Consumer medicine information

Yescarta

Axicabtagene ciloleucel

BRAND INFORMATION

Brand name

Yescarta

Active ingredient

Axicabtagene ciloleucel

Schedule

Unscheduled

What is in this leaflet

Read all of this leaflet carefully before you start taking this medicine. This leaflet answers some of the common questions about YESCARTA. It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist about your medical condition or treatment. If you have further questions, please ask your healthcare professional.

Keep this leaflet handy. You may need to read it again.

What YESCARTA is used for

How YESCARTA works

YESCARTA is a type of medicine called a “genetically-modified cell therapy”.

YESCARTA is made from your own normal, white blood cells, which have been genetically modified to identify and attack your lymphoma cells.

Lymphoma is a cancer of the blood which affects a type of white blood cell called lymphocytes. The lymphocytes become abnormal causing them to multiply too quickly and live for too long. Too many of these abnormal white blood cells accumulate in your body and this is the cause of the symptoms you may have. YESCARTA is used to treat these conditions when other available medicines have stopped working for you.

Use in children
The use of YESCARTA in children and adolescents under 18 years of age has not yet been studied.

Before you are given YESCARTA

When you must not be given YESCARTA

You should not be given YESCARTA if you are allergic to any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Before you are given it

Tell your healthcare professional if you have, or have had, any of the following medical conditions:

have problems with your nervous system (such as fits, stroke, or memory loss).
have kidney problems.
have low blood cell levels (blood counts).
have had a stem cell transplant in the last 4 months.
have any lung, heart or blood pressure (low or raised) problems.
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 YESCARTA infusion.
have had hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection.

If any of the above apply to you (or you are not sure), talk to your doctor before being given YESCARTA.

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 YESCARTA.

If you are pregnant or breast feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before being given this medicine. This is because the effects of YESCARTA 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. YESCARTA 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 YESCARTA, talk to your doctor immediately.

Taking other medicines

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

Before you are given YESCARTA 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 YESCARTA.

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 YESCARTA cells.
During YESCARTA treatment.
After treatment while the immune system is recovering.

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

Do not start any new medicines after being given YESCARTA without first talking with your doctor or pharmacist.

How YESCARTA is given

Test and checks

Before you are given YESCARTA your doctor will:

Check your lungs, heart and blood pressure.
Look for signs of infection; any infection will be treated before you are given YESCARTA.
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.

Medicines and treatments given before YESCARTA infusion

Since YESCARTA 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 YESCARTA. It usually takes about 3 to 4 weeks to receive your YESCARTA therapy but the time may vary.
Prior to receiving YESCARTA, you will be given preparative chemotherapy (called lymphodepleting chemotherapy), which will allow your modified white blood cells in YESCARTA 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 YESCARTA. For example:

If YESCARTA infusion is delayed for more than 2 weeks after you have received preparatory chemotherapy you may have to receive more preparative chemotherapy.

How YESCARTA is given

YESCARTA will always be given to you by a healthcare professional.
YESCARTA is a one-time treatment. It will not be given to you again.
During the 30 to 60 minutes before you are given YESCARTA 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 YESCARTA into your vein for approximately 30 minutes.
YESCARTA is the genetically modified version of your normal white blood cells. Your healthcare professional handling YESCARTA 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 YESCARTA.
You will receive YESCARTA 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.

If you take too much (overdose)

As YESCARTA is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, it you experience any side effects after being given YESCARTA, tell your doctor immediately.

Side Effects

Like all medicines, YESCARTA can have side effects, although not everybody gets them. Some may be serious and need medical attention.

YESCARTA can cause side effects to your immune system that may be serious or life-threatening, and can lead to death.

Tell your doctor at the certified clinical facility immediately or go to the accident and emergency department at the nearest hospital if you get any of the following side effects:

Fever
Difficulty breathing
Chills or shaking chills
Confusion
Dizziness or lightheadedness
Severe nausea, vomiting, or diarrhoea
Fast or irregular heartbeat
Severe fatigue or weakness

It is important to tell your doctor that you received YESCARTA and to show them your YESCARTA Patient Alert Card.

The following side effects have been reported in clinical trials with YESCARTA.

Very common side effects

Fever, chills, reduced blood pressure which may cause symptoms such as dizziness, lightheadedness, fluid in the lungs, which may be severe and can be fatal (all symptoms of a condition called cytokine release syndrome).
Fever or chills.
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.
Low blood pressure, dizziness.
Feeling sick, constipation, diarrhoea, pain in the stomach or being sick.
Headache, depressed level of consciousness, difficulty in speaking, agitation, shaking.
Decrease in the number of normal white blood cells, which are important for fighting infections.
Decreased levels of calcium, sodium, phosphate, or potassium which will show up on blood tests.
Changes in the rhythm or rate of the heartbeat.
Anxiety
Decrease in the number of cells that help clot the blood (thrombocytopenia).
Infections in the blood caused by bacteria, viruses, fungi or other types of infection.
Shortness of breath, cough.
Low levels of antibodies called immunoglobulins, which may lead to infections.
High blood pressure.
Swelling in the limbs, fluid around the lungs (pleural effusion).
Muscle pains, back pain.
Extreme tiredness.
Dehydration.

Common side effects

Difficulty understanding numbers, memory loss, fits, loss of control of body movements.
Failure of the kidneys causing your body to hold onto fluid which can be serious or life threatening.
Fluid in the lungs.
Lung infection.
Sudden, unexpected stopping of the heart (cardiac arrest); this is serious and life-threatening.
Heart failure.
Muscle spasms.
Leakage of fluids from blood vessels into surrounding tissue. This can lead to a weight gain and difficulty in breathing.
Decreased levels of calcium which will show up on blood tests.
Infections in the blood caused by fungi.

Tell your doctor immediately if you get any of the side effects listed above. Do not try to treat your symptoms with other medicines on your own.

After you are given YESCARTA

Plan to stay within proximity of the hospital where you were treated for at least 4 weeks after you have been given YESCARTA. 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 certified clinical facility as soon as possible to reschedule your appointment.

Things to be careful of

Be careful driving or operating machinery. Some people may feel tired, dizzy or have some shaking after being given YESCARTA. If this happens to you, do not drive or use heavy machines until at least 8 weeks after infusion or until your doctor tells you that you have completely recovered.

Product Description

What YESCARTA looks like

YESCARTA 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.

What YESCARTA contains

The active substance is axicabtagene ciloleucel. 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 x 10⁶ anti-CD19 CAR-positive viable T cells/kg.

The other ingredients (excipients) are:

Cryostor CS10,
sodium chloride,
human albumin.

Sponsor

YESCARTA is supplied in Australia by:

Gilead Sciences Pty Ltd
Level 6, 417 St Kilda Road
Melbourne, Victoria 3004

Date of preparation: 21 February 2020

ARTG No: 329770

YESCARTA 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 May 2020

BRAND INFORMATION

Brand name

Yescarta

Active ingredient

Axicabtagene ciloleucel

Schedule

Unscheduled

1 Name of Medicine

Yescarta (axicabtagene ciloleucel), 1 x 10⁶ - 2.4 x 10⁶ anti-CD19 CAR T cells/kg suspension for infusion.

2 Qualitative and Quantitative Composition

General description.

Yescarta (axicabtagene ciloleucel) is a CD19-directed genetically modified autologous T cell immunotherapy. To prepare Yescarta, 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.
Yescarta is prepared from the patient's peripheral blood mononuclear cells, which are obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells and activated with anti-CD3 antibody in the presence of IL-2, then transduced with the replication incompetent retroviral vector containing the anti-CD19 CAR transgene. The transduced T cells are expanded in cell culture, washed, formulated into a suspension, and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in a patient-specific infusion bag. The product is thawed prior to infusion.
In addition to T cells, Yescarta may contain NK and NK-T cells. The formulation contains 5% dimethylsulfoxide (DMSO) and 2.5% albumin (human).

Qualitative and quantitative composition.

Each patient-specific single infusion bag of Yescarta contains a suspension of anti-CD19 CAR-positive viable 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 - 2.4 x 10⁶ cells/kg), with a maximum of 2 x 10⁸ anti-CD19 CAR T cells.

Excipients with known effect.

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

3 Pharmaceutical Form

Suspension for infusion.
A clear to opaque, white to red dispersion.

4 Clinical Particulars

4.1 Therapeutic Indications

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

Large B-cell lymphoma.

Patients with relapsed or refractory large B-cell lymphoma (LBCL).
Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.

Follicular lymphoma.

Patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy.

4.2 Dose and Method of Administration

Yescarta must be administered in a qualified clinical setting.
Yescarta 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 4 doses of tocilizumab be available. However, at least 1 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.
Yescarta must not be irradiated.

Dosage (dose and interval).

Each single infusion bag of Yescarta contains a suspension of anti-CD19 CAR-positive viable 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 - 2.4 x 10⁶ cells/kg), with a maximum of 2 x 10⁸ anti-CD19 CAR T cells.

Method of administration.

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

Pre-treatment.

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 Yescarta.

Premedication.

Administer paracetamol 500-1000 mg PO and diphenhydramine 12.5 mg IV or PO (or equivalent) approximately 1 hour before Yescarta infusion.
Preparation of Yescarta for infusion. Coordinate the timing of Yescarta thaw and infusion. Confirm the infusion time in advance, and adjust the start time of Yescarta thaw such that it will be available for infusion when the patient is ready.
Confirm patient identity: prior to Yescarta preparation, match the patient's identity with the patient identifiers on the Yescarta cassette.
Do not remove the Yescarta 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 Yescarta 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 Yescarta 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 Yescarta in new media prior to infusion.
Once thawed, Yescarta 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 Yescarta.
Confirm that the patient's identity matches the patient identifiers on the Yescarta product bag.
Prime the tubing with normal saline prior to infusion.
Infuse the entire contents of the Yescarta bag within 30 minutes by either gravity or a peristaltic pump. Yescarta is stable at room temperature for up to 3 hours after thaw.
Gently agitate the product bag during Yescarta infusion to prevent cell clumping.
After the entire content of the product bag is infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered.
Yescarta 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 Yescarta.
Monitoring advice. Administer Yescarta at a qualified healthcare/clinical facility.
Monitor patients daily for at least 7 days at the qualified healthcare/clinical facility 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 limited 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 (see Section 6.1 List of Excipients; Section 4.4 Special Warnings and Precautions for Use, Hypersensitivity reactions). Contraindications of the lymphodepleting chemotherapy must be considered.

4.4 Special Warnings and Precautions for Use

General.

Yescarta 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 Yescarta infusion bag and cassette. Do not infuse Yescarta 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 Yescarta. CRS occurred in 92% of patients with LBCL and 82% of patients with indolent non-Hodgkin lymphoma (iNHL), including ≥ grade 3 (Lee grading system) CRS in 8% of patients with LBCL and 7% of patients with iNHL. The median time to onset of CRS was 3 days (range: 1 to 12 days) for patients with LBCL and 4 days (range 1-15 days) for patients with iNHL. The median duration of CRS was 7 days (range: 2 to 58 days) for patients with LBCL and 6 days (range: 1 to 27 days) for patients with iNHL. Key manifestations of CRS (> 5%) include pyrexia, hypotension, chills, sinus tachycardia, hypoxia, headache, tachycardia, fatigue, nausea, vomiting and malaise. Serious events that may be associated with CRS include pyrexia, hypotension, hypoxia, tachycardia, tachypnea, cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), renal insufficiency, headache, cardiac failure, dyspnoea, cardiac arrest, capillary leak syndrome and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (see Section 4.8 Adverse Effects (Undesirable Effects)).
The impact of tocilizumab and/or corticosteroids on the incidence and severity of CRS was assessed in two separate cohorts of LBCL patients. Among patients who received tocilizumab and/or corticosteroids for ongoing Grade 1 events (see Table 1). CRS occurred in 93% (38/41) of these patients and 2% had Grade 3 CRS, with no patients experiencing a Grade 4 or 5 event. The median time to onset of CRS was 2 days (range: 1 to 8 days) and the median duration of CRS was 7 days (range: 2 to 16 days). Among patients who received prophylactic corticosteroids in addition to tocilizumab and/or corticosteroids at the onset of Grade 1 events, CRS occurred in 80% (32/40) of these patients, with no patients experiencing a Grade 3 or higher event. The median time to onset of CRS was 5 days (range: 1 to 15 days) and the median duration of CRS was 4 days (range: 1 to 11 days). The key manifestations of CRS were consistent with the overall LBCL population treated with Yescarta (see Section 4.8 Adverse Effects (Undesirable Effects)).
CRS should be managed at the physician's discretion, based on the patient's clinical presentation and according to the CRS management algorithm provided in Table 1. Interleukin-6 (IL-6) receptor inhibitor-based therapy such as tocilizumab has been administered for moderate or severe CRS associated with Yescarta. 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 daily for at least 7 days at the qualified healthcare facility 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 toxicity.

Neurologic toxicity which may include immune effect cell-associated neurotoxicity syndrome (ICANS) that were fatal or life-threatening have occurred following treatment with Yescarta. Neurologic toxicities occurred in 62% of patients with LBCL and 59% of patients with iNHL, with 25% of patients with LBCL and 19% of patients with iNHL experiencing Grade 3 or higher (severe or life-threatening) neurologic adverse reactions. Neurologic toxicities occurred within the first 7 days of Yescarta infusion for 76% of patients with LBCL and 66% of patients with iNHL. The median time to onset was 6 days (range: 1 to 133 days) for patients with LBCL and 7 days (1 to 177 days) for patients with iNHL. The median duration of neurologic toxicities was 11 days, with resolution occurring within 3 weeks for 63% of patients following the first onset of neurologic toxicities.
The most common neurologic toxicities (> 5%) included tremor, confusional state, encephalopathy, aphasia, somnolence and agitation. Serious events including encephalopathy, aphasia, confusional state, somnolence, agitation, tremor, delirium, leukoencephalopathy, dysarthria, hypoaesthesia, lethargy, memory impairment, mental status changes, seizures, spinal cord oedema, myelitis, quadriplegia, and dysphagia have occurred with Yescarta. Fatal and serious cases of cerebral oedema have occurred in patients treated with Yescarta.
The impact of tocilizumab and/or corticosteroids on the incidence and severity of neurologic toxicities was assessed in two separate cohorts of LBCL patients who received corticosteroids at the onset of Grade 1 toxicities (see Table 2). Neurologic toxicities occurred in 61% of these patients and 17% had Grade 3 neurologic toxicities with no patients experiencing a Grade 4 or 5 event. The median time to onset of neurologic toxicities was 6 days (range 1 to 93 days) with a median duration of 8 days (range 1 to 144 days). Among patients who received prophylactic corticosteroids in addition to tocilizumab and/or corticosteroids at the onset of Grade 1 events, neurologic toxicities occurred in 58% (23/40) of these patients, with 13% (5/40) experiencing a Grade 3 or higher neurologic event. The median time to onset of neurologic toxicities was 6 days (range: 2 to 162 days) with a median duration of 18.5 days (range: 1 to 103 days). The most common neurologic toxicities were consistent with the overall LBCL population treated with Yescarta (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitor patients daily for at least 7 days at the qualified healthcare facility 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/ICANS.

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 levetiracetam for seizure prophylaxis for any grade of neurologic toxicities.

Serious infections.

Severe or life-threatening infections occurred in patients after Yescarta infusion. Infections occurred in 45% of patients. Grade 3 or higher infections occurred in 19% of patients including infections with an unspecified pathogen, fungal infections, bacterial infections, and viral infections. Yescarta should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after Yescarta infusion and treat appropriately. Administer prophylactic anti-microbials according to local guidelines.
Febrile neutropenia was observed in 15% of patients with LBCL (2% and 34% in ZUMA-7 and ZUMA-1 studies, respectively) and 3% of patients with iNHL after Yescarta 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 including disseminated fungal infections and viral reactivation (e.g. HHV-6 and progressive multifocal leukoencephalopathy) have been reported. The possibility of these infections should be considered in patients with neurologic events and appropriate diagnostic evaluations should be performed.

Hepatitis B virus 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 Yescarta. Serious hypersensitivity reactions including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) or residual gentamicin in Yescarta.

Prolonged cytopenias.

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Yescarta infusion. Grade 3 or higher cytopenias not resolved by day 30 or present on or after day 30 following Yescarta infusion included neutropenia (27%), thrombocytopenia (12%), and anaemia (6%). Monitor blood counts after Yescarta infusion.

Hypogammaglobulinaemia.

B-cell aplasia and hypogammaglobulinaemia can occur in patients receiving treatment with Yescarta. Hypogammaglobulinaemia occurred in 15% of patients treated with Yescarta. Monitor immunoglobulin levels after treatment with Yescarta and manage using infection precautions, antibiotic prophylaxis and immunoglobulin replacement in case of recurrent infections.

Secondary malignancies.

Patients treated with Yescarta 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 conditioning 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 Yescarta in patients with primary CNS lymphoma. Therefore the risk/benefit of Yescarta has not been established in this population.

Use in the elderly.

No dose adjustment is required in patients ≥ 65 years of age. There is limited experience with Yescarta in patients ≥ 75 years of age. Generally, safety and efficacy were similar between patients ≥ 65 years and patients < 65 years of age treated with Yescarta.

Paediatric use.

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

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Yescarta.

Live vaccines.

The safety of immunisation with live viral vaccines during or following Yescarta 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 Yescarta treatment, and until immune recovery following treatment with Yescarta.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No animal or clinical data on the effect of axicabtagene ciloleucel on fertility are available.
(Category C)
There are no available data with Yescarta use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with Yescarta to assess whether it can cause fetal harm when administered to a pregnant woman (see Section 5.3 Preclinical Safety Data). It is not known if Yescarta has the potential to be transferred to the fetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia. Therefore, Yescarta is not recommended for women who are pregnant. Pregnancy after Yescarta 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 Yescarta.
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 Yescarta.
It is unknown whether Yescarta is excreted in human milk or transferred to the breastfeeding child. Breastfeeding women should be advised of the potential risk to the breastfed 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 Yescarta are at risk for altered or decreased consciousness or coordination in the 8 weeks following Yescarta 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.

Relapsed or refractory LBCL ZUMA-7. Assessment of adverse reactions reflects exposure to Yescarta in ZUMA-7, a Phase 3 study that included 338 patients with relapsed or refractory LBCL who received CAR-positive T cells or standard of care therapy (SOCT), after first-line rituximab and anthracycline-based chemotherapy. The median duration of follow-up was 19.6 months.
The most common adverse reactions (incidence ≥ 20%) include fever, CRS, fatigue, encephalopathy, hypotension, tachycardia, diarrhoea, headache, nausea, musculoskeletal pain, chills, cough, tremor, transaminases increased, unspecified pathogen infections, dizziness, decreased appetite, hypoxia, edema, abdominal pain, and constipation. Serious adverse reactions occurred in 51% of patients. The most common serious adverse reactions (> 2%) included CRS, fever, encephalopathy, hypotension, unspecified pathogen infections, B-cell lymphoma, viral infection, neutropenia, tremor, and arrhythmia.
The most common (≥ 10%) Grade 3 or higher reactions included leukopenia, neutropenia, lymphopenia, anemia, thrombocytopenia, encephalopathy, hyponatremia, hyperglycemia and hypotension.
Sixty-six percent (112/170) of patients received tocilizumab after infusion of Yescarta.
Table 3 summarizes the adverse reactions that occurred in at least 10% of patients treated with Yescarta and Table 4 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 Yescarta include the following:

Blood and lymphatic system disorders.

Coagulopathy (9%).

Cardiac disorders.

Cardiac failure (1%).

Nervous system disorders.

Ataxia (5%), seizure (3%), myoclonus (2%), facial paralysis (1%).

Respiratory, thoracic and mediastinal disorders.

Dyspnoea (8%), pleural effusion (6%), respiratory failure (2%).

Vascular disorders.

Hypertension (9%), thrombosis (8%).

ZUMA-1. The safety data described in this section reflect exposure to Yescarta in ZUMA-1, a phase 1/2 study in which 108 patients with relapsed/refractory B-cell NHL received CAR-positive T cells based on a recommended dose which was weight based (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Patients with a history of CNS disorders (such as seizures or cerebrovascular ischemia) or autoimmune disease requiring systemic immunosuppression were ineligible. The median duration of follow-up was 27.4 months. The median age of the study population was 58 years (range: 23 to 76 years); 68% were men. The baseline ECOG performance status was 43% with ECOG 0, and 57% with ECOG 1.
The most common adverse reactions (incidence ≥ 20%) include CRS, encephalopathy, fatigue, decreased appetite, headache, fever, febrile neutropenia, diarrhoea, nausea, tremor, tachycardia, cough, infections-pathogen unspecified, vomiting, viral infections, dizziness, constipation, and oedema. Serious adverse reactions occurred in 56% of patients. The most common serious adverse reactions (> 2%) include encephalopathy, other pathogen infections, CRS, bacterial infections, febrile neutropenia, viral infections, fever, aphasia, delirium, cardiac arrest, dyspnoea, arrhythmia, pulmonary oedema, and hypotension.
The most common (≥ 10%) grade 3 or higher reactions include febrile neutropenia, encephalopathy, infections-pathogen unspecified, and CRS.
Forty-five percent (49/108) of patients received tocilizumab after infusion of Yescarta.
Table 5 summarises the adverse reactions that occurred in at least 10% of patients treated with Yescarta 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 Yescarta include the following:

Blood and lymphatic system disorders.

Coagulopathy (2%).

Cardiac disorders.

Cardiac failure (2%) and cardiac arrest (3%).

Immune system disorders.

Haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) (1%), hypersensitivity (2%).

Infections and infestations disorders.

Fungal infections (6%).

Nervous system disorders.

Ataxia (6%), seizure (4%), dyscalculia (2%), and myoclonus (2%), neuropathy (6%).

Psychiatric disorders SOC.

Insomnia (9%).

Renal and urinary disorders.

Renal insufficiency (8%).

Respiratory, thoracic and mediastinal disorders.

Pulmonary oedema (7%).

Skin and subcutaneous tissue disorders.

Rash (6%).

Vascular disorders.

Capillary leak syndrome (1%), thrombosis (6%).

A subsequent, open label, safety management cohort in ZUMA-1 evaluated the safety and efficacy of Yescarta with the use of prophylactic corticosteroids (given prior to Yescarta infusion on Day 0, Day 1, and Day 2) and prophylactic levetiracetam (750 mg PO or IV) in addition to tocilizumab and/or corticosteroid use for Grade 1 CRS or neurologic events (see Tables 1 and 2). A total of 42 patients with r/r LBCL were enrolled and 40 patients were treated with Yescarta. Of the remaining 2 patients who were not treated, 1 patient no longer met eligibility criteria and the other patient was not treated due to manufacturing failure. Twenty-one of the 40 patients treated with Yescarta received bridging therapy between leukapheresis and lymphodepleting chemotherapy. All patients treated with Yescarta received prophylactic corticosteroids; among the patients who received steroids including prophylaxis use, the median cumulative dose was 1252 mg (N=40) and 2504 mg excluding prophylaxis use (N=25), respectively. Thirty-nine patients (97%) received prophylactic corticosteroids Days 0, 1, and 2.
Twenty-four patients (60%) received corticosteroid for CRS and/or neurologic events. Nine out of 24 patients with Grade 2 CRS and 7 out of 24 with Grade 1 neurologic events received corticosteroids therapy. The median time to onset of corticosteroid therapy to treat CRS or neurologic events was 5.0 days (range 3 to 9 days) after Yescarta infusion. Overall, 15 patients (37%) required no further corticosteroid doses between the time of Yescarta infusion and the time of hospital discharge.
Relapsed or refractory iNHL, including FL and MZL subtypes ZUMA-5. Assessment of adverse reactions reflects exposure to Yescarta in ZUMA-5, a Phase 2 study that included 148 patients with iNHL (124 FL patients and 24 MZL patients) who received CAR-positive T cells. Patients with a history of CNS disorders or autoimmune disease requiring systemic immunosuppression were ineligible. The median age was 61 years (range: 34 to 79 years), 43% were female, 93% were white, 3% were black, and 1% were Asian. See Table 7.

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

Blood and lymphatic system disorders.

Coagulopathy (6%), febrile neutropenia (3%).

Cardiac disorders.

Cardiac failure (2%).

Eye disorders.

Visual impairment (5%).

Gastrointestinal disorders.

Dysphagia (5%).

General disorders and administration site conditions.

Multiple organ dysfunction syndrome (1%).

Hepatobiliary disorders.

Hyperbilirubinemia (3%).

Infections and infestations.

Bacterial infections (9%).

Musculoskeletal and connective tissue disorders.

Rhabdomyolysis (1%).

Nervous system disorders.

Seizure (2%), hemiparesis (2%).

Renal and urinary disorders.

Renal insufficiency (7%).

Respiratory, thoracic and mediastinal disorders.

Respiratory failure (1%).
See Table 8.

Immunogenicity.

Yescarta has the potential to induce anti-product antibodies. A screening method 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 was employed to rapidly identify positive samples. In the screening ELISA, 4% of patients with LBCL (11 out of 278) showed baseline and persisting, but not elevated levels of anti FMC 63 antibodies. In patients with iNHL, 20 patients (14%) were antibody-positive at baseline, and 4 patients (3%) who had negative test results at baseline had positive test results after Day 0 in the screening ELISA. Results of a confirmatory cell-based assay, leveraging a properly folded and expressed extracellular portion of the CAR (scFv, hinge and linker) demonstrated that all patients treated with Yescarta who had a positive result in the screening ELISA were antibody negative at all time points tested. There is no evidence that the kinetics of initial expansion and persistence of Yescarta, or the safety or effectiveness of Yescarta, was altered in these patients.

Post-approval experience.

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

Nervous system disorders.

Spinal cord oedema, myelitis, quadriplegia, dysphagia (see Section 4.4 Special Warnings and Precautions for Use), status epilepticus and immune effector cell-associated neurotoxicity syndrome (ICANS).

Immune system disorders.

Infusion related reaction.

Vascular disorders.

Haemorrhage - gastrointestinal haemorrhage, cerebral haemorrhage, pulmonary haemorrhage, haemorrhage intracranial, shock haemorrhagic, haemorrhage, cystitis haemorrhagic, subarachnoid haemorrhage.

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 Yescarta.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: other antineoplastic agents, ATC code: L01X.

Mechanism of action.

Yescarta, 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 Yescarta 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, IFN-γ, and sIL2Rα were analyzed. Peak elevation was observed within the first 14 days after infusion and levels generally returned to baseline within 28 days.
Due to the on target effect of Yescarta a period of B-cell aplasia is expected.

LBCL.

Among evaluable patients with LBCL and with an ongoing response at 24 months in the ZUMA-7 study, 34% had no detectable B cells at baseline, and a majority of subjects at Month 3 (62%) and Month 6 (62%) had no detectable B cells. At Month 24, 83% of subjects had detectable B cells.
Among evaluable patients with LBCL and with an ongoing response at 24 months in the ZUMA-1 study, 45% had no detectable B cells at baseline, and a majority of subjects at month 3 (80%) and month 6 (78%) had no detectable B cells. At month 24, 75% of patients had detectable B cells.

FL and MZL.

Among evaluable patients with FL and MZL in the ZUMA-5 study, 104 out of 133 (78.2%) had detectable B cells at baseline, at Month 3, 47 out of 120 patients (39.2%) had detectable B cells with median of 0.47% (range: 0.02 to 47.35%). At Month 18, 26 of 37 subjects (70.27%) had detectable B cells with median of 11.84% (range: 0.03 to 43.91%).

Clinical trials.

Relapsed or refractory large B-cell lymphoma ZUMA-7. A phase 3 randomized, open-label, multicenter study evaluated the efficacy and safety of Yescarta in adult patients with relapsed or refractory LBCL after first-line rituximab and anthracycline-based chemotherapy. In total, 359 patients were randomized in a 1:1 ratio to receive a single infusion of Yescarta or to receive SOCT (defined as 2 to 3 cycles of standard of care chemoimmunotherapy (R-ICE, R-DHAP, R-ESHAP, or R-GDP) followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT) in those with disease response). Randomization was stratified by response to first-line therapy (primary refractory, vs relapse ≤ 6 months of first-line therapy vs relapse > 6 and ≤ 12 months of first-line therapy) and second-line age-adjusted International Prognostic Index (IPI) (0 to 1 vs 2 to 3) as assessed at the time of screening. The study excluded patients with active or serious infections, prior haematopoietic stem cell transplantation (HSCT), detectable cerebrospinal fluid malignant cells or brain metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, and any history of central nervous system lymphoma.
Following lymphodepleting chemotherapy, Yescarta was administered as a single intravenous infusion at a target dose of 2 x 10⁶ anti-CD19 CAR T cells/kg (maximum 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 5th, 4th, and 3rd day before Yescarta. Corticosteroid bridging therapy administered between leukapheresis and lymphodepleting chemotherapy was permitted for patients with high disease burden at screening.
In the overall study population, the median age was 59 years (range: 21 to 81 years); 66% were male, and 83% were white. Diagnoses were DLBCL Not Otherwise Specified (NOS) (63%), double expressor lymphoma per investigator (22%), high grade B-cell lymphoma (HGBL) with or without MYC and BCL-2 and/or BCL-6 gene rearrangement (including double/triple hit) per investigator (19%), and large cell transformation from FL (13%). Seventy-four percent of patients had primary refractory LBCL and 26% of patients had relapsed within 12 months of first-line therapy. Patients had a second-line age-adjusted IPI score of 0-1 (55%) or 2-3 (45%) and an ECOG performance status of 0 (54%) or 1 (46%).
Of the 180 patients randomized to receive Yescarta, 178 underwent leukapheresis and 170 were treated with Yescarta. Of the patients treated, 60 (35%) received bridging corticosteroid therapy. There were no manufacturing failures. Eight patients (4%) were not treated following leukapheresis, primarily due to progressive disease, serious adverse events, or death. The median time from leukapheresis to product release was 13 days (range: 10 to 24 days), leukapheresis to product delivery was 18 days (range: 13 to 49 days), and leukapheresis to Yescarta infusion was 26 days (range: 16 to 52 days). The median dose was 2.0 x 10⁶ antiCD19 CAR T cells/kg. All 170 patients who received Yescarta were monitored at a healthcare facility for a minimum of 7 days. Of the 179 patients randomized to receive SOCT, 64 patients (36%) initiated received HDT and ASCT.
The primary endpoint was event-free survival (EFS) as determined by blinded central review.
The study demonstrated a statistically significant improvement in EFS for patients randomized to Yescarta compared to SOCT (HR: 0.398 [95% CI: 0.308, 0.514]). The 24-month event-free survival was 40.5% [95% CI: 33.2, 47.7] in the Yescarta arm and 16.3% [95% CI: 11.1, 22.2] in the SOCT arm. The median duration of response (DOR) was 26.9 months (range: 0 to 29 months) in the Yescarta arm compared with 8.9 months (range: 0 to 32 months) in the SOCT arm (HR: 0.736 [95% CI: 0.488, 1.108]). At the time of the primary EFS analysis, the median study duration was 24.9 months.
The primary analysis of overall survival (OS), a key secondary endpoint, was performed at the protocol-specified timepoint of five years from the first subject enrolled. A statistically significant improvement in OS with Yescarta over SOCT was demonstrated with a 27.4% reduction in risk of death (HR 0.726 [95% CI: 0.540, 0.977]). Median OS was not reached in the Yescarta arm as compared to 31.1 months in the SOCT arm, with estimated 48-month overall survival rates of 54.6% and 46.0%, respectively. The median follow-up times for OS were 47.0 months [95% CI: 45.4, 48.3 months] in the Yescarta arm and 45.8 months [95% CI: 44.2, 47.8 months] in the SOCT arms by the reverse KM approach. The median study duration is 47.2 months. Fifty-seven percent of patients received cellular immunotherapy after no response to or relapse after randomization to SOCT.
The summary of efficacy results is shown in Table 9 and the Kaplan-Meier curves for EFS and OS are shown in Figure 1 and Figure 2, respectively. Subgroup analyses were generally consistent with the overall results of EFS and OS favoring Yescarta over SOCT (Figure 3 and 4).

Patient-reported outcomes measured patients' health-related Quality of Life (QoL), with prespecified hypotheses regarding the global health status QoL scale and physical functioning domain of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30 (EORTC QLQ-C30) and the visual analog scale (VAS) of the EuroQOL, 5 dimensions, 5 levels (EQ-5D-5L) survey instrument. There was a clinically meaningful and statistically significant difference in mean change of scores from baseline with Yescarta compared to SOCT for EORTC global health status/QOL and physical functioning at Day 100, and for EQ-5D-5L VAS at Day 100 and Day 150.
ZUMA-1. A phase 2 single-arm, open-label, multicenter trial evaluated the efficacy of a single infusion of Yescarta in adult patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (large B-cell lymphoma).
Eligible patients were ≥ 18 years of age with refractory disease defined as progressive disease (PD) or stable disease (SD) as best response to last line of therapy, or disease progression within 12 months after autologous stem cell transplant (ASCT). Patients who are refractory to chemotherapy or who relapse after two or more lines of systemic therapy are generally ineligible for autologous HSCT.
The study excluded patients with prior allogeneic HSCT, any history of central nervous system lymphoma, ECOG performance status of 2 or greater, absolute lymphocyte count less than 100/microL, creatinine clearance less than 60 mL/min, hepatic transaminases more than 2.5 times the upper limit of normal, cardiac ejection fraction less than 50%, or active serious infection.
Following lymphodepleting chemotherapy, Yescarta was administered as a single intravenous infusion at a target dose of 2 x 10⁶CAR-positive viable T cells/kg (maximum 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 5th, 4th, and 3rd day before Yescarta. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was not permitted. All patients were hospitalised for Yescarta infusion and for a minimum of 7 days afterward.
Of 111 patients who underwent leukapheresis in phase 2, 101 received Yescarta. Efficacy was based on 101 patients in phase 2, including histologically confirmed DLBCL (N=77), primary mediastinal large B-cell lymphoma (N=8) or DLBCL arising from follicular lymphoma, (N=16) based on the 2008 WHO classification. DLBCL in ZUMA-1 included patients with DLBCL NOS, other DLBCL subtypes, and high-grade B cell lymphoma (HGBCL) based on the 2016 WHO classification. Forty patients were evaluable for MYC, BCL-2, and BCL-6 status. Twenty-seven were found to have double expressor DLBCL (overexpression of both MYC and BCL-2 protein); 4 were found to have HGBCL with MYC, BCL-2 or BCL-6 gene rearrangement (double- and triple hit); and 2 were found to have HGBCL not otherwise specified. Sixty six patients were evaluable for cell of origin classifications (germinal center B cell type [GCB] or activated B cell type [ABC]). Of these, 49 patients had GCB type and 17 patients had ABC type. The median number of prior therapies was 3 (range: 1 to 10), 76% of the patients had refractory disease to a second or greater line of therapy, and 21% had relapsed within 1 year of autologous HSCT. Of the patients treated, the median age was 58 years (range: 23 to 76), 67% were male, and 86% were white.
One of 111 patients who underwent leukapheresis did not receive the product due to manufacturing failure. Nine other patients were not treated, primarily due to progressive disease or serious adverse events following leukapheresis. The median time from leukapheresis to product delivery was 17 days (range: 14 to 51 days), and the median time from leukapheresis to infusion was 24 days (range: 16 to 73 days). The median dose was 2.0 x 10⁶ anti-CD19 CAR T cells/kg. ITT was defined as all patients who underwent leukapheresis, mITT was defined as all patients who received Yescarta.
Efficacy was established on the basis of complete remission (CR) rate and DOR, as determined by an independent review committee (Table 10 and Table 11). The primary endpoint was objective response rate (ORR). Secondary endpoints included DOR, OS and severity of adverse events. The ORR was pre-specified to be tested in the first 92 treated patients and was significantly higher than the pre-specified rate of 20% (P < 0.0001).
In the primary analysis, based on the mITT population the ORR was 72% and CR rate was 51%, as determined by an independent review committee.
With a median follow-up of 27.1 months (range: 22.9 to 32.4 months), and as determined by an independent review committee the ORR was 74% and CR rate was 54%. The median time to response was 1.0 months (range: 0.8 to 12.2 months). The duration of response was not reached but it was longer in patients who achieved CR, as compared to patients with a best response of partial remission (PR). Of the 55 patients who achieved CR, 7 patients had stable disease (SD) and 10 had PR at their initial tumor assessment and converted to CR as late as 15.3 months. Median overall survival has not yet been reached (Table 12 and Figure 3). In a 36 month analysis (median study follow-up of 39.1 months) the median overall survival time was 25.8 months with 47 patients still alive. In a 48-month analysis (median study follow-up of 51.1 months) the median overall survival time was 25.8 months with 43 patients still alive. The Kaplan-Meier estimates of the 3-year and 4-year OS rates were 47% and 44% respectively.
Among patients who achieved CR/PR/SD by month 3, PFS rates at 12 months and 24 months were 70% and 63%. Among patients who achieved CR by month 3, PFS estimates at 12 months and 24 months were 77% and 72%.

In the phase 1 part of ZUMA-1, 7 patients were treated. Five patients responded including 4 CRs. At the time of the 12 month follow-up analysis, 3 patients remained in CR 24 months after Yescarta infusion. At the time of the 24 month follow-up analysis, these 3 patients remained in CR at 30 to 35 months after Yescarta infusion.
The safety and efficacy of Yescarta was evaluated in two subsequent cohorts of LBCL patients. In the first subsequent, open label, safety management cohort in ZUMA-1 that evaluated the safety and efficacy of corticosteroid and/or tocilizumab use for Grade 1 CRS or neurologic events (see Tables 1 and 2), a total of 46 patients with relapsed or refractory LBCL were enrolled and 41 patients were treated with Yescarta. Eligible patients had relapsed or refractory DLBCL (N=26), PMBCL (N=2), TFL (N=10) or HGBCL (N=3) after 2 or more lines of systemic therapy. Of the 41 patients treated with Yescarta, the median age was 61 years (range: 19 to 77), 68% were male, and 80% were white. Of the 41 patients treated with Yescarta, 28 patients (68%) received bridging therapy.
In the 12-month analysis, the investigator read ORR was 73% [95% CI: 57, 86] and CR rate was 51% [95% CI: 35, 67]. The median DOR was not reached (range: 0.0 to 18.0 months) with a median follow-up time of 11.8 months.
In the second subsequent, open label, safety management cohort in ZUMA-1 that evaluated the safety and efficacy of Yescarta with earlier intervention with prophylactic corticosteroids in addition to tocilizumab and/or corticosteroids, a total of 42 patients with relapsed or refractory LBCL were enrolled and 40 patients were treated with Yescarta. Eligible patients had relapsed or refractory DLBCL (N=24) 60%, TFL (N=9) 23% or HGBCL (N=7) 18% after 2 or more lines of systemic therapy. Of the 40 patients treated with Yescarta, the median age was 64.5 years (range: 37 to 85 years), 58% were male, and 85% were white. Of the 40 patients treated with Yescarta, 21 patients (53%) received bridging therapy. In the 12-month analysis, the investigator read ORR was 95% [95% CI: 83, 99] and CR rate was 80% [95% CI: 64, 91]. The median DOR was not reached [95% CI: 7.8, NE] with a median follow-up time of 12.1 months.
Supportive studies.

Study 09-C-0082.

A phase 1, single arm, open label, study of anti-CD19 CAR T cells was conducted in patients with relapsed/refractory B cell malignancies. Thirteen patients had aggressive B-cell NHL. Anti-CD19 CAR T cells were administered as a single infusion after conditioning chemotherapy regimen.
The ORR was 69% [95% CI: 39%, 91%], with 8 CRs (62%) and 1 PR (8%). The median duration of response was not reached (range: 2.8+ to 23+ months).

SCHOLAR-1.

A retrospective, patient-level, pooled analysis of outcomes in refractory aggressive NHL (N=636) was conducted (Crump et al., 2017) to provide confirmation of the prespecified control response rate of 20% and historical context for interpreting the ZUMA-1 results. The analysis included patients who had not responded (stable disease [SD] or PD) to their last line of therapy, or had relapsed within 12 months after ASCT. The ORR was 26% [95% CI (21, 31)] and CR rate was 7% [95% CI (3, 15)], with a median OS of 6.3 months.

Relapsed or refractory iNHL, including FL and MZL subtypes: ZUMA-5.

A Phase 2 single-arm, open-label, multicenter study evaluated the efficacy and safety of Yescarta in adult patients with relapsed or refractory B-cell iNHL of FL or MZL histological subtypes after two of more prior lines of therapy, including a combination of anti-CD20 and alkylating agent. In the primary analysis, in total, 146 patients with iNHL (124 patients with FL and 22 patients with MZL) were treated with Yescarta; 84 FL patients and 20 MZL patients were evaluable for efficacy. The study excluded patients with active or serious infections, transformed lymphoma, prior allogeneic HSCT, or CNS involvement.
Following lymphodepleting chemotherapy, Yescarta was administered to patients as a single intravenous infusion at a target dose of 2 x 10⁶ anti-CD19 CAR T cells/kg. The lymphodepleting regimen consisted of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously, both given on the 5th, 4th, and 3rd day before Yescarta.
Among the 104 patients (84 FL and 20 MZL) who were evaluable for efficacy, the median age was 63 years (range: 34 to 79 years), 48% were female, and 93% were white. The median number of prior therapies was 3 (range: 2 to 9), patients had ECOG performance status of 0 (61%) or 1 (39%), while 53 patients (51%) had a Follicular Lymphoma International Prognostic Index (FLIPI) total score of ≥ 3. Forty-nine patients (47%) were classified as having high tumor bulk as defined by GELF criteria. Thirty-five (34%) patients received a prior PI3K inhibitor, 76 patients (73%) were refractory (progression of disease < 6 months) to their last regimen prior to study entry and 57 patients (55%) had progression of disease within 24 months of initiating their first chemoimmunotherapy.
The median time from leukapheresis to product release was 12 days (range: 10 to 37 days), leukapheresis to product delivery was 17 days (range: 13 to 72 days), and leukapheresis to Yescarta infusion was 28 days (range: 19 to 330 days). The median dose was 2.0 x 10⁶ antiCD19 CAR-T cells/kg. All patients received Yescarta infusion on day 0 and were hospitalized until at least day 7.
The primary endpoint was ORR in the 84 efficacy evaluable FL patients treated with Yescarta as determined by an independent review committee. The ORR was 94% with a CR rate of 79% with a median follow-up time of 18.5 months. The median time to response was 1 month (range: 0.8 to 3.1 months) with a median DOR that was not reached (range: 0.0 to 25.0 months). Among 25 patients with FL who initially had a PR, 13 patients later achieved a CR. Subgroup analysis included ORR in patients who were refractory [93% (95% CI: 85, 98)], FLIPI score ≥ 3 [94% (95% CI: 84, 99)], high tumor burden [96% (95% CI: 86, 100)], progression of disease within 24 months of first immunotherapy [93% (95% CI: 83, 98)] and prior treatment with a PI3K inhibitor [94% (95% CI: 81, 99)]. Key efficacy results for iNHL patients overall and FL/MZL subtypes are summarised in Table 13.
In the 18-month follow-up analysis, the ORR and CR rates in the 86 efficacy evaluable FL patients were 94% and 79%, respectively (see Table 9). The median time to response was 0.99 months (range: 0.8 to 3.1 months) with a median DOR that was not reached (range: 0.0 to 25.0 months). The proportion of responders who remained in response at Months 12 and 18 were 75.2% (95% CI: 63.9%, 83.4) and 69.4% (95% CI: 56.7%, 79.1%). The duration of response was longer in FL patients who achieved CR, as compared to FL patients with a best response of PR. Among the 26 patients with FL who initially had PR, 13 patients later achieved a CR. See Table 14.

5.2 Pharmacokinetic Properties

Following infusion of Yescarta, 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 7-14 days after Yescarta infusion.
Age (range: 21 - 80 years) and sex had no significant impact on AUC_0-28 and C_max of Yescarta.

LBCL.

Among patients with LBCL in the ZUMA-7 study, the number of anti-CD19 CAR T cells in blood was positively associated with objective response. The median anti-CD19 CAR T cell C_max levels in responders (n=142) were about 275% higher compared to the corresponding level in nonresponders (n=20) (28.9 cells/microL vs 10.5 cells/microL). Median AUC_0-28 in responding patients (n=142) was about 418% higher compared to the corresponding level in nonresponders (n=20) (292.9 days x cells/microL vs. 70.1 days x cells/microL).
Among patients with LBCL in the ZUMA-1 study, the number of anti-CD19 CAR T cells in blood was positively associated with objective response [CRPR]. The median anti-CD19 CAR T-cell C_max level in responders (n=82) was 277% higher compared with the corresponding level in nonresponders (n=16) (43.2 cells/microL vs 15.6 cells/microL). Median AUC_0-28 in responding patients (n=82) was 570% of the corresponding level in nonresponders (n=16) (550.1 days x cells/microL vs. 95.9 days x cells/microL).

FL and MZL.

Among patients with FL in the ZUMA-5 study, the median peak of anti-CD19 CAR T-cell levels in responders (n=79) versus nonresponders (n=3) were 37.62 cells/microL and 35.31 cells/microL, respectively. The median AUC_0-28 in responders versus nonresponders were 451.17 cells/microL.days and 247.14 cells/microL.days, respectively. Among patients with MZL, there were no nonresponders. The median peak of anti-CD19 CAR T-cell level in responders (n=17) was 71.21 cells/microL and the median AUC_0-28 was 1244.41 cells/microL.days).

Pharmacokinetics in special populations.

Hepatic and renal impairment studies of Yescarta were not conducted.

5.3 Preclinical Safety Data

Genotoxicity.

Conventional genotoxicity assays have not been performed with axicabtagene ciloleucel and are not appropriate for cell therapy products. Experience in clinical studies suggest a low risk of insertional mutagenesis following T cell transduction with γ-retroviral CAR constructs compared to transduction of haematopoietic stem cells (HSC) and T cells with γ-retroviral vectors.

Carcinogenicity.

Standard rodent carcinogenicity studies have not been performed with axicabtagene ciloleucel 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

Cryostor CS10 (5% DMSO), sodium chloride, human 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 12 months when stored frozen in the vapor phase of liquid nitrogen (≤ -150°C).
Once thawed, Yescarta may be stored at room temperature (20°C to 25°C) for up to 3 hours.

6.4 Special Precautions for Storage

Yescarta 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

Yescarta is supplied in a cryostorage bag.
Each infusion bag is individually packed in a metal cassette.
Yescarta 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.
Yescarta 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 Yescarta 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 Yescarta (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.

Axicabtagene ciloleucel 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 axicabtagene ciloleucel.

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Yescarta

Axicabtagene ciloleucel

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