TECELRA

TECELRA (afamitresgene autoleucel) is a melanoma-associated antigen A4 (MAGE- A4)-directed genetically modified autologous T cell immunotherapy product consisting of CD4 and CD8 positive T cells transduced with a self-inactivating lentiviral vector (LV) expressing an affinity-enhanced T cell receptor (TCR) specific for the human MAGE-A4. Autologous T cells transduced with MAGE-A4-c1032 LV express the affinity-enhanced TCR on the cell surface. The TCR recognizes an HLA-A*02 restricted MAGE-A4 peptide. MAGE-A4 is an intracellular cancer-testis antigen that has restricted expression in normal tissues and is expressed in synovial sarcoma. TECELRA is prepared from the patient's peripheral blood mononuclear cells (PBMCs), which are obtained via a standard leukapheresis procedure. The PBMCs are enriched for T cells and are then transduced with a replication-incompetent LV containing the MAGE-A4 TCR transgene. The transduced T cells are expanded, washed, formulated into a suspension, and cryopreserved. The product must pass a sterility test before release and shipping as a frozen suspension in one or more infusion bag(s). The product is thawed prior to infusion back into the patient [see Preparation and Administration ( 2.2 ), How Supplied/Storage and Handling ( 16 )]. The drug product formulation contains 5% dimethyl sulfoxide (DMSO).

TECELRA is a melanoma-associated antigen A4-(MAGE-A4)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This indication is approved under accelerated approval based on overall response rate and durability of response [see Clinical Studies ( 14 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. TECELRA is a melanoma-associated antigen A4 (MAGE-A4)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive and whose tumor expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This indication is approved under accelerated approval based on overall response rate and duration of response ( 14 ). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

For autologous use only. For intravenous use only. For autologous use only. For intravenous use only. Prior to infusion Verify patient's identity prior to infusion ( 2.2 ). Administer a lymphodepleting regimen of cyclophosphamide and fludarabine ( 2.2 ). Premedicate with acetaminophen and an H1-antihistamine ( 2.2 ). TECELRA Dose and Administration The recommended dose is between 2.68 x 10 9 to 10 x 10 9 MAGE-A4 T cell receptor (TCR) positive T cells ( 2.1 ). Administer each infusion bag within one hour of thawing. DO NOT USE a leukodepleting filter ( 2.2 ). DO NOT USE prophylactic systemic corticosteroids ( 2.2 ). 2.1 Recommended Dose The recommended dose is between 2.68 x 10 9 to 10 x 10 9 MAGE-A4 T cell receptor (TCR) positive T cells administered as a single intravenous infusion. TECELRA is provided as a single dose for infusion in one or more infusion bag(s). Verify the number of bags received for the indicated dose prior to preparation for infusion. 2.2 Preparation and Administration Receipt of TECELRA Plan for TECELRA to arrive prior to beginning lymphodepleting chemotherapy. Ensure storage conditions in vapor phase of liquid nitrogen (≤ -130°C). TECELRA is shipped directly to the healthcare facility in the vapor phase of a liquid nitrogen shipper. Upon receipt of TECELRA confirm the patient's identifiers on the metal cassette and product bag. Inspect the product for obvious signs of damage and contact 1-855-246-9232 if any anomalies are identified at the time of receipt. Transfer TECELRA in the original packaging, containing the cassette(s) protecting the infusion bag(s), to onsite storage at ≤ -130°C before the shipper expires. Store TECELRA in a manner that is consistent with How Supplied/Storage and Handling ( 16 ) . If unforeseen circumstances prevent proper storage of TECELRA consistent with How Supplied/Storage and Handling ( 16 ) , contact 1-855-246-9232 to arrange for return shipment. Preparing Patient for TECELRA Administration Confirm availability of TECELRA at the healthcare facility prior to starting the lymphodepleting chemotherapy regimen. Match the patient's identity with the patient identifiers on the TECELRA cassette(s) and infusion bag(s). Do not infuse TECELRA if the information on the patient-specific label(s) does not match the intended patient. Administer a lymphodepleting chemotherapy regimen of fludarabine 30 mg/m 2 /day intravenously for 4 days starting on the seventh day before TECELRA infusion (Day-7 to Day -4) and cyclophosphamide 600 mg/m 2 /day intravenously for 3 days starting the seventh day before TECELRA infusion (Day -7 to Day -5). Refer to fludarabine prescribing for information on fludarabine dosage in patients with renal impairment. Short-acting or pegylated granulocyte-colony stimulating factor (G-CSF) may be administered at the discretion of the physician, and according with institutional standards, from 24 hours after last day of lymphodepleting chemotherapy (from Day -3) until resolution of neutropenia. Premedication Premedicate with an H1-antihistamine and acetaminophen according to institutional standard practice, approximately 30-60 minutes prior to TECELRA infusion. Avoid prophylactic systemic corticosteroids, as it may interfere with the activity of TECELRA. Preparation of TECELRA for Administration Do not thaw the product until it is ready to be used. Coordinate the timing of TECELRA thaw and infusion. Confirm infusion time in advance and adjust the start time of TECELRA thaw such that it will be available for infusion when the patient is ready. A TECELRA dose may be contained in one or more infusion bag(s). Verify the number of bags received for the indicated dose prior to preparation of TECELRA for infusion. If more than one bag will be infused for the treatment dose, thaw and administer the contents of each infusion bag completely before proceeding to thaw and infuse the contents of the next infusion bag. 1. Confirm patient identity. Prior to TECELRA preparation, match the patient's identity with the patient identifiers on each TECELRA cassette. Do not remove the TECELRA infusion bag(s) from the cassette(s) if the information on the patient-specific label does not match the patient's identity. Contact 1-855-246-9232 if there are any discrepancies between the labels and the patient identifiers. 2. Once patient identity is confirmed, remove TECELRA infusion bag(s) from the cassette(s) and check that the patient identifiers on the cassette label match the patient identifiers on the bag label. Contact 1-855-246-9232 if there are any discrepancies between the patient identifiers on the cassette and bag labels. 3. Inspect the infusion bag for any breaches of container integrity such as breaks or cracks before thawing. If the bag is compromised, do not infuse the contents and call 1-855-246-9232. 4. Place the infusion bag inside a second sealable, preferably sterile bag per institutional standard practice. 5. Thaw the infusion bag at approximately 37°C using a water bath or dry thaw method, until there is no visible ice in the infusion bag. 6. Gently mix the contents of the bag by massaging, to disperse visible cell clumps. Small clumps of cellular material should disperse with gentle manual massaging. Do not infuse TECELRA if clumps are not dispersed. Call 1-855-246-9232. 7. Keep TECELRA at ambient temperature (20°C to 25°C) once thawed. Do not pre-filter into a different container, wash, spin down, or resuspend TECELRA in new media prior to infusion. 8. Administer within one hour. TECELRA Administration 9. Do not use a leukodepleting filter. 10. Follow universal precautions and local biosafety guidelines for handling and disposal of TECELRA to avoid potential transmission of infectious diseases, due to the presence of human blood cells that are genetically modified with replication incompetent, self-inactivating lentiviral vector. 11. Confirm patient identity with the patient identifiers on the infusion bag(s). Do not infuse TECELRA if the information on the patient-specific label does not match the intended patient. Call 1-855-246-9232. Prime the tubing of the infusion set with 0.9% sodium chloride solution prior to infusion. 12. Administer the TECELRA infusion bag via intravenous infusion within one hour. Administer the entire contents of the TECELRA infusion bag. 13. After the entire contents of the TECELRA infusion bag are infused, rinse the infusion bag with approximately 50mL 0.9% sodium chloride solution to ensure all product is delivered. 14. If more than one infusion bag has been received, administer the content of each infusion bag completely before proceeding to thaw and infuse the content of the next infusion bag, following steps 1-14 for all subsequent infusion bags.

DO NOT use TECELRA in adults who are heterozygous or homozygous for HLA- A*02:05P. DO NOT use TECELRA in adults who are heterozygous or homozygous for HLA-A*02:05P ( 4 ).

Most common adverse reactions (≥ 20%) were, cytokine release syndrome, nausea, vomiting, fatigue, infections, pyrexia, constipation, dyspnea, abdominal pain, non-cardiac chest pain, decreased appetite, tachycardia, back pain, hypotension, diarrhea, and edema. Grade 3 or 4 laboratory abnormalities (≥20%) were lymphocyte count decreased, neutrophil count decreased, white cell blood count decreased, red blood cell decreased, and platelet count decreased ( 6.1 ). The most common serious adverse reactions (≥ 5%) were cytokine release syndrome and pleural effusion ( 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 data described in this section reflects the exposure to TECELRA in 44 patients with advanced synovial sarcoma treated in the SPEARHEAD-1 clinical trial (Cohort 1). Patients with synovial sarcoma received TECELRA across a dose of 2.68 x 10 9 to 10 x 10 9 MAGE-A4 TCR positive T cells [see Clinical Studies ( 14 )]. Serious adverse reactions occurred in 52% of patients with synovial sarcoma. The most common serious adverse reactions (occurring in ≥ 5%) included CRS (9%) and pleural effusion (7%). 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 (Cohort 1) SOC Grouped Term (N=44) All Grades n (%) Grade ≥ 3 n (%) Investigations Weight decreased 5 (11) 1 (2) Gastrointestinal disorders Nausea 29 (66) 1 (2) Vomiting 16 (36) 0 (0) Constipation 14 (32) 0 (0) Abdominal pain 11 (25) 2 (5) Diarrhea 9 (21) 0 (0) General disorders and administration site conditions Fatigue 15 (34) 0 (0) Pyrexia 14 (32) 2 (5) Non-cardiac chest pain 10 (23) 1 (2) Chills 7 (16) 0 (0) Edema 9 (21) 0 (0) Asthenia 7 (16) 1 (2) Chest pain 6 (14) 0 (0) Immune system disorders Cytokine Release Syndrome As per American Society for Transplantation and Cellular Therapy (ASTCT) criteria 1 33 (75) 1 (2) Infections and infestations Any infection Any infection includes all infection terms under the 'Infections and infestations' System Organ Class 14 (32) 6 (14) Nervous system disorders Headache 8 (18) 1 (2) Dizziness 5 (11) 0 (0) Metabolism and nutrition disorders Decreased appetite 10 (23) 1 (2) Musculoskeletal and connective tissue disorders Back pain 9 (21) 2 (5) Pain in extremity 6 (14) 0 (0) Respiratory, thoracic, and mediastinal disorders Dyspnea 11 (25) 2 (5) Cough 8 (18) 0 (0) Vascular disorders Hypotension 9 (21) 0 (0) Hypertension 7 (16) 1 (2) Cardiac disorders Sinus Tachycardia/ Tachycardia 9 (21) 0 (0) Skin and subcutaneous tissue disorders Alopecia 6 (14) 0 (0) Other clinically important adverse reactions occurring in patients receiving TECELRA include Grade 1 ICANS reported in one patient (2%). Table 2. Laboratory Abnormalities Abnormalities are laboratory values that were considered an adverse event Worsened from Baseline in ≥10% of Patients in SPEARHEAD-1 (Cohort 1) Laboratory Abnormalities N=44 All Grades n (%) Grade 3 or 4 n (%) Grading based on NCI CTCAE version 5.0. Lymphocyte count decreased 43 (98) 43 (98) Neutrophil count decreased 42 (96) 40 (91) White blood cell decreased 42 (96) 38 (86) Red blood cell decreased 42 (96) 14 (32) Platelet count decreased 36 (82) 9 (21) Alanine aminotransferase increased 20 (46) 2 (5)

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