Consumer medicine information

Tecartus

Brexucabtagene autoleucel

BRAND INFORMATION

Brand name

Tecartus

Active ingredient

Brexucabtagene autoleucel

Schedule

Unscheduled

SUMMARY CMI

TECARTUS^®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I given TECARTUS?

TECARTUS also known as brexucabtagene autoleucel is a type of medicine called a “genetically modified cell therapy”. TECARTUS is used to treat mantle cell lymphoma and B-cell precursor acute lymphoblastic leukaemia in adults. Mantle cell lymphoma and B-cell precursor acute lymphoblastic leukaemia are cancers that affects part of the immune system (the lymph tissue). They affect a type of white blood cell called B-lymphocytes. In both mantle cell lymphoma and B-cell precursor acute lymphoblastic leukaemia, B-lymphocytes grow in an uncontrolled way and build up in the lymph tissue, bone marrow or blood. TECARTUS is used to treat this condition when other available medicines have stopped working for you.

For more information, see Section 1. Why am I given TECARTUS? in the full CMI.

2. What should I know before I am given TECARTUS?

Do not use if you have ever had an allergic reaction to brexucabtagene autoleucel or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I am given TECARTUS? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TECARTUS and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How am I given TECARTUS?

TECARTUS is made specially for you as a single administration of your own modified white blood cells.
Your doctor will give you TECARTUS by a drip (infusion) into a vein (intravenously).

More instructions can be found in Section 4. How am I given TECARTUS? in the full CMI.

5. What should I know after I am given TECARTUS?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you have been given TECARTUS. Plan to stay within proximity (i.e. within 2 hours) of the hospital where you will be treated for at least 4 weeks after you have been given TECARTUS.
Driving or using machines	Do not drive or operate machinery in the 8 weeks after receiving TECARTUS.

For more information, see Section 5. What should I know after I am given TECARTUS? in the full CMI.

6. Are there any side effects?

There can be some serious side effects before and after TECARTUS treatment. Serious side effects may include symptoms of cytokine release syndrome (CRS), disturbances of brain function or infection.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNINGS

CYTOKINE RELEASE SYNDROME

Cytokine Release Syndrome (CRS), including fatal or life‐threatening reactions, occurred in patients receiving TECARTUS. Do not administer TECARTUS to patients with active infection or inflammatory disorders. Treat severe or life‐threatening CRS with tocilizumab or tocilizumab and corticosteroids.

IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, has occurred following treatment with TECARTUS, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with TECARTUS. Provide supportive care and/or corticosteroids as needed.

FULL CMI

TECARTUS^®

Active ingredient(s): brexucabtagene autoleucel

Consumer Medicine Information (CMI)

This leaflet provides important information about using TECARTUS. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TECARTUS.

Where to find information in this leaflet:

1. Why am I given TECARTUS?
2. What should I know before I am given TECARTUS?
3. What if I am taking other medicines?
4. How am I given TECARTUS?
5. What should I know after I am given TECARTUS?
6. Are there any side effects?
7. Product details

1. Why am I given TECARTUS?

TECARTUS also known as brexucabtagene autoleucel is a type of medicine called a “genetically modified cell therapy”. TECARTUS is made specially for you as a single administration of your own modified white blood cells. It is given by a drip (infusion) into a vein (intravenously).

TECARTUS is used to treat mantle cell lymphoma (MCL) and B-cell precursor acute lymphoblastic leukaemia (ALL) in adults. Mantle cell lymphoma and B-cell precursor acute lymphoblastic leukaemia are cancers that affects part of the immune system (the lymph tissue). They affect a type of white blood cell called B‐lymphocytes. In both mantle cell lymphoma and B-cell precursor acute lymphoblastic leukaemia, B‐lymphocytes grow in an uncontrolled way and build up in the lymph tissue, bone marrow or blood. TECARTUS is used to treat this condition when other available medicines have stopped working for you.

2. What should I know before I am given TECARTUS?

Warnings and Precautions

Do not use TECARTUS if:

You are allergic to brexucabtagene autoleucel, or any of the ingredients listed at the end of this leaflet.

Tell your doctor (or your doctor will check) if you:

have problems with your nervous system (such as fits, stroke, or memory loss).
have kidney problems.
have low blood cell levels (blood counts).
have any problems with your lungs, heart or blood pressure (low or high).
have had a stem cell transplant in the last 4 months
have signs or symptoms of graft versus host disease.
This happens when transplanted cells attack your body, causing symptoms such as rash, nausea, vomiting, diarrhoea and bloody stools.
notice the symptoms of your cancer are getting worse. If you have lymphoma this might include fever, feeling weak, night sweats, sudden weight loss
have an infection. The infection will be treated before the TECARTUS infusion.
have had hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Plan to stay within proximity (i.e. within 2 hours) of the hospital where you will be treated for at least 4 weeks after you have been given TECARTUS.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

This is because the effects of TECARTUS in pregnant or breast feeding women are not known, and it may harm your unborn baby or your breast feeding child.

You will be given a pregnancy test before treatment starts. TECARTUS should only be given if the results show you are not pregnant.

If you are pregnant or think you may be pregnant after treatment with TECARTUS, talk to your doctor immediately.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Before you are given TECARTUS tell your doctor or nurse if you are taking any medicines that weaken your immune system such as corticosteroids, since these medicines may interfere with the effect of TECARTUS.

In particular, you must not be given certain vaccines called live vaccines:

In the 6 weeks before you are given the short course of chemotherapy (called lymphodepleting chemotherapy) to prepare your body for the TECARTUS cells.
During TECARTUS treatment.
After treatment while the immune system is recovering.

Talk to your doctor if you need to have any vaccinations.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TECARTUS.

4. How am I given TECARTUS?

Tests and Checks

Before you are given TECARTUS your doctor will:

Check your lungs, heart and blood pressure.
Look for signs of infection; any infection will be treated before you are given TECARTUS.
Check if your cancer is getting worse.
Look for signs of graft‐versus‐host disease that can happen after a transplant.
Check your blood for uric acid and for how many cancer cells there are in your blood. This will show if you are likely to develop a condition called tumour lysis syndrome. You may be given medicines to help prevent the condition.
Check for hepatitis B, hepatitis C or HIV infection.
Check if you had a vaccination in the previous 6 weeks or are planning to have one in the next few months.

How much you will be given

Since TECARTUS is made from your own white blood cells, your cells will be collected from you to prepare your medicine.
Your doctor will take some of your blood using a catheter placed in your vein (a procedure call leukapheresis [loo‐kah‐fur‐ee‐sis]).
Some of your white blood cells are separated from your blood and the rest of your blood is returned to your vein. This can take 3 to 6 hours and may need to be repeated.
Your white blood cells are sent away to make TECARTUS. It usually takes about 2 to 3 weeks to receive your TECARTUS therapy but the time may vary.
Prior to receiving TECARTUS, you will be given preparative chemotherapy (called lymphodepleting chemotherapy), which will allow your modified white blood cells in TECARTUS to multiply in your body when the medicine is given to you.
Your doctor or nurse will check carefully that this medicine is yours.
In some cases, it might not be possible to go ahead with the planned treatment with TECARTUS. For example: if TECARTUS infusion is delayed for more than 2 weeks after you have received preparatory chemotherapy you may have to receive more preparative chemotherapy.

How you are given TECARTUS

TECARTUS will always be given to you by a healthcare professional.
TECARTUS is a single infusion treatment.
During the 30 to 60 minutes before you are given TECARTUS you may be given other medicines. This is to help prevent infusion reactions and fever.

These other medicines may include:

Paracetamol
An antihistamine such as diphenhydramine or similar.
Your doctor or nurse will give you a single infusion of TECARTUS into your vein for approximately 30 minutes.
TECARTUS is the genetically modified version of your normal white blood cells. Your healthcare professional handling TECARTUS will therefore take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases and will follow local biosafety guidelines to clean up or dispose of any material that has been in contact with TECARTUS.
You must receive TECARTUS infusion in a qualifed clinical facility and be discharged only when your doctor thinks it is safe for you to go home.
You will be monitored where you received your treatment daily for at least 7 days after the infusion.
Your doctor may do blood tests to check for side effects.

5. What should I know after I am given TECARTUS?

Things you should do

Plan to stay within 2 hours of the hospital where you were treated for at least 4 weeks after you have been given TECARTUS.

Your doctor will recommend that you return to the hospital daily for at least 7 days and will consider whether you need to stay at the hospital as an inpatient for at least 7 days after infusion. This is so your doctor can check if your treatment is working and help you if you have any side effects.

If you miss any appointments, call your doctor or the qualified clinical facility as soon as possible to reschedule your appointment.

Driving or using machines

Be careful driving or operating machinery.

TECARTUS can cause problems such as altered or decreased consciousness, confusion and seizures (fits) in the 8 weeks following infusion.

Do not drive, use machines, or take part in activities that need you to be alert until at least 8 weeks after your infusion or until your doctor tells you that you have completely recovered.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Very Serious Side Effects

Very Serious Side Effects

What to do

Symptoms of cytokine release syndrome such as fever, chills, nausea, diarrhoea, headaches, rapid heartbeat, low blood pressure, dizziness, lightheadedness, and trouble breathing
Disturbances of brain function such as loss of consciousness or decreased level of consciousness, confusion or memory loss, difficulty speaking or slurred speech, involuntary shaking of a body part (tremor), delirium, agitation, disorientation, hallucination, irritability
Fever, chills, which may be signs of an infection
Decrease of oxygen reaching body tissues
Leakage of fluids from blood vessels into surrounding tissue.
This can lead to a weight gain and difficulty in breathing (oedema)
Failure of the kidneys causing your body to hold onto fluid which can be serious or life threatening
Decreased output of urine (due to kidney problems described above)
Fluid around the lungs (pleural effusion)
Swelling, pain, and warmth in your leg, shortness of breath, or chest pain may be a sign of blood clots
Infections caused by fungi
Breathlessness (respiratory failure)
Changes in heart rhythm
Fits (seizures)
Increase of the pressure inside your skull
Alteration of the blood ability to form clots (coagulopathy): symptoms can include excessive or prolonged bleeding or bruising.
Anaphylaxis

Tell your doctor at the qualified clinical facility immediately or go to the accident and emergency department at the nearest hospital.
It is important to tell your doctor that you received TECARTUS and to show them your TECARTUS Patient Alert Card.

Serious Side Effects

Serious Side Effects

What to do

Decrease in the number of white blood cells, which are important for fighting infections
Decrease in the number of cells that help clot the blood (thrombocytopenia)
Low blood pressure, high blood pressure
Decrease in the number of red blood cells (cells that carry oxygen) which may cause you to feel extremely tired with a loss of energy
Extreme tiredness
Changes in rate of the heartbeat
Nausea, constipation, diarrhoea, abdominal pain, vomiting, difficulty swallowing
Muscle pain, joint pain, bone pain, pain in the extremities of the body
Lack of energy or strength, muscular weakness, difficulty moving, muscle spasm
Headache
Abnormal blood test results (high level of uric acid; sugar (glucose) bilirubin or magnesium, low level of sodium, phosphate, potassium or calcium)
Swelling in the limbs
Skin rash or skin problems
Low levels of antibodies called immunoglobulins, which may lead to infections
Changes in blood test result that report on how the liver is working (high levels of liver enzymes)
Dizziness
Nerve pain
Pain
Loss of control of body movements
Dehydration
Abnormal blood test results (low level of albumin)
Changes in vision which makes it difficult to see things (visual impairment)
Hypersensitivity: symptoms such as rash, hives, itching, swelling
Infusion reactions such as flushing, rash, itching, fever, alterations in heart rate and blood pressure, shortness of breath or vomiting.

Tell your doctor immediately.

Less Serious Side Effects	What to do
Dry mouth Decreased appetite, sore mouth) Difficulty sleeping, anxiety	Tell your doctor immediately.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only used in a qualified treatment centre.

What TECARTUS contains

Active ingredient
(main ingredient)

brexucabtagene autoleucel
The active substance is autologous anti-CD19-transduced CD3+ cells. Each patient-specific single infusion bag contains a dispersion of anti-CD19 CAR T cells in approximately 68 mL for a target dose of 2 × 10⁶ anti-CD19 CAR-positive viable T cells/kg for mantle cell lymphoma patients and a target dose of 1 × 10⁶ anti CD19 CAR-positive viable T cells/kg for B-cell precursor acute lymphoblastic leukaemia patients.

Other ingredients
(inactive ingredients)

5% DMSO
sodium chloride
human serum albumin

Do not take this medicine if you are allergic to any of these ingredients.

What TECARTUS looks like

TECARTUS is a clear to opaque, white to red dispersion for infusion, supplied in an infusion bag individually packed in a metal cassette. A single infusion bag contains approximately 68 mL of cell dispersion.

ARTG No: 371431, 396794

Who distributes TECARTUS

Gilead Sciences Pty Ltd
Level 28, 385 Bourke Street
Melbourne, Victoria 3000

This leaflet was prepared in November 2024.

TECARTUS is a trademark of Gilead Sciences, Inc., or its related companies. Other brands listed are trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Tecartus

Active ingredient

Brexucabtagene autoleucel

Schedule

Unscheduled

1 Name of Medicine

Tecartus (brexucabtagene autoleucel), 1 x 10⁶ - 2 x 10⁶ anti-CD19 CAR T cells/kg suspension (dispersion) for infusion.

2 Qualitative and Quantitative Composition

General description.

Tecartus (brexucabtagene autoleucel) is a CD19 directed genetically modified autologous T cell immunotherapy. To prepare Tecartus, a patient's own T cells are harvested and genetically modified ex vivo by retroviral transduction to express a chimeric antigen receptor (CAR) comprising a murine anti-CD19 single chain variable fragment (scFv) linked to CD28 and CD3-zeta co-stimulatory domains. The anti-CD19 CAR-positive viable T cells are expanded and infused back into the patient, where they can recognise and eliminate CD19-expressing target cells.

Qualitative and quantitative composition.

Mantle cell lymphoma.

Each patient specific single infusion bag of Tecartus contains a dispersion of anti-CD19 CAR T cells in approximately 68 mL for a target dose of 2 x 10⁶ CAR T cells per kg body weight (range: 1 x 10⁶ - 2 x 10⁶ cells/kg), with a maximum of 2 x 10⁸ anti-CD19 CAR T cells.

Acute lymphoblastic leukaemia.

Each patient specific single infusion bag of Tecartus contains a dispersion of anti-CD19 CAR T cells in approximately 68 mL for a target dose of 1 x 10⁶ CAR T cells per kg body weight, with a maximum of 1 x 10⁸ anti-CD19 CAR T cells.

Excipients with known effect.

Each bag of Tecartus contains 300 mg sodium.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Dispersion for infusion.
A clear to opaque, white to red dispersion of cells for infusion.

4 Clinical Particulars

4.1 Therapeutic Indications

Tecartus is a genetically modified autologous immunocellular therapy for the treatment of:

Mantle cell lymphoma.

Patients with relapsed or refractory mantle cell lymphoma (MCL), who have received two or more lines of therapy, including a BTK inhibitor (unless ineligible or intolerant to treatment with a BTK inhibitor).

Acute lymphoblastic leukaemia.

Adult patients ≥ 18 years of age with relapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL).

4.2 Dose and Method of Administration

Tecartus must be administered in a qualified clinical setting.
Tecartus therapy should be initiated under the direction of and supervised by a healthcare professional experienced in the treatment of haematological malignancies. Emergency equipment and adequate supplies of tocilizumab must be available at the time of infusion. It is recommended that at least four doses of tocilizumab be available.
However, at least one dose of tocilizumab must be available at the time of infusion and the qualified healthcare facility must have access to an additional dose of tocilizumab within 8 hours of each previous dose.
Single infusion product.
For autologous use only.
To be administered via intravenous (IV) infusion only.
Tecartus must not be irradiated.

Dosage (dose and interval).

Mantle cell lymphoma.

Each single infusion bag of Tecartus contains a suspension of anti-CD19 CAR T cells in approximately 68 mL for a target dose of 2 x 10⁶ anti-CD19 CAR T cells/kg body weight (range: 1 x 10⁶ - 2 x 10⁶ cells/kg), with a maximum of 2 x 10⁸ anti-CD19 CAR T cells.

Acute lymphoblastic leukaemia.

Each single infusion bag of Tecartus contains a suspension of anti-CD19 CAR T cells in approximately 68 mL for a target dose of 1 x 10⁶ anti-CD19 CAR T cells/kg body weight, with a maximum of 1 x 10⁸ anti-CD19 CAR T cells.

Method of administration.

Tecartus is for autologous use only.
The patient's identity must match the patient identifiers on the Tecartus cassette and infusion bag.
Do not infuse Tecartus if the information on the patient-specific label does not match the intended patient.
Preparing patient for Tecartus infusion. Confirm availability of Tecartus prior to starting the lymphodepleting regimen.

Pre-treatment.

MCL: Administer a lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² IV and fludarabine 30 mg/m² IV on the 5th, 4th, and 3rd day before infusion of Tecartus.
ALL: Administer a lymphodepleting chemotherapy regimen of fludarabine 25 mg/m² intravenously over 30 minutes on the 4th, 3rd, and 2nd day and administer cyclophosphamide 900 mg/m² over 60 minutes on the 2nd day before infusion of Tecartus.

Premedication.

Administer paracetamol 500-1000 mg PO and diphenhydramine 12.5 mg to 25.0 mg IV or PO (or equivalent) approximately 1 hour before Tecartus infusion.
Avoid prophylactic use of systemic steroids as it may interfere with the activity of Tecartus.
Preparation of Tecartus for infusion. Coordinate the timing of Tecartus thaw and infusion. Confirm the infusion time in advance, and adjust the start time of Tecartus thaw such that it will be available for infusion when the patient is ready.
Confirm patient identity: Prior to Tecartus preparation, match the patient's identity with the patient identifiers on the Tecartus cassette.
Do not remove the Tecartus product bag from the cassette if the information on the patient-specific label does not match the intended patient.
Once patient identification is confirmed, remove the Tecartus product bag from the cassette and check that the patient information on the cassette label matches the bag label.
Inspect the product bag for any breaches of container integrity such as breaks or cracks before thawing. If the bag is compromised, follow the local guidelines.
Place the infusion bag inside a second sterile bag or per local guidelines.
Thaw Tecartus at approximately 37°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag.
Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or re-suspend Tecartus in new media prior to infusion.
Once thawed, Tecartus should be administered within 30 minutes but may be stored at room temperature (20°C to 25°C) for up to 3 hours.
Administration. For autologous use only.
Ensure that tocilizumab and emergency equipment are available prior to infusion and during the monitoring period.
Do not use a leukodepleting filter.
To be administered via intravenous (IV) infusion only.
Central venous access is recommended for the administration of Tecartus.
Confirm that the patient's identity matches the patient identifiers on the Tecartus product bag.
Prime the tubing with normal saline prior to infusion.
Infuse the entire contents of the Tecartus bag within 30 minutes by either gravity or a peristaltic pump. Tecartus is stable at room temperature for up to 3 hours after thaw.
Gently agitate the product bag during Tecartus infusion to prevent cell clumping.
After the entire contents of the product bag is infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered.
Tecartus contains human blood cells that are genetically modified with replication incompetent retroviral vector. Follow universal/ standard precautions for blood borne pathogens to avoid potential transmission of infectious diseases, and regional and local biosafety guidelines for handling and disposal of Tecartus.
Monitoring advice. Administer Tecartus at a qualified healthcare/clinical facility.
Monitor patients at the qualified healthcare/clinical facility for at least 7 days following infusion for signs and symptoms of cytokine release syndrome (CRS) and neurologic toxicities.
Instruct patients to remain within proximity of the qualified healthcare/clinical facility for at least 4 weeks following infusion.

Special populations.

Patients with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection.

There is no clinical experience in patients with active HIV, HBV or HCV infection.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 (see Section 4.4, Hypersensitivity reactions). Contraindications of the lymphodepleting chemotherapy must be considered.

4.4 Special Warnings and Precautions for Use

General.

Tecartus is intended solely for autologous use and should under no circumstances be administered to other patients. Before infusion, the patient's identity must match the patient identifiers on the Tecartus infusion bag and cassette. Do not infuse Tecartus if the information on the patient-specific label does not match the intended patient.

Cytokine release syndrome (CRS).

CRS, including fatal or life-threatening reactions, occurred following treatment with Tecartus. CRS occurred in 91% of patients with MCL including ≥ Grade 3 (Lee grading system) CRS in 13% of patients. The median time to onset of CRS was 3 days (range: 1 to 13 days) and the median duration of CRS was 10 days (range: 1 to 50 days) for patients with MCL.
CRS occurred in 91% of patients with ALL, including ≥ Grade 3 (Lee grading system) CRS in 25% of patients. The median time to onset of CRS was 5 days (range: 1 to 12 days) and the median duration of CRS was 8 days (range: 2 to 63 days) for patients with ALL.
Among all patients with CRS, key manifestations (> 10%) included pyrexia (94%), hypotension (64%), hypoxia (32%), chills (31%), tachycardia (27%), sinus tachycardia (23%), headache (24%), fatigue (16%), and nausea (13%). Serious adverse reactions associated with CRS included hypotension, fever, hypoxia, dyspnea, and tachycardia (see Section 4.8 Adverse Effects (Undesirable Effects)).
It is recommended that at least 4 doses of tocilizumab be available, however at least 1 dose of tocilizumab per patient must be on site and available for administration prior to infusion. The qualified healthcare facility must have access to an additional dose of tocilizumab within 8 hours of each previous dose. Monitor patients at the qualified healthcare facility for at least 7 days following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for 4 weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

Management of CRS.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, manage according to the recommendations in Table 1. Patients who experience Grade 2 or higher CRS (e.g. hypotension, not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac telemetry and pulse oximetry. For patients experiencing severe CRS, consider performing an echocardiogram to assess cardiac function. For severe or life-threatening CRS, consider intensive care supportive therapy.

Neurologic toxicities.

Neurologic toxicity, which may include immune effector cell-associated neurotoxicity syndrome (ICANS), including those that were fatal or life-threatening, occurred following treatment with Tecartus. Neurologic events occurred in 68% of patients with MCL, 33% of whom experienced Grade 3 or higher (severe or life threatening) adverse reactions. The median time to onset for neurologic events was 8 days (range: 1 to 262 days) for patients with MCL and neurologic events resolved for 47 out of 56 patients with a median duration of 13 days (range: 1 to 567 days).
Neurologic events occurred in 68% of patients with ALL, including ≥ Grade 3 in 32% of patients. The median time to onset for neurologic events was 7 days (range: 1 to 31 days) for patients with ALL and neurologic adverse reactions resolved for 61 out of 68 (89%) patients with a median duration of 10 days (range: 1 to 236 days). Ninety-four percent of all treated patients experienced the first CRS or neurological adverse reaction within the first 7 days after Tecartus infusion.
The most common neurologic events (> 10%) included tremor (32%), encephalopathy (27%), confusional state (27%), aphasia (20%), and agitation (11%). Serious events (> 2%) including encephalopathy, aphasia, confusional stage, seizures and immune effector cell-associated neurotoxicity syndrome (ICANS) have occurred after treatment with Tecartus. Monitor patients at the qualified healthcare facility for at least 7 days following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicity/ICANS for 4 weeks after infusion and treat promptly.

Management of neurologic toxicities.

Monitor patients for signs and symptoms of neurologic toxicity/ICANS (Table 2). Rule out other causes of neurologic symptoms. Patients who experience Grade 2 or higher neurologic toxicities should be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive care supportive therapy for severe or life threatening neurologic toxicities. Consider non-sedating, anti-seizure medicines (e.g. levetiracetam) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities.

Serious infections.

Severe or life-threatening infections occurred in patients after Tecartus infusion. Infections occurred in 56% of patients with MCL and 41% of patients with ALL. Grade 3 or higher infections occurred in 30% of patients with MCL including bacterial, viral and fungal infections. Grade 3 or higher infections occurred in 27% of patients with ALL including bacterial, viral and fungal infections. Tecartus should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Tecartus infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.
Febrile neutropenia was observed in 6% of patients with MCL and 17% of patients with ALL after Tecartus 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.
In immunosuppressed patients, life-threatening and fatal opportunistic infections have been reported. The possibility of rare infectious etiologies (e.g. fungal and viral infections such as HHV-6 and progressive multifocal leukoencephalopathy) should be considered in patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B reactivation.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs directed against B cells. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Hypersensitivity reactions.

Allergic reactions may occur with the infusion of Tecartus. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Tecartus.

Prolonged cytopenias.

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion. Grade 3 or higher cytopenias not resolved by Day 30 following Tecartus infusion included thrombocytopenia, neutropenia, and anaemia. Monitor blood counts after Tecartus infusion.

Hypogammaglobulinaemia.

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinemia occurred in 16% of patients with MCL and Grade 3 or higher occurred in one patient. Hypogammaglobulinemia occurred in 7% of patients with ALL and no Grade 3 or higher events occurred.
Monitor immunoglobulin levels after treatment with Tecartus and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement in case of recurrent infections.

Secondary malignancies.

Patients treated with Tecartus may develop secondary malignancies. Monitor life-long for secondary malignancies of T cell origin. In the event that a secondary malignancy of T cell origin occurs, the company should be contacted to obtain instructions on patient samples to collect for testing.

Tumour lysis syndrome (TLS).

TLS, which may be severe, has occasionally been observed. To minimise risk of TLS, patients with elevated uric acid or high tumour burden should receive allopurinol, or an alternative prophylaxis, prior to initiation of lymphodepleting chemotherapy. Signs and symptoms of TLS should be monitored and events managed according to standard guidelines.

Primary central nervous system (CNS) lymphoma.

There is no experience of use of Tecartus in patients with primary CNS lymphoma. Therefore the risk/benefit of Tecartus has not been established in this population.

Use in the elderly.

Of the 82 patients treated with Tecartus for MCL, 42 (51%) were 65 years of age and over. Of the 55 patients treated with Tecartus for ALL, 8 (15%) were 65 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients.

Paediatric use.

The safety and efficacy of Tecartus in patients less than 18 years of age have not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Table 4.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Tecartus.

Live vaccines.

The safety of immunisation with live viral vaccines during or following Tecartus treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Tecartus treatment, and until immune recovery following treatment with Tecartus.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No animal or clinical data on the effect of Tecartus on fertility are available.
(Category C)
There are no available data with Tecartus use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with brexucabtagene autoleucel to assess whether Tecartus can cause fetal harm when administered to a pregnant woman. It is not known if Tecartus has the potential to be transferred to the fetus. Based on the mechanism of action of Tecartus, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, Tecartus is not recommended for women who are pregnant. Pregnancy after Tecartus infusion should be discussed with the treating physician.
Pregnancy status of females with reproductive potential should be verified. Sexually-active females of reproductive potential should have a pregnancy test prior to starting treatment with Tecartus.
See the product 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 Tecartus.
It is unknown whether Tecartus is excreted in human milk or transferred to the breast feeding child. Breastfeeding women should be advised of the potential risk to the breast fed child.

4.7 Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving Tecartus are at risk for altered or decreased consciousness or coordination in the 8 weeks following Tecartus 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.

4.8 Adverse Effects (Undesirable Effects)

The following adverse reactions are described in more detail, see Section 4.4 Special Warnings and Precautions for Use:
Cytokine release syndrome; neurologic adverse reactions; hypersensitivity reactions; serious infections; prolonged cytopenias; hypogammaglobulinaemia.

Experience from clinical studies in patients with relapsed/refractory mantle cell lymphoma.

The safety of Tecartus was evaluated in a phase 2 single-arm, clinical study (ZUMA-2) in which a total of 82 patients with relapsed/refractory MCL received a single dose of CAR-positive viable T cells (2 x 10⁶ or 0.5 x 10⁶ anti-CD19 CAR T cells/kg) that was weight-based (see Section 5.1, Clinical trials).
The most common adverse reactions (incidence ≥ 20%) were pyrexia, CRS, hypotension, encephalopathy, fatigue, tachycardia, infection - pathogen unspecified, chills, hypoxia, cough, tremor, musculoskeletal pain, headache, nausea, oedema, motor dysfunction, constipation, diarrhoea, decreased appetite, dyspnea, rash, insomnia, pleural effusion, aphasia, and renal insufficiency. Serious adverse reactions occurred in 66% of patients. The most common serious adverse reactions (> 2%) were encephalopathy, pyrexia, infection - pathogen unspecified, CRS, hypoxia, aphasia, renal insufficiency, pleural effusion, respiratory failure, bacterial infections, dyspnoea, fatigue, arrhythmia, tachycardia and viral infections.
The most common (≥ 10%) Grade 3 or higher reactions were anaemia, neutropenia, thrombocytopenia, hypotension, hypophosphataemia, encephalopathy, leukopenia, pyrexia, hyponatraemia, hypertension, hypocalcaemia and lymphopenia.
Table 3 summarises the adverse reactions that occurred in at least 10% of patients treated with Tecartus and Table 4 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.

In the ZUMA-2 24-month analysis, there were no new safety signals identified and the safety profile remained generally consistent with the primary analysis.
Other clinically important adverse reactions (any grade) that occurred in less than 10% of patients treated with Tecartus 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 oedema (4%).

Skin and subcutaneous tissue disorders.

Rash (9%).

Vascular disorders.

Haemorrhage (7%).

Experience from clinical studies in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukaemia.

Assessment of adverse reactions reflects exposure to Tecartus in a phase 1/2 single arm, clinical study (ZUMA-3, Study KTE-C19-103) in which a total of 100 patients with relapsed/refractory ALL received a single dose of CAR-positive viable T cells (0.5 x 10⁶, 1 x 10⁶, or 2 x 10⁶ anti-CD19 CAR T cells/kg) that was weight-based (see Section 5.1, Clinical trials).
The most common adverse reactions (incidence ≥ 20%) were pyrexia, cytokine release syndrome, hypotension, tachycardias, encephalopathy, headache, chills, oedema, fatigue, nausea, diarrhoea, hypoxia, musculoskeletal pain, abdominal pain, motor dysfunction, pain, tremor, unspecified pathogen infections, hypomagnesemia, aphasia, constipation, rash, decreased appetite, and delirium.
Serious adverse reactions occurred in 78% of patients. The most common serious adverse reactions (≥ 2%) were hypotension, cytokine release syndrome, encephalopathy, pyrexia, unspecified pathogen infections, hypoxia, bacterial infections, tachycardias, aphasia, respiratory failure, febrile neutropenia, seizure, motor dysfunction, dyspnoea, oedema, fungal infections, musculoskeletal pain, viral infections, coagulopathy, delirium, fatigue, and hemophagocytic lymphohistiocytosis.
The most common (≥ 10%) Grade 3 or higher reactions were leukopenia, neutropenia, lymphopenia, thrombocytopenia, anaemia, hypophosphatemia, pyrexia, hypotension, alanine aminotransferase increased, cytokine release syndrome, aspartate aminotransferase increased, hyperglycemia, encephalopathy, hypoxia, blood uric acid increased, direct bilirubin increased, hypocalcemia, hyponatremia, unspecified pathogen infections, febrile neutropenia, hypokalemia, aphasia, bacterial infections, bilirubin increased, and respiratory failure.
Table 5 summarises the adverse reactions that occurred in at least 10% of patients treated with Tecartus and Table 6 describes the laboratory abnormalities of Grade 3 or 4 that occurred in at least 10% of patients.

Other clinically important adverse reactions that occurred in less than 10% of patients treated with Tecartus include the following:

Cardiac disorder.

Non-ventricular arrhythmias (6%).

Gastrointestinal disorders.

Oral pain (9%), dry mouth (8%), dysphagia (3%).

Immune system disorders.

Hypogammaglobulinemia (7%), hemophagocytic lymphohistiocytosis (3%), hypersensitivity (3%).

Infections and infestations.

Viral infections (5%).

Metabolism and nutrition disorders.

Dehydration (5%).

Nervous system disorders.

Seizure (9%), neuropathy (8%), ataxia (4%), increased intracranial pressure (1%).

Renal and urinary disorders.

Renal insufficiency (9%), urine output decreased (8%).

Respiratory, thoracic and mediastinal disorders.

Pulmonary edema (7%), pleural effusion (6%).

Vascular disorders.

Thrombosis (4%).

No new safety concerns were identified in the 21-month analysis, which included a potential follow-up of > 18 months and median duration of follow-up of 20.5 months.

Immunogenicity.

Tecartus has the potential to induce anti-product antibodies, which has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against FMC63, the originating antibody of the anti-CD19 CAR. To date, no anti-CAR T-cell antibody immunogenicity has been observed in ZUMA-2. Based on an initial screening assay, 17 patients in ZUMA-2 at any time point tested positive for antibodies; however, an orthogonal cell-based confirmation assay demonstrated that all 17 patients in ZUMA-2 were antibody negative at all time points tested. Based on an initial screening assay, 16 patients in ZUMA-3 tested positive for antibodies at any timepoint. Among patients with evaluable samples for confirmatory testing, two patients were confirmed to be antibody-positive after treatment. One of the two patients had a confirmed positive antibody result at month 6. The second patient had a confirmed antibody result at retreatment day 28 and month 3. There is no evidence that the kinetics of initial expansion and persistence of Tecartus, or the safety or effectiveness of Tecartus, was altered in these patients.

Postmarketing experience.

In addition to adverse reactions from clinical studies, the following adverse reaction was identified during post-approval use of Tecartus. Because this reaction was reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Immune system disorders.

Infusion related reaction.

Nervous system disorders.

Immune effector cell-associated neurotoxicity syndrome (ICANS).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There have been no instances of overdose from Tecartus.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: not yet assigned.

Mechanism of action.

Tecartus, a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19 expressing cancer cells and normal B cells. Studies demonstrated that following anti-CD19 CAR T cell engagement with CD19 expressing target cells, the CD28 co-stimulatory domain and CD3-zeta signalling domain activate downstream signaling cascades that lead to T cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines. This sequence of events leads to killing of CD19-expressing cells.

Pharmacodynamic effects.

After Tecartus infusion, pharmacodynamic responses were evaluated over a 4-week interval by measuring transient elevation of cytokines, chemokines, and other molecules in blood. Levels of cytokines and chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-α, IFNγ, and sIL2Rα were analysed. Peak elevation was generally observed within the first 8 days after infusion and levels generally returned to baseline within 28 days.
Due to the on target effect of Tecartus a period of B-cell aplasia is expected.

Clinical trials.

Relapsed or refractory mantle cell lymphoma: ZUMA-2.

A phase 2 single-arm, open-label, multicentre trial evaluated the efficacy and safety of a single infusion of Tecartus in adult patients with relapsed or refractory mantle cell lymphoma who had previously received anthracycline or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton's tyrosine kinase inhibitor (BTKi) (ibrutinib or acalabrutinib). In total, 74 patients were enrolled (and leukapheresed), 68 patients were treated with Tecartus and 60 patients had the opportunity to be followed for at least 6 months after their week 4 disease assessment and were therefore evaluable for efficacy (inferential analysis set). Eligible patients also had disease progression after last regimen or refractory disease to the most recent therapy. The study excluded patients with active or serious infections, prior allogeneic haematopoietic stem cell transplantation (HSCT), detectable cerebrospinal fluid malignant cells or brain metastases, and any history of central nervous system lymphoma or CNS disorders.
Following lymphodepleting chemotherapy, Tecartus was administered to patients as a single intravenous infusion at a target dose of 2 x 10⁶ anti-CD19 CAR T cells/kg (maximum permitted dose: 2 x 10⁸ cells). The lymphodepleting regimen consisted of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously, both given on the fifth, fourth, and third day before Tecartus. Bridging therapy between leukapheresis and lymphodepleting chemotherapy was permitted to control disease burden.
Of the 68 patients treated with Tecartus, the median age was 65 years (range: 38 to 79 years), 84% were male, and 91% were White. Most (85%) had stage IV disease and 54% had bone marrow involvement. The median number of prior therapies was 3 (range: 1 to 5); 43% of patients relapsed after autologous HSCT, while the remaining either relapsed (18%) or were refractory to (40%) their last therapy for MCL. Twenty-five percent of patients had blastoid MCL; out of 49 patients tested 82% had Ki-67 expression ≥ 30% in tumor cells and a median Ki67 expression of 65%. Twenty-five patients received bridging therapy (BTKi and/or steroids).
Three patients did not receive Tecartus due to manufacturing failure. Two other patients were not treated, primarily due to progressive disease (death) following leukapheresis. One patient who underwent leukapheresis and received lymphodepleting chemotherapy was not treated with Tecartus due to ongoing active atrial fibrillation. The median time from leukapheresis to product release was 13 days (range: 9 to 20 days), the median time from leukapheresis to product delivery was 16 days (range: 11 to 42 days, with the exception of one outlier of 128 days), and the median leukapheresis to Tecartus infusion was 27 days (range: 19 to 74 days, with the exception of one outlier of 134 days). The median dose was 2.0 x 10⁶ anti-CD19 CAR T cells/kg. All patients received Tecartus infusion on day 0 and were hospitalized until day 7 at the minimum.
The primary endpoint was objective response rate (ORR) as determined by Lugano 2014 criteria by an independent review committee. Secondary endpoints included duration of response (DOR), overall survival (OS), progression free survival (PFS) and severity of adverse events (Table 7).
For the primary analysis, an inferential analysis set (IAS), the analysis set was defined a priori which consisted of the first 60 patients treated with Tecartus who were evaluated for response 6 months after the Week 4 disease assessment after Tecartus infusion. In this analysis set of 60 patients the ORR was 93% with a CR rate of 67%. The ORR was significantly higher than the prespecified historical control rate of 25% at a 1 sided significance level of 0.025 (p < 0.0001). The median time to response was 1 month (range: 0.8 to 3.1 months). The DOR was longer in patients who achieved CR, as compared to patients with a best response of partial remission (PR). Of the 40 patients who achieved CR, 3 had stable disease and 21 had PR at their initial tumor assessment and converted to CR with a median time to conversion of 2.2 months (range: 1.8 to 8.3 months). ORRs were consistent across subgroups of patients including those with blastoid MCL (0.93; 95% CI: 0.66, 1.00) Ki-67 immunohistochemistry (IHC) ≥ 30% (0.95; 95% CI: 0.82, 0.99) and were generally consistent with the ORR observed for all patients. Twenty-eight patients had potential follow-up for ≥ 24 months, with median overall survival (OS) not reached and a survival rate at 24 months of 68% (95% CI: 47.3, 81.8). Twelve (43%) of these patients remained in remission.
The updated 24-month follow-up analyses of efficacy were conducted using the modified intent to treat (mITT) analysis set, which consisted of 68 patients treated with Tecartus. In the 24-month follow-up analysis, the ORR and CR rates in the 68 patients in the mITT analysis set were 91% and 68%, respectively. The 24-month analysis showed that for the 46 patients who achieved a CR, the KM median DOR was 46.7 months (95% CI: 24.8 months, NE). The KM estimates of the proportion of responders who remained in response at 12 months, 18 months, and 24 months from first response were 64.6%, 57.6%, and 57.6%, respectively. See Figures 1 and 2.

Relapsed or refractory B-cell precursor acute lymphoblastic leukaemia: ZUMA-3.

A phase 2, open-label, multicenter trial evaluated the efficacy and safety of Tecartus in adult patients with B-precursor ALL. Relapsed or refractory was defined as one of the following: primary refractory; first relapse following a remission lasting ≤ 12 months; relapsed or refractory after second-line or higher therapy; relapsed or refractory after allogeneic stem cell transplant (allo-SCT) (provided the transplant occurred ≥ 100 days prior to enrollment and that no immunosuppressive medications were taken ≤ 4 weeks prior to enrollment). A total of 71 patients were enrolled, 55 patients were treated with Tecartus and were evaluable for efficacy in the modified intent-to-treat (mITT) analysis set. The study excluded patients with active or serious infections, active graft-vs-host disease, and any history of CNS disorders including CNS-2 disease with clinically evident neurologic changes and CNS-3 disease irrespective of neurological changes.
Following lymphodepleting chemotherapy, Tecartus was administered to patients as a single intravenous infusion at a target dose of 1 x 10⁶ anti-CD19 CAR T cells/kg (maximum permitted dose: 1 x 10⁸ cells). The lymphodepleting regimen consisted of fludarabine 25 mg/m² intravenously over 30 minutes on the 4th, 3rd, and 2nd day and cyclophosphamide 900 mg/m² over 60 minutes on the 2nd day before Tecartus. Of the 55 patients who received Tecartus, 51 patients received bridging therapy between leukapheresis and lymphodepleting chemotherapy to control disease burden.
Of the 55 patients treated with Tecartus, the median age was 40 years (range: 19 to 84 years), 60% were male, and 67% were White. Thirty-three percent of patients had primary refractory disease, 78% had relapsed or refractory disease after ≥ 2 lines of therapy, and 16 patients (29%) had first relapse with first remission ≤ 12 months. The median number of prior therapies was 2 (range: 1 to 8) and 47% of patients received ≥ 3 lines of therapy. Among prior therapies, 42% of patients were previously treated with allo-SCT, 45% with blinatumomab, and 22% with inotuzumab. Twenty-seven percent of patients were Philadelphia chromosome positive (Ph⁺).
Six patients did not receive Tecartus due to manufacturing failure. Eight other patients were not treated, primarily due to AEs following leukapheresis. Two patients who underwent leukapheresis and received lymphodepleting chemotherapy were not treated with Tecartus; one patient experienced bacteremia and neutropenic fever and the other patient did not meet eligibility criteria after lymphodepleting chemotherapy. The median time from leukapheresis to product delivery was 16 days (range: 11 to 42 days) and the median leukapheresis to Tecartus infusion was 29 days (range: 20 to 60 days). The median dose was 1.0 x 10⁶ anti-CD19 CAR T cells/kg. All patients received Tecartus infusion on day 0 and were hospitalized until day 7 at the minimum.
The primary endpoint was overall complete remission rate (complete remission [CR] + complete remission with incomplete hematologic recovery [CRi]) in patients treated with Tecartus as determined by an independent review. The OCR rate was 70.9% with a CR rate of 56.4% in the mITT analysis set (Table 8). Among the 39 patients who achieved a CR or CRi, the median time to response was 1.1 months (range: 0.85 to 2.99 months). Across all evaluable subgroups, OCR were generally consistent with the OCR observed for all subjects, including patients previously treated with blinatumomab (60%; 95% CI: 39.0, 79.0), inotuzumab (67%; 95% CI: 35.0, 90.0), allo-SCT (70%; 95% CI: 47.0, 87.0), patients who were Ph⁺ (80%; 95% CI: 52.0, 96.0), primary refractory disease patients (78%; 95% CI: 52.0, 94.0), and patients who had first relapse with first remission ≤ 12 months (69%; 95% CI: 41.0, 89.0).
All treated patients had potential follow-up for ≥ 18 months with a median follow-up time of 20.5 months (95% CI: 0.3, 32.6 months) and a median follow-up time for OS of 24.0 months (95% CI: 23.3, 24.6). See Figures 3 and 4.

5.2 Pharmacokinetic Properties

Following infusion (target dose of 2 x 10⁶ anti-CD19 CAR T cells/kg) of Tecartus in ZUMA-2, anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 3 months. Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 15 days after Tecartus infusion. Following infusion of a target dose of 1 x 10⁶ anti-CD19 CAR T cells/kg of Tecartus in ZUMA-3 (phase 2), anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 6 months. Median time to peak levels of anti-CD19 CAR T cells was within the first 15 days after Tecartus infusion.
Among patients with MCL, the number of anti-CD19 CAR T cells in blood was associated with objective response [complete remission (CR) or partial remission (PR)]. The median peak anti-CD19 CAR T-cell level in responders vs non-responders was 97.52 cells/microL (range: 0.24 to 2589.47 cells/microL; n = 62), and 0.39 cells/microL (range: 0.16 to 22.02 cells/microL, n = 5; Wilcoxon rank rank-sum test p = 0.0020), respectively. The median AUC_0-28 in subjects with an objective response was 1386.28 cells/microL.days (range: 3.83 to 2.77E + 04 cells/microL.days; n = 62) vs 5.51 cells/microL.days in non-responders (range: 1.81 to 293.86 cells/microL.days; Wilcoxon rank-sum p = 0.0013; n = 5).
Median peak anti-CD19 CAR T-cell values were 74.08 cells/microL in subjects ≥ 65 years of age (n = 39) and 112.45 cells/microL in subjects < 65 years of age (n = 28). Median anti-CD19 CAR T-cell AUC values were 876.48 cells/microL.day in subjects ≥ 65 years of age and 1640.21 cells/microL.day in subjects < 65 years of age.
Among patients with ALL, the median peak anti-CD19 CAR T-cell level over time by best overall response per independent review was 38.35 cells/microL (range: 1.31 to 1,533.40 cells/microL; n = 36) in patients who had overall complete remission (CR + CRi), and 0.49 cells/microL (range: 0.00 to 183.50 cells/microL, n = 14) in patients who had non-complete remission. The median AUC_0-28 in patients who had overall complete remission (CR + CRi) was 424.03 cells/microL.days (range: 14.12 to 19,390.42 cells/microL.days; n = 36) vs 4.12 cells/microL.days in patients who had non-complete remission (range: 0.00 to 642.25 cells/microL.days; n = 14).
Gender had no significant impact on AUC_{Day 0-28} and C_max of Tecartus.

Pharmacokinetics in special populations.

Hepatic and renal impairment studies of Tecartus were not conducted.

5.3 Preclinical Safety Data

Genotoxicity.

Conventional genotoxicity studies have not been performed with brexucabtagene autoleucel, and are not appropriate for cell therapy products. However, a review of the literature comparing transduction of haematopoietic stem cells (HSC) and differentiated T cells with γ-retroviral vectors, and clinical studies employing γ-retroviral vector transduced T cells, was conducted. The reviewed data suggest a low risk of insertional mutagenesis following T cell transduction with γ-retroviral vectors.

Carcinogenicity.

Standard rodent carcinogenicity studies have not been performed with brexucabtagene autoleucel and are not appropriate for cell therapy products. A review of published clinical studies employing γ-retroviral vector transduced T cells did not reveal any cases of secondary malignancies.

6 Pharmaceutical Particulars

6.1 List of Excipients

5% DMSO; sodium chloride; human serum albumin.

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf Life

Final product is stable for 1 year when stored frozen in the vapor phase of liquid nitrogen (≤ -150°C).
Once thawed, Tecartus may be stored at room temperature (20°C to 25°C) for up to 3 hours.

6.4 Special Precautions for Storage

Tecartus must be stored in the vapor phase of liquid nitrogen (≤ -150°C) and it must remain frozen until the patient is ready for treatment to assure viable live autologous cells are available for patient administration.
Thawed product should not be refrozen.

6.5 Nature and Contents of Container

Tecartus is supplied in a cryostorage bag.
Each infusion bag is individually packed in a metal cassette.
Tecartus is shipped frozen in a liquid nitrogen dry vapor shipper labeled for the specific patient.

6.6 Special Precautions for Disposal

For autologous single use only.
Do not use a leukodepleting filter.
Do not irradiate.
Tecartus must be stored frozen in the vapor phase of liquid nitrogen.
The identity of the patient must be matched with the patient identifiers on the infusion bag before infusion.
Health care professionals should employ local biosafety guidelines for blood borne pathogens when handling Tecartus to avoid potential transmission of infectious diseases.
Unused medicine must be disposed of in compliance with local guidelines for the disposal of medicinal products containing genetically modified cells. All material that has been in contact with Tecartus (solid and liquid waste) should be handled and disposed of as potentially infectious waste in accordance with local biosafety guidelines.

6.7 Physicochemical Properties

Chemical structure.

Tecartus is an engineered autologous T cell immunotherapy by which a patient's own T cells are harvested and engineered ex vivo by retroviral transduction of a chimeric antigen receptor (CAR) construct encoding an anti-CD19 CAR. Therefore a defined structure is not available for brexucabtagene autoleucel.

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