2.1 Recommended Dose

The recommended dose is between 1.62 × 109 to 10 × 109 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

Pretreatment

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/m2/day intravenously for 4 days starting on the seventh day before TECELRA infusion (Day-7 to Day -4) and cyclophosphamide 600 mg/m2/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.

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.

6.1 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 × 109 to 10 × 109 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.

Other clinically important adverse reactions occurring in patients receiving TECELRA include Grade 1 and Grade 2 ICANS reported in six patients (4%).

8.1 Pregnancy

Risk Summary

There are limited available data with TECELRA use in pregnant women. In the SPEARHEAD-1 clinical trial, there were two pregnancies in patients treated with TECELRA. One patient became pregnant 6 months following treatment with TECELRA and the outcome of this pregnancy was premature birth (30 weeks gestation) with healthy infant. A second patient was found to be pregnant two months following treatment with TECELRA and the pregnancy was electively terminated.

No animal reproductive and developmental toxicity studies have been conducted with TECELRA to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known if TECELRA has the potential to be transferred to the fetus and cause fetal toxicity. Therefore, TECELRA is not recommended for women who are pregnant, and pregnancy after TECELRA administration should be discussed with the treating physician. Report all pregnancies following treatment with TECELRA to 1-855-246-9232.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation

Risk Summary

There is no information regarding the presence of TECELRA in human milk, the effect on the breastfed infant, and the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TECELRA and any potential adverse effects on the breastfed infant from TECELRA or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

Pregnancy Testing

Verify pregnancy status of females with reproductive potential prior to starting treatment with TECELRA.

Contraception

See the Prescribing Information for fludarabine and cyclophosphamide for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.

There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with TECELRA.

Infertility

There are no data on the effects of TECELRA on human fertility.

8.4 Pediatric Use

The safety and effectiveness of TECELRA have been established in pediatric patients 12 years and older. Use of TECELRA is supported by a single arm trial of TECELRA (SPEARHEAD-1) in adults and pediatric patients 12 years and older, which enrolled 6 pediatric patients aged 13 years to less than 17 years. TECELRA exposure in pediatric patients 12 years and older is comparable to that of adults and the courses of unresectable or metastatic synovial sarcoma is sufficiently similar in pediatric patients aged 12 years and older to that of adults to allow extrapolation of safety and efficacy. [See Adverse Reactions (6.1), Clinical Pharmacology (12), and Clinical Studies (14)]

The safety and effectiveness of TECELRA in pediatric patients aged less than 12 years have not been established.

8.5 Geriatric Use

Of the 137 patients with synovial sarcoma in the SPEARHEAD-1 study that received TECELRA, 5.8% were 65 years of age or older. Clinical studies of TECELRA did not include sufficient numbers of patients aged 65 and over to conclude whether they respond differently from younger patients.

12.1 Mechanism of Action

TECELRA is a genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating LV to express an affinity-enhanced TCR specific for human MAGE-A4 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. Antigen-specific activation of TECELRA via TCR-peptide-HLA-A*02 complex results in T cell proliferation, cytokine secretion, and killing of MAGE-A4/HLA-A*02 expressing synovial sarcoma cells.

12.2 Pharmacodynamics

In adult patients with synovial sarcoma who were treated with TECELRA, serum concentrations of cytokines and other soluble factors involved in cellular homeostasis, T cell activation, and inflammation (e.g. IFNγ, IL-6, GMCSF, IL-8, and IL-2Rα) increased post-infusion, peaking between Days 3-8. IL-15 increased following lymphodepletion.

Similar to adults, in pediatric patients with synovial sarcoma who were treated with TECELRA, increases in serum concentration of cytokines (e.g., IFNγ, IL-6, GMCSF, and IL-2Rα) were observed post-infusion, peaking between Days 3-8. IL-15 increased following lymphodepletion.

12.3 Pharmacokinetics

TECELRA exhibited an initial engraftment and expansion phase followed by contraction, and then persistence. High inter-individual variability was observed.

The pharmacokinetics of TECELRA in patients with synovial sarcoma are summarized in Table 3.

Persistence of Tecelra has been observed for greater than 3 years following infusion.

Specific Populations

The pharmacokinetics of afamitresgene autoleucel (Cmax, AUC0-7D, AUC0-28D, AUC0-3M, AUC0-6M) were not impacted by body weight, body mass index, sex, age and baseline tumor sum of longest diameter (SLD).

Hepatic and renal impairment studies of TECELRA were not conducted.

Pediatric Patients

The exposure of TECELRA in pediatric patients 12 years of age and older is within the range of that observed in adults at the approved recommended dosage (Table 3a).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with TECELRA.

A genomic insertion site analysis was performed on TECELRA products from five patients. There was no evidence for preferential integration near genes of concern. No studies have been conducted to evaluate the effects of TECELRA on fertility.

TECELRA is shipped in a liquid nitrogen dry vapor shipper at less than or equal to -130°C.

Store TECELRA in the original packaging, containing the cassette(s) protecting the infusion bag(s), in the vapor phase of liquid nitrogen at less than or equal to -130°C.