0) Abdominal pain Is a composite that includes multiple related terms. 25 (18) 5 (4) General disorders and administration site conditions Fatigue 72 (53) 2 (2) Pyrexia 41 (30) 5 (4) Edema Edema includes ascites, fluid retention, hypervolemia, edema peripheral, pleural effusion, face edema, localized edema, peripheral swelling, and swelling. 29 (21) 3 (2) Chills 21 (15) 0 (0) Immune system disorders Cytokine Release Syndrome As per American Society for Transplantation and Cellular Therapy (ASTCT) criteria 1 98 (72) 3 (2) Infections and infestations Any infection Any infection includes all infection terms under the 'Infections and infestations' System Organ Class 48 (35) 16 (12) Nervous system disorders Headache 36 (26) 2 (2) Dizziness 22 (16) 0 (0) Encephalopathy Encephalopathy includes confusional state, dysgeusia, cognitive disorder, somnolence, aphasia, dysarthria, and amnesia. 17 (12) 0 (0) Neuropathy peripheral 14 (10) 0 (0) Metabolism and nutrition disorders Decreased appetite 25 (18) 3 (2) Musculoskeletal and connective tissue disorders Musculoskeletal pain 60 (44) 5 (4) Respiratory, thoracic, and mediastinal disorders Cough 34 (25) 0 (0) Dyspnea 27 (20) 5 (4) Renal and urinary disorders Renal insufficiency 15 (11) 1 (1) Vascular disorders Hemorrhage 26 (19) 2 (2) Hypotension 25 (18) 2 (2) Hypertension 15 (11) 3 (2) Cardiac disorders Tachycardia 30 (22) 0 (0) Skin and subcutaneous tissue disorders Rash 28 (20) 3 (2) Alopecia 17 (12) 0 (0) Psychiatric disorders Insomnia 16 (12) 0 (0) Other clinically important adverse reactions occurring in patients receiving TECELRA include Grade 1 and Grade 2 ICANS reported in six patients (4%). Table 2. Laboratory Abnormalities Abnormalities are laboratory values that were considered an adverse event Worsened from Baseline in ≥10% of Patients in SPEARHEAD-1 (Cohorts 1, 2, 3) N=137 Laboratory Abnormalities All Grades n (%) Grade 3 or 4 n (%) Grading based on NCI CTCAE version 5.0. Lymphocyte count decreased 137 (100) 137 (100) Neutrophil count decreased 132 (96) 122 (89) White blood cell decreased 134 (98) 121 (88) Red blood cell decreased 130 (95) 33 (24) Platelet count decreased 118 (86) 25 (18) Aspartate aminotransferase increased 82 (60) 8 (6) Alanine aminotransferase increased 64 (47) 8 (6)