Tecartus is a CD19-directed genetically modified autologous T cell immunotherapy indicated for the treatment of:

Mantle Cell Lymphoma

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.

Acute Lymphoblastic Leukemia

Adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

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 2 doses of tocilizumab for use in the event of cytokine release syndrome (CRS) and emergency equipment must be available prior to infusion.

Posology

Each single infusion bag of Tecartus contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL.

Recommended Dosage for MCL

The target dose is 2 × 10⁶ CAR-positive viable T cells per kg body weight, with a maximum of 2 × 10⁸ CAR-positive viable T cells.

Recommended Dosage for ALL

The target dose is 1 × 10⁶ CAR-positive viable T cells per kg body weight, with a maximum of 1 × 10⁸ CAR-positive viable T cells.

Confirm availability of Tecartus prior to starting the lymphodepleting chemotherapy regimen.

Pre-treatment

• MCL: Administer a lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously on each of the fifth, fourth, and third day before infusion of Tecartus.

·         ALL: Administer a lymphodepleting chemotherapy regimen of fludarabine 25 mg/m² intravenously over 30 minutes on the fourth, third, and second day and administer cyclophosphamide 900 mg/m² over 60 minutes on the second day before infusion of Tecartus.

Pre-medication

• Premedicate with acetaminophen/paracetamol and diphenhydramine or another H1-antihistamine approximately 30 to 60 minutes prior to Tecartus infusion.
• Avoid prophylactic use of systemic corticosteroids as it may interfere with the activity of Tecartus.

Monitoring

• Administer Tecartus at a certified healthcare facility.
• Monitor patients at the certified healthcare facility daily for at least 7 days following infusion for signs and symptoms of Cytokine Release Syndrome (CRS), neurologic events and other toxicities. Physicians can consider hospitalisation for the first 7 days  or at the first signs or sympstoms or CRS and/or neurologic events.
• After the first 7 days following the infusion, the patient is to be monitored at the physician’s discretion.
• Patients must remain within proximity of the certified healthcare facility 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 autologous use only. The patient’s identity must match the patient identifiers on the Tecartus cassette and infusion bag. Do not infuse Tecartus if the information on the patient-specific label does not match the intended patient.

Precautions to be taken before handling or administering Tecartus

Tecartus contains human blood cells that are genetically modified with replication-incompetent retroviral vector. Follow universal precautions and local biosafety guidelines for handling and disposal of Tecartus to avoid potential transmission of infectious diseases.

Preparation of Tecartus for infusion

Coordinate the timing of Tecartus thaw and infusion. Confirm the infusion time in advance, and adjust the start time of Tecartus thaw such that Tecartus will be available for infusion when the patient is ready.

• Confirm patient identity: Prior to Tecartus preparation, match the patient’s identity with the patient identifiers on the Tecartus cassette.
• Do not remove the Tecartus infusion bag from the cassette if the patient information on the cassette label does not match the intended patient.
• Once patient identity is confirmed, remove the Tecartus infusion bag from the cassette and check that the patient information on the cassette label matches the patient information on the bag label.
• Inspect the infusion 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 per local guidelines.
• Thaw the infusion bag at approximately 37°C using either a water bath or dry-thaw method until there is no visible ice in the infusion bag.
• Gently mix the contents of the bag to disperse clumps of cellular material. If visible cell clumps remain, continue to gently mix the contents of the bag. Small clumps of cellular material should disperse with gentle manual mixing. Do not wash, spin down, and/or re-suspend Tecartus in new media prior to infusion.
• Once thawed, Tecartus should be administered within 30 minutes but may be stored at room temperature (20°C to 25°C) for up to three hours.

Administration

·         For autologous use only.

·         Ensure that tocilizumab and emergency equipment are available prior to infusion and during the recovery period.

·         Do NOT use a leukodepleting filter.

·         Central venous access is recommended for the administration of Tecartus.

·         Confirm that the patient’s identity matches the patient identifiers on the Tecartus infusion bag.

·         Prime the tubing with normal saline prior to infusion.

·         Infuse the entire contents of the Tecartus bag within 30 minutes by either gravity or a peristaltic pump. Tecartus is stable at room temperature for up to three hours after thaw.

·         Gently agitate the Tecartus bag during infusion to prevent cell clumping.

·         After the entire contents of the Tecartus bag are infused, rinse the tubing with normal saline at the same infusion rate to ensure all product is delivered.

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

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 must be kept for a period of 10 years.

Autologous use

Tecartus is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Before infusion, the patient’s identity must match the patient identifiers on the Tecartus infusion bag and cassette. Do not infuse Tecartus if the information on the patient specific cassette label does not match the intended patient’s identity.

General

Warnings and precautions of lymphodepleting chemotherapy must be considered.

Monitoring after infusion

Patients must be monitored daily for the first 7 days following infusion for signs and symptoms of potential CRS, neurologic events and other toxicities. Physicians can consider hospitalisation for the first 7 days post infusion or at the first signs/symptoms of CRS and/or neurologic events. After the first 7 days following infusion, the patient is to be monitored at the physician’s discretion.

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

Reasons to delay treatment

Due to the risks associated with Tecartus treatment, infusion must 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 must be administered again (see section 4.2)

Serological testing

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

Blood, organ, tissue and cell donation

Patients treated with Tecartus must 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 brain metastases confirmed by imaging.  In ALL, asymptomatic patients with a maximum of CNS-2 disease (defined as white blood cells <5/µL in cerebral spinal fluid with presence of lymphoblasts) without clinically evident neurological changes were treated with Tecartus, however, data is limited in this population. Therefore, the benefit/risk of Tecartus has not been established in these populations.  

Concomitant disease

Patients with a history of or active CNS disorder or inadequate renal, hepatic, pulmonary, or cardiac function were excluded from the studies. 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 fatal, was  observed with Tecartus with a median time to onset of 3 days (range: 1 to 13 days). Patients must 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 is to 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 2 doses per patient of tocilizumab, an interleukin‑6 (IL‑6) receptor inhibitor, must be on site and available for administration prior to Tecartus infusion.

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) must 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 must be managed by standards of critical care and measures such as echocardiography is to 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) is to 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

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, also known as immune effector cell-associated neurotoxicity syndrome (ICANS), have been observed in patients treated with Tecartus, which could be life-threatening or fatal. The median time to onset was 7 days (range: 1 to 262 days) following Tecartus infusion (see section 4.8).

Patients who experience Grade 2 or higher neurologic toxicity/ICANS must be monitored with continuous cardiac telemetry and pulse oximetry. Provide intensive‑care supportive therapy for severe or life‑threatening neurologic toxicity/ICANS. Non‑sedating, anti‑seizure medicines are to 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/ICANS grading and management guidance

Infections and febrile neutropenia

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

Patients must be monitored for signs and symptoms of infection before, during and after infusion and treated appropriately. Prophylactic antibiotics must 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 must 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 must 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 must 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 must be taken according to 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 must be monitored life‑long for secondary malignancies. In the event that a secondary malignancy occurs, contact the company 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 must 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.

Long-term follow up

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.

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. As a precautionary measure, 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.

Pregnancy

There are no available data with Tecartus use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with Tecartus to assess whether Tecartus can cause fetal harm when administered to a pregnant woman. It is not known if Tecartus has the potential to be transferred to the fetus. Based on the mechanism of action of Tecartus, if the transduced cells cross the placenta, they may cause fetal toxicity, including B cell lymphocytopenia. Therefore, Tecartus is not recommended for women who are pregnant. Pregnancy after Tecartus infusion should be discussed with the treating physician. 

Breast-feeding

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

Pregnancy Testing

Pregnancy status of females with reproductive potential should be verified. Sexually active females of reproductive potential should have a negative pregnancy test prior to starting treatment with Tecartus.

Contraception

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

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

Infertility

There are no data on the effect of Tecartus on fertility.

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving Tecartus are at risk for altered or decreased consciousness or coordination in the eight weeks following Tecartus infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Summary of the safety profile

Mantle cell lymphoma

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 CRS (91%), infections (55%) and encephalopathy (51%).

Serious adverse reactions occurred in 56% of patients. The most common serious adverse reactions included encephalopathy (26%), infections (28%) and CRS (15%).

Grade 3 or higher adverse reactions were reported in 67% of patients. The most common Grade 3 or higher non‑haematological adverse reactions included infections (34%) 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%).

Acute lymphoblastic leukaemia

The safety data described in this section reflect exposure to Tecartus in ZUMA‑3, a Phase 1/2 study in which a total of 100 patients with relapsed/refractory B-cell precursor ALL received a single dose of CAR-positive viable T cells (0.5 × 106, 1 × 106, or 2 × 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 CRS (91%), encephalopathy (57%), and infections (41%).

Serious adverse reactions occurred in 70% of patients. The most common serious adverse reactions included CRS (25%), infections (22%) and encephalopathy (21%).

Grade 3 or higher adverse reactions were reported in 76% of patients. The most common Grade 3 or higher non-haematological adverse reactions included infections (27%), CRS (25%) and encephalopathy (22%).

Tabulated list of adverse reactions

Adverse reactions described in this section were identified in a total of 182 patients exposed to Tecartus in two multi-centre pivotal clinical studies, ZUMA‑2 (n=82) and ZUMA-3 (n=100). 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

Description of selected adverse reactions from ZUMA-2 and ZUMA-3 (n=182)

Cytokine release syndrome

CRS occurred in 91% of patients. Twenty percent (20%) 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 9 days (range: 1 to 63 days). Ninety-seven percent (97%) of patients  recovered from CRS.

The most common signs or symptoms associated with CRS among the patients who experienced CRS included pyrexia (94%), hypotension (64%), hypoxia (32%), chills (31%), tachycardia (27%), sinus tachycardia (23%), headache (22%), fatigue (16%), and nausea (13%).Serious adverse reactions that

may be associated with CRS included hypotension (22%), pyrexia (15%), hypoxia (9%), tachycardia (3%), dyspnoea (2%) and sinus tachycardia. See section 4.4 for monitoring and management guidance.

Neurologic events and adverse reactions

Neurologic adverse reactions occurred in 69% of patients. Thirty‑two percent (32%) of patients experienced Grade 3 or higher (severe or life‑threatening) adverse reactions. The median time to onset was 7 days (range: 1 to 262 days). Neurologic events resolved for 113 out of 125 patients (90.4%) with a median duration of 12 days (range: 1 to 708 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. Ninety-three 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 tremor (32%), confusional state (27%), encephalopathy (27%), aphasia (21%), and agitation (11%). Serious adverse reactions including encephalopathy (15%), aphasia (6%) and confusional state (5%) have been reported in patients administered Tecartus. ICANS was reported as a serious adverse neurologic reaction at a low frequency (2%) in clinical trials. ICANS observed during clinical studies are represented under the adverse reaction encephalopathy. 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.

ICANS was reported in the context of neurologic toxicity in the post marketing setting.

Febrile neutropenia and infections

Febrile neutropenia was observed in 12% of patients after Tecartus infusion. Infections occurred in 87% of the 182 patients treated with Tecartus in ZUMA‑2 and ZUMA-3. Grade 3 or higher (severe, life‑threatening or fatal) infections occurred in 30% of patients including unspecified pathogen, bacterial, fungal and viral infections in 23%, 8%, 2% 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 48% of patients and included neutropenia (34%), thrombocytopenia (27%) and anaemia (15%). See section 4.4 for management guidance.

Hypogammaglobulinaemia

Hypogammaglobulinaemia occurred in 12% 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 in MCL patients. Based on an initial screening assay, 17 patients in ZUMA-2 at any time point tested positive for antibodies; however, a confirmatory orthogonal cell‑based assay demonstrated that all 17 patients in ZUMA-2 were antibody negative at all time points tested. Based on an initial screening assay, 16 patients in ZUMA-3 tested positive for antibodies at any timepoint. Among patients with evaluable samples for confirmatory testing, two patients were confirmed to be antibody-positive after treatment. One of the 2 patients had a confirmed positive antibody result at Month 6. The second patient had a confirmed positive antibody result at retreatment Day 28 and Month 3. 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, were altered in these patients.

There are no data regarding the signs of overdose with Tecartus.

Pharmacotherapeutic group: Other antineoplastic agents, ATC code: L01XL06

Mechanism of action

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

Pharmacodynamic effects

After Tecartus infusion, pharmacodynamic responses were evaluated over a four-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 generally observed within 8 days after infusion, and levels generally returned to baseline within 28 days.

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

Clinical efficacy and safety

Relapsed or Refractory Mantle Cell Lymphoma

A single-arm, open-label, multicenter trial (ZUMA-2; NCT02601313) evaluated the efficacy and safety of a single infusion of Tecartus in adult patients with relapsed or refractory mantle cell lymphoma (MCL) who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton tyrosine kinase inhibitor (BTKi; ibrutinib or acalabrutinib). Eligible patients also had disease progression after their last regimen or refractory disease to their most recent therapy. The study excluded patients with active or serious infections, prior allogeneic hematopoietic stem cell transplant (HSCT), detectable cerebrospinal fluid malignant cells or brain metastases, and any history of central nervous system (CNS) lymphoma or CNS disorders.

Seventy-four patients were leukapheresed, five (7%) of whom did not begin conditioning chemotherapy or receive Tecartus: three (4%) experienced manufacturing failure, one (1%) died of progressive disease, and one (1%) withdrew from the study. One patient (1%) received lymphodepleting chemotherapy but did not receive Tecartus due to ongoing active atrial fibrillation. Sixty-eight of the patients who were leukapheresed received a single infusion of Tecartus, and 60 of these patients were followed for at least six months after their first objective disease response, qualifying them as efficacy-evaluable. Among the 60 efficacy-evaluable patients, 2 × 10⁶ CAR-positive viable T cells/kg were administered to 54 (90%). The remaining six (10%) patients received doses of 1.0, 1.6, 1.8, 1.8, 1.9, and 1.9 × 10⁶ CAR-positive viable T cells/kg.

Of the 60 efficacy-evaluable patients, the median age was 65 years (range: 38 to 79 years), 51 (85%) were male, and 56 (93%) were white. Most (50 patients; 83%) had stage IV disease. Twenty patients (33% of 60) had baseline bone marrow examinations performed per protocol; of these, ten (50%) were negative, eight (40%) were positive, and two (10%) were indeterminate. The median number of prior therapies among all 60 efficacy-evaluable patients was three (range: two to five). Twenty-six (43%) of the patients had relapsed after or were refractory to autologous HSCT. Twenty-one (35%) had relapsed after their last therapy for MCL, while 36 (60%) were refractory to their last therapy for MCL. Among the 60 efficacy-evaluable patients, 14 (23%) had blastoid MCL. Following leukapheresis and prior to administration of Tecartus, 21 (35%) of the 60 patients received bridging therapy. Sixteen (27%) were treated with a BTKi, 9 (15%) with a corticosteroid, and 4 (7%) with both a BTKi and a corticosteroid.

Among the 60 efficacy-evaluable patients, the median time from leukapheresis to product delivery was 15 days (range: 11 to 28 days), and the median time from leukapheresis to product infusion was 27 days (range: 19 to 63 days). The protocol-defined lymphodepleting chemotherapy regimen of cyclophosphamide 500 mg/m² intravenously and fludarabine 30 mg/m² intravenously, both given on each of the fifth, fourth, and third days before Tecartus infusion, was administered to 53 (88%) of the 60 efficacy-evaluable patients. The remaining seven patients (12%) either received lymphodepletion over four or more days or received Tecartus four or more days after completing lymphodepletion. All treated patients received Tecartus infusion on Day 0 and were hospitalized until at least Day 7.

The primary endpoint of objective response rate (ORR) per the Lugano Classification (2014) in patients treated with Tecartus as determined by an independent review committee is provided in Table 7. The median time to response was 28 days (range: 24 to 92 days) with a median follow-up time for DOR of 8.6 months.

Table 7.      Efficacy Results in Adult Patients with Relapsed/Refractory MCL

CI, confidence interval; CR, complete remission; DOR, duration of response; NE, not estimable; NR, not reached; PR, partial remission.

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

b.        A + sign indicates a censored value.

c.        At the time of primary analysis.

Relapsed or Refractory B-cell precursor Acute Lymphoblastic Leukemia

The efficacy of Tecartus was evaluated in ZUMA-3 (NCT02614066), an open-label, single-arm, multicenter trial in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). Eligible patients were adults with primary refractory ALL, first relapse following a remission lasting ≤ 12 months, relapsed or refractory ALL after second-line or higher therapy, or relapsed or refractory ALL at least 100 days after allogeneic stem cell transplantation (HSCT). The study excluded patients with active or serious infections, active graft-vs-host disease or taking immunosuppressive medications within 4 weeks prior to enrollment, and any history of CNS disorders, including CNS-2 disease with neurologic changes and CNS-3 disease irrespective of neurological changes.  Treatment consisted of lymphodepleting chemotherapy (fludarabine 25 mg/m² iv daily on Days -4, -3 and -2; cyclophosphamide 900 mg/m² iv on Day -2) followed by a single intravenous infusion of Tecartus at a target dose of 1 × 10⁶ anti-CD19 CAR T cells/kg (maximum 1 × 10⁸ cells) on Day 0. All treated patients were hospitalized until at least Day 7.

Seventy-one patients were enrolled and leukapheresed; six of these patients did not receive Tecartus due to manufacturing failure, eight patients were not treated primarily due to adverse events following leukapheresis, two patients underwent leukapheresis and received lymphodepleting chemotherapy but were not treated with Tecartus, and one patient treated with Tecartus was inevaluable for efficacy. Among the remaining 54 efficacy-evaluable patients, the median time from leukapheresis to product delivery was 16 days (range: 11 to 39 days) and the median time from leukapheresis to Tecartus infusion was 29 days (range: 20 to 60 days).

Of the 54 patients who were efficacy evaluable, the median age was 40 years (range: 19 to 84 years), 61% were male, and 67% were White, 6% were Asian, 2% were Black or African American, and 2% were American Indian or Alaska Native. At enrollment, 46% had refractory relapse, 26% had primary refractory disease, 20% had untreated second or later relapse, and 7% had first untreated relapse. Among prior therapies, 43% of patients were previously treated with allo-SCT, 46% with blinatumomab, and 22% with inotuzumab. Twenty-six percent of patients were Philadelphia chromosome positive (Ph⁺). Fifty (93%) patients had received bridging therapy between leukapheresis and lymphodepleting chemotherapy to control disease burden.

The efficacy of Tecartus was established on the basis of complete remission (CR) within 3 months after infusion and the duration of CR (DOCR). Twenty-eight (51.9%) of the 54 evaluable patients achieved CR, and with a median follow-up for responders of 7.1 months, the median DOCR was not reached (Table 8). The median time to CR was 56 days (range: 25 to 86 days).  All efficacy evaluable patients had potential follow-up for ≥ 10 months with a median actual follow-up time of 12.3 months (range: 0.3 to 22.1 months). 

Table 8:      Efficacy Results in Adult Patients with Relapsed/Refractory B-cell precursor ALL

CI, confidence interval; CR, complete remission; CRi, complete remission with incomplete blood count recovery; DOR, duration of remission; NE, not estimable; NR, not reached, OCR, overall complete remission; NE, not estimable

a.        Of the 71 patients that were enrolled (and leukapheresed), 57 patients received lymphodepleting chemotherapy, and 55 patients received Tecartus. 54 patients were included in the efficacy evaluable population. 

b.        A + sign indicates a censored value.

Following infusion (target dose of 2 × 10⁶ anti-CD19 CAR T cells/kg) of Tecartus in ZUMA-2, anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by three months. Peak levels of anti-CD19 CAR T cells occurred within the first 15 days after Tecartus infusion. Following infusion (target dose of 1 × 10⁶ anti-CD19 CAR T cells/kg) of Tecartus in ZUMA-3 (Phase 2), anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 6 months. Median anti- CD19 CAR T-cell time to peak was 15 days after Tecartus infusion.

Description of Pharmacokinetics in Adult r/r MCL

The number of anti-CD19 CAR T cells in blood was associated with objective response [complete remission (CR) or partial remission (PR)]. Median peak anti-CD19 CAR T cell level in responders was 102.4 cells/μL (range: 0.2 to 2589.5 cells/μL; n = 51), and in nonresponders was 12.0 cells/μL (range: 0.2 to 1364.0 cells/μL, n = 8). The median AUC_{Day 0-28} in patients with an objective response was 1487.0 cells/μL•days (range: 3.8 to 2.77E+04 cells/μL•days; n = 51) versus 169.5 cells/μL•days in nonresponders (range: 1.8 to 1.17E+04 cells/μL•days; n = 8).

Median peak anti-CD19 CAR T-cell and AUC_0-28 levels in patients who received neither corticosteroids nor tocilizumab (peak: 24.7 cells/μL; AUC_0-28: 360.4 cells/μL•days, n = 18) was similar to patients who received corticosteroids alone (peak: 24.2 cells/μL; AUC_0-28: 367.8 cells/μL•days, n = 2); both groups were lower than patients who received tocilizumab alone (peak: 86.5 cells/μL; AUC_0-28: 1188.9 cells/μL•days, n = 10); the highest exposure was in patients who received both corticosteroids and tocilizumab (peak: 167.2 cells/μL; AUC_0-28: 1996.0 cells/μL•days, n = 37).

Median peak anti-CD19 CAR T-cell values were 74.1 cells/μL in patients ≥ 65 years of age (n = 39) and 112.5 cells/μL in patients < 65 years of age (n = 28). Median anti-CD19 CAR T-cell AUC _{Day 0-28} values were 876.5 cells/μL•day in patients ≥ 65 years of age and 1640.2 cells/μL•day in patients < 65 years of age.

Gender had no significant impact on AUC_{Day 0-28} and C_max of Tecartus.

Description of Pharmacokinetics in Adult r/r B-cell precursor ALL

Median peak anti-CD19 CAR T-cell levels over time by best overall response per independent review was 38.4 cells/μL (range: 1.31 to 1,533.4 cells/μL; n = 32) in patients who had overall complete remission (CR+CRi), and 0.5 cells/μL (range: 0.00 to 183.5 cells/μL, n = 17) in patients who had non-complete remission. The median AUC_0-28 in patients who had overall complete remission (CR+CRi) was 424.0 cells/μL•days (range: 14.12 to 19,390.4 cells/μL•days; n = 32) vs 7.9 cells/μL•days in patients who had non-complete remission (range: 0.00 to  889.0 cells/μL•days; n=17).

Median peak anti-CD19 CAR T-cell and AUC _0-28 levels in patients who received neither corticosteroids nor tocilizumab (peak 5.7 cells/µL; AUC _0-28: 60.7 cells/µL•days, n=11) were higher than patients who received corticosteroids alone (peak: 36.2 cells/ µL; AUC _0-28: 423.1 cells/μL•days, n= 1); both groups were lower than evaluable patients who received tocilizumab alone (peak 11.2 cells/ µL; AUC _0-28: 137.4  cells/μL•days, n=9); the highest exposure was in evaluable patients who received both corticosteroids and tocilizumab (peak: 49.2 cells/µL; AUC _0-28: 454.1 cells/ μL•days, n=34).

Hepatic and renal impairment studies of Tecartus were not conducted.

No carcinogenicity or genotoxicity studies have been conducted with Tecartus. No studies have been conducted to evaluate the effects of Tecartus on fertility.

Cryostor CS10 (contains DMSO)

Sodium chloride

Human albumin

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

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. Thawed product must not be refrozen.

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

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

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

Irradiation could lead to inactivation of the product.

Precautions to be taken before handling or administering the medicinal product

Tecartus must be transported within the facility in closed, break‑proof, leak‑proof containers.

This medicinal product 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.

Precautions to be taken for the disposal of the medicinal product

Unused medicinal product and all material that has been in contact with Tecartus (solid and liquid waste) must be handled and disposed of as potentially infectious waste in accordance with local guidelines on the handling of waste of human-derived material.

Accidental exposure

In case of accidental exposure to Tecartus local guidelines on handling of human‑derived material must be followed. Work surfaces and materials which have potentially been in contact with Tecartus must be decontaminated with appropriate disinfectant.