This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

Tecartus 0.4 – 2 × 108 cells dispersion for infusion

2. Qualitative and quantitative composition

2.1 General description

Tecartus (autologous anti-CD19-transduced CD3+ cells) is a gene therapy medicinal product containing autologous T cells genetically modified ex vivo using a retroviral vector encoding an anti-CD19 chimeric antigen receptor (CAR) comprising a murine anti-CD19 single chain variable fragment (scFv) linked to CD28 co-stimulatory domain and CD3-zeta signalling domain.

2.2 Qualitative and quantitative composition

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 body weight (range: 1 x 106 – 2 x 106 cells/kg), with a maximum of 2 x 108 anti-CD19 CAR-positive viable T cells.

Excipient(s) with known effect

This medicinal product contains 300 mg sodium.

Each dose contains 0.05 mL of dimethyl sulfoxide (DMSO) per mL of Tecartus.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Dispersion for infusion.

A clear to opaque, white to red dispersion.

4. Clinical particulars
4.1 Therapeutic indications

Tecartus is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after two or more lines of systemic therapy including a Bruton's tyrosine kinase (BTK) inhibitor.

4.2 Posology and method of administration

Tecartus must be administered in a qualified treatment centre by a physician with experience in the treatment of haematological malignancies and trained for administration and management of patients treated with Tecartus. At least 1 dose of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion. The qualified treatment centre must have access to an additional dose of tocilizumab within 8 hours of each previous dose.

Patients are expected to enrol in a registry and will be followed in the registry in order to better understand the long-term safety and efficacy of Tecartus.

Posology

Tecartus is intended for autologous use only (see section 4.4).

A single dose of Tecartus contains 2 × 106 CAR-positive viable T cells per kg of body weight (range: 1 x 106–2 x 106 cells/kg), or maximum of 2 × 108 CAR-positive viable T cells for patients 100 kg and above in approximately 68 mL dispersion in an infusion bag.

Tecartus is recommended to be infused 3 to 14 days after completion of the lymphodepleting chemotherapy. The availability of the treatment must be confirmed prior to starting the lymphodepleting regimen.

Pre-treatment (lymphodepleting chemotherapy)

• A lymphodepleting chemotherapy regimen consisting of cyclophosphamide 500 mg/m² and fludarabine 30 mg/m² should be administered intravenously on the 5th, 4th, and 3rd day before infusion of Tecartus.

Pre-medication

• To minimise potential acute infusion reactions, it is recommended that patients be pre-medicated with paracetamol 500 to 1,000 mg given orally and diphenhydramine 12.5 to 25 mg intravenous or oral (or equivalent) approximately 1 hour prior to infusion.

• Prophylactic use of systemic corticosteroids is not recommended (see section 4.5).

Monitoring after infusion

• Patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs/symptoms of CRS and/or neurologic events.

• After the first 10 days following the infusion, the patient should be monitored at the physician's discretion.

• Patients should be instructed to remain within proximity (within 2 hours of travel) of a qualified treatment centre for at least 4 weeks following infusion.

Special populations

Elderly

No dose adjustment is required in patients ≥65 years of age.

Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV)

There is no experience with manufacturing Tecartus for patients with a positive test for HIV, active HBV, or active HCV infection. Therefore, the benefit/risk has not yet been established in this population.

Paediatric population

The safety and efficacy of Tecartus in children and adolescents aged less than 18 years have not yet been established. No data are available.

Method of administration

Tecartus is for intravenous use only.

Tecartus must not be irradiated. Do NOT use a leukodepleting filter.

Precautions to be taken before handling or administering the medicinal product

This medicinal product contains genetically modified human blood cells. Healthcare professionals handling Tecartus should take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases (see section 6.6).

Preparation for infusion

• Verify that the patient's identity (ID) matches the patient identifiers on the Tecartus metal cassette.

• The Tecartus infusion bag must not be removed from the metal cassette if the information on the patient-specific label does not match the intended patient.

• Once the patient ID is confirmed, remove the infusion bag from the metal cassette.

• Check that the patient information on the metal cassette label matches that on the bag label.

• Inspect the infusion bag for any breaches of container integrity before thawing. If the bag is compromised, follow the local guidelines for handling of waste of human-derived material (or immediately contact Kite).

• Place the infusion bag inside a second bag.

• 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. Tecartus should not be washed, spun down, and/or re-suspended in new media prior to infusion. Thawing should take approximately 3 to 5 minutes.

• Once thawed, Tecartus is stable at room temperature (20 °C – 25 °C) for up to 3 hours. However, Tecartus infusion should begin within 30 minutes of thaw completion.

Administration

• For autologous single use only.

• Tocilizumab and emergency equipment should be available prior to infusion and during the monitoring period.

• A leukodepleting filter must not be used.

• Central venous access is recommended for the administration.

• Verify the patient ID again to match the patient identifiers on the Tecartus bag.

• Prime the tubing with sodium chloride 9 mg/mL (0.9%) solution for injection (0.154 mmol sodium per mL) prior to infusion.

• Infuse the entire content of the Tecartus bag within 30 minutes by either gravity or a peristaltic pump.

• Gently agitate the bag during infusion to prevent cell clumping.

• After the entire content of the bag is infused, rinse the tubing at the same infusion rate with sodium chloride 9 mg/mL (0.9%) solution for injection (0.154 mmol sodium per mL) to ensure all the treatment is delivered.

For instructions on the handling, accidental exposure to and disposal of the medicinal product, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Contraindications of the lymphodepleting chemotherapy must be considered.

4.4 Special warnings and precautions for use

Traceability

The traceability requirements of cell-based advanced therapy medicinal products must apply. To ensure traceability the name of the product, the batch number and the name of the treated patient should be kept for a period of 30 years.

General

Warnings and precautions of lymphodepleting chemotherapy must be considered.

Patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs/symptoms of CRS and/or neurologic events. After the first 10 days following infusion, the patient should be monitored at the physician's discretion.

Counsel patients to remain within the proximity of a qualified treatment centre for at least 4 weeks following infusion and to seek immediate medical attention should signs or symptoms of CRS or neurological adverse reactions occur. Monitoring of vital signs and organ functions should be considered depending on the severity of the reaction.

Reasons to delay treatment

Due to the risks associated with Tecartus treatment, infusion should be delayed if a patient has any of the following conditions:

• Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions, or hypotension) including from preceding chemotherapies.

• Active uncontrolled infection or inflammatory disease.

• Active graft-versus-host disease (GvHD).

In some cases, the treatment may be delayed after administration of the lymphodepleting chemotherapy regimen. If the infusion is delayed for more than 2 weeks after the patient has received the lymphodepleting chemotherapy, lymphodepleting chemotherapy regimen should be administered again (see section 4.2)

Serological testing

Screening for HBV, HCV, and HIV should be performed before collection of cells for manufacturing of Tecartus (see section 4.2).

Blood, organ, tissue and cell donation

Patients treated with Tecartus should not donate blood, organs, tissues, or cells for transplantation.

Active central nervous system (CNS) lymphoma

There is no experience of use of this medicinal product in patients with active CNS lymphoma defined as detectable cerebrospinal fluid malignant cells or brain metastases confirmed by imaging. Therefore, the benefit/risk of Tecartus has not been established in this population.

Concomitant disease

Patients with a history of or active CNS disorder or inadequate renal, hepatic, pulmonary, or cardiac function were excluded from the study. These patients are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.

Cytokine release syndrome

Nearly all patients experienced some degree of CRS. Severe CRS, which can be life-threatening, was very commonly observed with Tecartus with a median time to onset of 3 days (range: 1 to 13 days). Patients should be closely monitored for signs or symptoms of these events, such as high fever, hypotension, hypoxia, chills, tachycardia and headache (see section 4.8). 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.

Diagnosis of CRS requires excluding alternate causes of systemic inflammatory response, including infection.

Management of cytokine release syndrome associated with Tecartus

At least 1 dose per patient of tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, must be on site and available for administration prior to Tecartus infusion. The qualified treatment centre should have access to an additional dose of tocilizumab within 8 hours of each previous dose.

Treatment algorithms have been developed to ameliorate some of the CRS symptoms experienced by patients on Tecartus. These include the use of tocilizumab or tocilizumab and corticosteroids, as summarised 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.

CRS has been known to be associated with end organ dysfunction (e.g., hepatic, renal, cardiac, and pulmonary). In addition, worsening of underlying organ pathologies can occur in the setting of CRS. Patients with medically significant cardiac dysfunction should be managed by standards of critical care and measures such as echocardiography should be considered. In some cases, macrophage activation syndrome (MAS) and haemophagocytic lymphohistiocytosis (HLH) may occur in the setting of CRS.

Evaluation for haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) should be considered in patients with severe or unresponsive CRS.

Tecartus continues to expand and persist following administration of tocilizumab and corticosteroids. Tumour necrosis factor (TNF) antagonists are not recommended for management of Tecartus-associated CRS.

Table 1 CRS grading and management guidance

CRS Grade (a)

Tocilizumab

Corticosteroids

Grade 1

Symptoms require symptomatic treatment only (e.g., fever, nausea, fatigue, headache, myalgia, malaise).

If not improving after 24 hours, administer tocilizumab 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

N/A

Grade 2

Symptoms require and respond to moderate intervention.

Oxygen requirement less than 40% FiO2 or hypotension responsive to fluids or low-dose of one vasopressor or Grade 2 organ toxicity (b).

Administer tocilizumab (c) 8 mg/kg intravenously over 1 hour (not to exceed 800 mg).

Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24 hour period; maximum total of 4 doses if no clinical improvement in the signs and symptoms of CRS, or if no response to second or subsequent doses of tocilizumab, consider alternative measures for treatment of CRS.

If improving, discontinue tocilizumab.

If no improvement within 24 hours after starting tocilizumab, manage as per Grade 3.

If improving, taper corticosteroids, and manage as Grade 1.

Grade 3

Symptoms require and respond to aggressive intervention.

Oxygen requirement greater than or equal to 40% FiO2 or hypotension requiring high-dose or multiple vasopressors or Grade 3 organ toxicity or Grade 4 transaminitis.

Per Grade 2

Administer methylprednisolone 1 mg/kg intravenously twice daily or equivalent dexamethasone (e.g., 10 mg intravenously every 6 hours) until Grade 1, then taper corticosteroids.

If improving, manage as Grade 2.

If not improving, manage as Grade 4.

Grade 4

Life-threatening symptoms.

Requirements for ventilator support or continuous veno-venous haemodialysis or Grade 4 organ toxicity (excluding transaminitis).

Per Grade 2

Administer methylprednisolone 1000 mg intravenously per day for 3 days.

If improving, taper corticosteroids, and manage as Grade 3.

If not improving, consider alternate immunosuppressants.

N/A = not available/not applicable

(a) Lee et al 2014.

(b) Refer to Table 2 for management of neurologic adverse reactions.

(c) Refer to tocilizumab summary of product characteristics for details.

Neurologic adverse reactions

Severe neurologic adverse reactions (encephalopathy, confusional state or delirium, decreased level of consciousness, seizures, aphasia), which could be life-threatening, were very commonly observed in patients treated with Tecartus with a median time to onset of 8 days (range: 1 to 262 days) (see section 4.8).

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. Non-sedating, anti-seizure medicines should be considered as clinically indicated for Grade 2 or higher adverse reactions. Treatment algorithms have been developed to ameliorate the neurologic adverse reactions experienced by patients on Tecartus. These include the use of tocilizumab (if concurrent CRS) and/or corticosteroids for moderate, severe, or life-threatening neurologic adverse reactions as summarised in Table 2.

Table 2 Neurologic adverse reaction grading and management guidance

Grading assessment

Concurrent CRS

No concurrent CRS

Grade 2

Administer tocilizumab as per Table 1 for management Grade 2 CRS.

If not improving within 24 hours after starting tocilizumab, administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less, then taper corticosteroids.

If improving, discontinue tocilizumab.

If still not improving, manage as Grade 3.

Administer dexamethasone 10 mg intravenously every 6 hours until the event is Grade 1 or less.

If improving, taper corticosteroids

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

Grade 3

Administer tocilizumab as per Table 1 for management of Grade 2 CRS.

In addition, administer dexamethasone 10 mg intravenously with the first dose of tocilizumab and repeat dose every 6 hours. Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids.

If improving, discontinue tocilizumab and manage as Grade 2.

If still not improving, manage as Grade 4.

Administer dexamethasone 10 mg intravenously every 6 hours.

Continue dexamethasone use until the event is Grade 1 or less, then taper corticosteroids.

If not improving, manage as Grade 4.

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

Grade 4

Administer tocilizumab as per Table 1 for management of Grade 2 CRS.

Administer methylprednisolone 1000 mg intravenously per day with first dose of tocilizumab and continue methylprednisolone 1000 mg intravenously per day for 2 more days.

If improving, then manage as Grade 3.

If not improving, consider alternate immunosuppressants.

Administer methylprednisolone 1000 mg intravenously per day for 3 days.

If improving, then manage as Grade 3.

If not improving, consider alternate immunosuppressants.

Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.

Infections and febrile neutropenia

Severe infections, which could be life-threatening, were very commonly observed with Tecartus (see section 4.8).

Patients should be monitored for signs and symptoms of infection before, during and after infusion and treated appropriately. Prophylactic antibiotics should be administered according to standard institutional guidelines.

Febrile neutropenia has been observed in patients after Tecartus infusion (see section 4.8) 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.

Viral reactivation

Viral reactivation, e.g. Hepatitis B virus (HBV) reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure, and death.

Prolonged cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Tecartus infusion and should be managed according to standard guidelines. Grade 3 or higher prolonged cytopenias following Tecartus infusion occurred very commonly and included thrombocytopenia, neutropenia, and anaemia (see section 4.8). Patient blood counts should be monitored after Tecartus infusion.

Hypogammaglobulinaemia

B-cell aplasia leading to hypogammaglobulinaemia can occur in patients receiving treatment with Tecartus. Hypogammaglobulinaemia was very commonly observed in patients treated with Tecartus (see section 4.8). Hypogammaglobulinaemia predisposes patients to have infections. Immunoglobulin levels should be monitored after treatment with Tecartus and managed using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement in case of recurrent infections and should be taken according standard guidelines.

Hypersensitivity reactions

Serious hypersensitivity reactions including anaphylaxis, may occur due to DMSO or residual gentamicin in Tecartus.

Secondary malignancies

Patients treated with Tecartus may develop secondary malignancies. Patients should be monitored life-long for secondary malignancies. In the event that a secondary malignancy 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 Tecartus infusion. Signs and symptoms of TLS should be monitored, and events managed according to standard guidelines.

Prior stem cell transplantation (GvHD)

It is not recommended that patients who underwent an allogeneic stem cell transplant and suffer from active acute or chronic GvHD receive treatment because of the potential risk of Tecartus worsening GvHD.

Prior treatment with anti-CD19 therapy

Tecartus is not recommended if the patient has relapsed with CD19-negative disease after prior anti-CD19 therapy.

Sodium content

This medicinal product contains 300 mg sodium per infusion, equivalent to 15% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Prophylactic use of systemic corticosteroids may interfere with the activity of Tecartus. Prophylactic use of systemic corticosteroids is therefore not recommended before infusion (see section 4.2).

Administration of corticosteroids as per the toxicity management guidelines does not impact the expansion and persistence of CAR T cells.

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.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception

The pregnancy status of women of childbearing potential must be verified before starting Tecartus treatment.

See the prescribing information for lymphodepleting chemotherapy 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.

Pregnancy

There are no available data with Tecartus use in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with Tecartus to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).

It is not known if Tecartus has the potential to be transferred to the foetus. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause foetal toxicity, including B-cell lymphocytopenia. Therefore, Tecartus is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Tecartus therapy should be discussed with the treating physician.

Assessment of immunoglobulin levels and B-cells in newborn infants of mothers treated with Tecartus should be considered.

Breast-feeding

It is unknown whether Tecartus is excreted in human milk or transferred to the breast-feeding child. Breast-feeding women should be advised of the potential risk to the breast-fed child.

Fertility

No clinical data on the effect of Tecartus on fertility are available. Effects on male and female fertility have not been evaluated in animal studies.

4.7 Effects on ability to drive and use machines

Tecartus has major influence on the ability to drive and use machines.

Due to the potential for neurologic events, including altered mental status or seizures, patients should not drive or operate heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of neurologic adverse reactions.

4.8 Undesirable effects

Summary of the safety profile

The safety data described in this section reflect exposure to Tecartus in ZUMA-2, a Phase 2 study in which a total of 82 patients with relapsed/refractory MCL received a single dose of CAR-positive viable T cells (2 × 106 or 0.5 × 106 anti-CD19 CAR T cells/kg) based on a recommended dose which was weight-based.

The most significant and frequently occurring adverse reactions were cytokine release syndrome (91%), infections (56%) and encephalopathy (51%).

Serious adverse reactions occurred in 57% of patients. The most common serious adverse reactions included encephalopathy (26%), infections (28%) and cytokine release syndrome (15%).

Grade 3 or higher adverse reactions were reported in 65% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (32%) and encephalopathy (24%). The most common Grade 3 or higher haematological adverse reactions included neutropenia (99%), leukopenia (98%), lymphopenia (96%), thrombocytopenia (65%) and anaemia (56%).

Tabulated list of adverse reactions

Adverse reactions described in this section were identified in patients exposed to Tecartus in ZUMA-2. These reactions are presented by system organ class and by frequency. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 3 Adverse drug reactions identified with Tecartus

System Organ Class (SOC)

Frequency

Adverse reactions

Infections and infestations

Very common

Unspecified pathogen infections

Viral infections

Bacterial infections

Fungal infections

Blood and lymphatic system disorders

Very common

Neutropeniaa

Lymphopeniaa

Leukopeniaa

Anaemiaa

Thrombocytopeniaa

Coagulopathy

Immune system disorders

Very common

Cytokine Release Syndromeb

Hypogammaglobulinaemia

Metabolism and nutrition disorders

Very common

Hypophosphataemiaa

Decreased appetite

Common

Dehydration

Hypoalbuminemiaa

Psychiatric disorders

Very common

Insomnia

Delirium

Anxiety

Nervous system disorders

Very common

Encephalopathy

Tremor

Headache

Aphasia

Dizziness

Neuropathy

Common

Ataxia

Seizure

Increased intracranial pressure

Cardiac disorders

Very common

Tachycardias

Bradycardias

Common

Non-ventricular arrhythmias

Vascular disorders

Very common

Hypotension

Hypertension

Thrombosis

Common

Haemorrhage

Respiratory, thoracic and mediastinal disorders

Very common

Cough

Pleural effusion

Dyspnoea

Hypoxia

Common

Respiratory failure

Pulmonary oedema

Gastrointestinal disorders

Very common

Constipation

Nausea

Diarrhoea

Oral pain

Abdominal pain

Vomiting

Dysphagia

Common

Dry mouth

Skin and subcutaneous tissue disorders

Very common

Rash

Musculoskeletal and connective tissue disorders

Very common

Motor dysfunction

Musculoskeletal pain

Renal and urinary disorders

Very common

Renal insufficiency

Urine output decreased

General disorders and administration site conditions

Very common

Fatigue

Oedema

Pyrexia

Pain

Chills

Investigations

Very common

Alanine aminotransferase increaseda

Aspartate aminotransferase increaseda

Hypokalaemiaa

Hyponatraemiaa

Hypocalcaemiaa

Blood uric acid increaseda

Only cytopenias that resulted in (i) new or worsening clinical sequelae or (ii) that required therapy or (iii) adjustment in current therapy are included in Table 3.

a Frequency based on Grade 3 or higher laboratory parameter.

b See section Description of selected adverse reactions.

Description of selected adverse reactions

Cytokine release syndrome

CRS occurred in 91% of patients. Fifteen percent (15%) of patients experienced Grade 3 or higher (severe or life-threatening) CRS. The median time to onset was 3 days (range: 1 to 13 days) and the median duration was 10 days (range: 1 to 50 days). All patients (100%) recovered from CRS.

The most common signs or symptoms associated with CRS among the patients who experienced CRS included pyrexia (99%), hypotension (60%), hypoxia (37%), chills (33%), tachycardia (27%), headache (24%), fatigue (16%), nausea (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (12%), diarrhoea (11%), and sinus tachycardia (11%). Serious adverse reactions that may be associated with CRS included hypotension, pyrexia, hypoxia, acute kidney injury, and tachycardia. See section 4.4 for monitoring and management guidance.

Neurologic events and adverse reactions

Neurologic adverse reactions occurred in 68% of patients. Thirty-three percent (33%) of patients experienced Grade 3 or higher (severe or life-threatening) adverse reactions. The median time to onset was 8 days (range: 1 to 262 days). Neurologic events resolved for 47 out of 56 patients with a median duration of 13 days (range: 1 to 567 days). Three patients had ongoing neurologic events at the time of death, including one patient with the reported event of serious encephalopathy and another patient with the reported event of serious confusional state. The remaining unresolved neurologic events were Grade 2. Eighty-five percent of all treated patients experienced the first CRS or neurological event within the first 7 days after Tecartus infusion.

The most common neurologic adverse reactions included encephalopathy (51%), tremor (38%), aphasia (20%), and delirium (18%). Serious adverse reactions including encephalopathy (26%), aphasia (6%) and seizure (2%) have been reported in patients administered with Tecartus. Serious cases of cerebral oedema which may become fatal have occurred in patients treated with Tecartus. See section 4.4 for monitoring and management guidance.

Febrile neutropenia and infections

Febrile neutropenia was observed in 6% of patients after Tecartus infusion. Infections occurred in 56% of patients in ZUMA-2. Grade 3 or higher (severe, life-threatening or fatal) infections occurred in 32% of patients including unspecified pathogen, bacterial, and viral infections in 26%, 6%, and 4% of patients respectively. See section 4.4 for monitoring and management guidance.

Prolonged cytopenias

Cytopenias are very common following prior lymphodepleting chemotherapy and Tecartus therapy.

Prolonged (present on or beyond Day 30 or with an onset at Day 30 or beyond) Grade 3 or higher cytopenias occurred in 55% of patients and included thrombocytopenia (38%), neutropenia (37%), and anaemia (17%). See section 4.4 for management guidance.

Hypogammaglobulinaemia

In ZUMA-2, hypogammaglobulinaemia occurred in 16% of patients. Grade 3 or higher hypogammaglobulinemia occurred in 1% of patients. See section 4.4 for management guidance.

Immunogenicity

The immunogenicity of Tecartus 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-CD19 CAR T-cell antibody immunogenicity has been observed. Based on an initial screening assay, 17 patients tested positive for antibodies; however, a confirmatory orthogonal cell-based assay demonstrated that all 17 patients were antibody negative at all time points tested. There is no evidence that the kinetics of initial expansion, CAR T-cell function and persistence of Tecartus, or the safety or effectiveness of Tecartus, was altered in these patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

There are no data regarding the signs of overdose with 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. Following anti-CD19 CAR T-cell engagement with CD19 expressing target cells, the CD28 co-stimulatory domain and CD3-zeta signalling domain activate downstream signalling 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

In ZUMA-2, 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, interferon-gamma (IFN-γ) and IL-2 receptor alpha were analysed. Peak elevation was generally observed between 4 and 8 days after infusion and levels generally returned to baseline within 28 days.

Due to the on target, off-tumour effect of Tecartus a period of B-cell aplasia is expected following treatment.

Translational analyses performed to identify associations between cytokine levels and incidence of CRS or neurologic events showed that higher levels (peak and AUC at 1 month) of multiple serum analytes were associated with Grade 3 or higher neurologic adverse reactions and Grade 3 or higher CRS.

Clinical efficacy and safety

Relapsed or refractory MCL: ZUMA-2

The efficacy and safety of Tecartus in adult patients with relapsed or refractory MCL who had previously received anthracycline or bendamustine-containing chemotherapy, an anti CD20 antibody, and a Bruton's tyrosine kinase inhibitor (BTKi) (ibrutinib or acalabrutinib), was evaluated in a phase 2 single-arm, open-label, multicenter trial. Eligible patients also had disease progression after last regimen or refractory disease to the most recent therapy. 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 were ineligible. In total, 74 patients were enrolled (i.e. leukapheresed) and 68 patients were treated with Tecartus. Three patients did not receive Tecartus due to manufacturing failure. Two other patients were not treated due to progressive disease (death) following leukapheresis. One patient was not treated with Tecartus after receiving lymphodepleting chemotherapy due to ongoing active atrial fibrillation. ITT was defined as all patients who underwent leukapheresis. A summary of the patient baseline characteristics is provided in Table 4.

Table 4 Summary of baseline characteristics for ZUMA-2

Category

All leukapheresed (ITT)

(N=74)

Age (years)

Median (min, max)

65 (38, 79)

≥ 65

58%

Male gender

84%

Median number of prior therapies (min, max)

3 (1; 5)

Relapsed/refractory subgroup

Relapsed after auto-SCT

42%

Refractory to last MCL therapy

39%

Relapsed after last MCL therapy

19%

Patients with disease stage IV

86%

Patients with bone marrow involvement

51%

Morphological characteristic

Classical MCL

54%

Blastoid MCL

26%

Other

1%

Unknown

19%

Received bridging therapy

Yes

38%

No

62%

Ki-67 IHC by central laboratory

N

49

Median

65%

Auto-SCT, autologous stem cell transplant; IHC, immunohistochemistry; Max, maximum; MCL, mantle cell lymphoma; Min, minimum;

Tecartus was administered to patients as a single intravenous infusion at a target dose of 2 × 106 anti-CD19 CAR T cells/kg (maximum permitted dose: 2 × 108 cells) after lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously, both given on the 5th, 4th, and 3rd day before treatment. Bridging chemotherapy between leukapheresis and lymphodepleting chemotherapy was permitted to control disease burden.

For patients treated with Tecartus, the median time from leukapheresis to product release was 13 days (range: 9 to 20 days) and the median time from 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 × 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.

An 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). Results in the ITT set are shown in Table 5.

Table 5 Summary of efficacy results for ZUMA-2

Category

All leukapheresed a(ITT)

(N = 74)

Objective response rate (ORR), n (%) [95% CI]

62 (84%) [73.4, 91.3]

CR n (%) [95% CI]

44 (59%) [47.4, 70.7]

PR n (%) [95% CI]

18 (24%) [15.1, 35.7]

Duration of response (DOR)b

Median in months [95% CI]

NR [10.4, NE]

Range c in months

0.0+, 35.0+

Ongoing responses, CR+PR, CR, n (%) d

32 (43%), 30 (41%)

Progression free survival

Median, months [95% CI]

16.2 [9.9, NE]

Overall survival

Median, months [95% CI]

NR [24.6, NE]

6 month OS (%) [95% CI]

83.6 [72.9, 90.3]

12 month OS (%) [95% CI]

76.6 [65.1, 84.8]

24 month OS (%) [95% CI]

66.5 [52.8, 77.1]

Median Follow-up in months (min, max)

16.8 [7.2, 37.6]

CI, confidence interval; CR, complete remission; ITT, intent to treat; NE, not estimable; NR, not reached; OS, overall survival; PR, partial remission.

a Of the 74 patients that were enrolled (i.e. leukapheresed), 69 patients received lymphodepleting chemotherapy, and 68 patients received Tecartus.

b Among all responders. DOR is measured from the date of first objective response to the date of progression or death.

c A + sign indicates a censored value.

d At the data cutoff date. Percentages are calculated using the total number of patients in the analysis set as the denominator.

Figure 1 Kaplan Meier DOR in the intent to treat set

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Tecartus in all subsets of the paediatric population in treatment of mantle cell lymphoma (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called 'conditional approval' scheme.

This means that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Following infusion of Tecartus, 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 the infusion.

The number of anti-CD19 CAR T cells in blood was associated with objective response (CR or PR) (Table 6).

Table 6 Kinetic parameters of autologous anti-CD19-transduced CD3+ cells in ZUMA-2

Number of anti-CD19 CAR T cell

Responding patients

(CR or PR)

Non-responding patients

P-Value

(N=63)

(N=5)

Peak (cells/μL)

Median [min; max], n

97.52 [0.24, 2589.47], 62

0.39 [0.16, 22.02], 5

0.0020

AUC0–28 (cells/μL·days)

Median [min; max], n

1386.28 [3.83 to 2.77 × 104], 62

5.51 [1.81, 293.86], 5

0.0013

P-value is calculated by Wilcoxon test

Median peak anti-CD19 CAR T-cell values were 74.08 cells/μL in patients ≥65 years of age (n=39) and 112.45 cells/μL in patients <65 years of age (n=28). Median anti-CD19 CAR T-cell AUC values were 876.48 cells/μL∙day in patients ≥65 years of age and 1640.21 cells/μL∙day in patients <65 years of age.

Gender had no significant impact on AUCDay 0–28 and Cmax of Tecartus.

Studies of Tecartus in patients with hepatic and renal impairment were not conducted.

5.3 Preclinical safety data

Tecartus comprises engineered human T cells; therefore, there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human product. Hence, traditional toxicology studies used for medicinal product development were not performed.

No carcinogenicity or genotoxicity studies have been conducted.

No studies have been conducted to evaluate the effects of this treatment on fertility, reproduction, and development.

6. Pharmaceutical particulars
6.1 List of excipients

Cryostor CS10

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

Tecartus is stable for 1 year when stored frozen in the vapour phase of liquid nitrogen (≤ − 150°C).

Tecartus is stable at room temperature (20 °C to 25 °C) for up to 3 hours after thawing. However, Tecartus infusion should begin within 30 minutes of thaw completion and the total infusion time should not exceed 30 min. Thawed product should not be refrozen.

6.4 Special precautions for storage

Tecartus must be stored in the vapour phase of liquid nitrogen (≤ − 150 °C) and must remain frozen until the patient is ready for treatment to ensure viable live autologous cells are available for patient administration.

For storage conditions after thawing of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Ethylene-vinyl acetate cryostorage bag with sealed addition tube and two available spike ports, containing approximately 68 mL of cell dispersion.

One cryostorage bag is individually packed in a shipping metal cassette.

6.6 Special precautions for disposal and other handling

Irradiation could lead to inactivation of the product.

Precautions to be taken for the transport and disposal of the medicinal product

Tecartus should be transported within the facility in closed, break-proof, leak-proof containers.

Tecartus contains genetically modified human blood cells. Local guidelines on handling of waste of human-derived material should be followed for unused medicinal products or waste material. All material that has been in contact with Tecartus (solid and liquid waste) should be handled and disposed of in accordance with local guidelines on handling of waste of human-derived material.

Accidental exposure to Tecartus must be avoided. Local guidelines on handling of human-derived material should be followed in case of accidental exposure, which may include washing of the contaminated skin and removal of contaminated clothes. Work surfaces and materials which have potentially been in contact with Tecartus must be decontaminated with appropriate disinfectant.

7. Marketing authorisation holder

Gilead Sciences Ltd

280 High Holborn

London

WC1V 7EE

United Kingdom

8. Marketing authorisation number(s)

PLGB 11972/0045

9. Date of first authorisation/renewal of the authorisation

01/01/2021

10. Date of revision of the text

01/01/2021