AUCATZYL Dispersion for infusion Ref.[115571] Active ingredients: Obecabtagene autoleucel

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 30 years after the expiry date of the product.

Autologous use

Aucatzyl is intended solely for autologous use and must not, under any circumstances, be administered to other patients. Aucatzyl must not be administered if the information on the product labels and RfIC do not match the patient's identity.

General

The availability of Aucatzyl must be confirmed before starting the lymphodepleting chemotherapy regimen.

Patients should be clinically re-assessed prior to administration of lymphodepleting chemotherapy and Aucatzyl to ensure that there are no reasons to delay therapy.

Warnings and precautions of lymphodepleting chemotherapy must be considered.

Reasons to delay or discontinue treatment

Aucatzyl should not be administered to patients with clinically significant active systemic infections, in the presence of significant safety concerns following lymphodepleting chemotherapy or patients who require supplementary oxygen for treatment of their medical condition (refer to section 4.2).

Cytokine release syndrome (CRS)

CRS was reported following treatment with Aucatzyl (see section 4.8). CRS is more probable in patients with a high tumour burden. CRS may appear up to 23 days post-infusion. Severe adverse reactions have been reported after Aucatzyl infusion. In general, CRS following CAR T treatment can be life-threatening.

Patients should be counselled to seek immediate medical attention should signs or symptoms of CRS occur at any time.

At the first sign of CRS, the patient should be timely evaluated for hospitalisation and for management as per guidance in Table 2 and for administration of supportive care. Use of myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) should be avoided during CRS, given the potential to worsen CRS symptoms.

Patients should be monitored daily for 14 days after the first infusion for signs and symptoms of potential CRS. The most common manifestations of CRS included fever, hypotension, and hypoxia. Frequency of monitoring after the first 14 days should be carried out at the physician's discretion and should be continued for at least 4 weeks after infusion (see section 4.2).

CRS should be managed based on the patient's clinical presentation and according to the CRS grading and management guidance provided in Table 2. At the first sign of CRS, treatment with tocilizumab or tocilizumab and corticosteroids should be instituted.

Ensure 24-hour immediate access to tocilizumab is available for each patient prior to infusion of Aucatzyl. In the exceptional case where tocilizumab is not available, suitable alternative anti-IL-6 therapy (e.g., siltuximab) to treat CRS must be available prior to infusion.

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

Resolution of any ongoing grade >2 CRS to grade 1 or less should be ensured prior to initiating the second split infusion/dose.

Table 2. CRS grading and management guidance:

BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; IL = interleukin; N/A = not applicable; NCI = National Cancer Institute.
^a Based on ASTCT/ASBMT = American Society for Transplantation and Cellular Therapy/American Society for Blood and Marrow Transplantation Consensus Grading and NCI CTCAE Version 5.0.
^b See Prescribing Information for each agent.
^c After each dose, assess need for subsequent dosing.

Immune effector cell-associated neurotoxicity syndrome (ICANS)

Severe, life-threatening or fatal neurologic adverse reactions, also known as ICANS, have been observed in patients treated with Aucatzyl (see section 4.8).

Patients should be monitored for signs and symptoms of ICANS and they should be counselled to seek immediate medical attention should signs or symptoms of neurotoxicity occur at any time. Transient neurological symptoms can be heterogeneous and include encephalopathy, aphasia, lethargy, headache, tremor, ataxia, sleep disorder, anxiety, agitation and signs of psychosis. Serious reactions include seizures and depressed level of consciousness.

Rule out other causes of neurologic signs or symptoms. Use caution when prescribing medicinal product that can cause central nervous system (CNS) depression, aside from anti-convulsant therapy which should be managed according to ICANS in Table 3. Conduct an electroencephalogram (EEG) for seizure activity for ≥ grade 2 neurotoxicity.

If concurrent CRS is suspected during the ICANS event, the following treatments should be administered:

• Corticosteroids according to the more aggressive intervention based on the CRS and ICANS grades in Table 2 and Table 3.
• Tocilizumab according to CRS grade in Table 2.
• Anti-seizure treatment according to ICANS in Table 3.

If ICANS is suspected, a neurology assessment and grading should be conducted at least twice a day to include cognitive assessment and motor weakness. A neurology consultation should be provided at the first sign of neurotoxicity, as well as MRI imaging with and without contrast (or brain CT if MRI is not feasible) for ≥ grade 2 neurotoxicity.

If ICANS is suspected, manage according to the recommendations in Table 3. Intravenous hydration is recommended in patients as an aspiration precaution. Provide intensive care supportive therapy for severe or life-threatening neurologic toxicities.

Appropriate therapeutic treatment should be provided, and resolution of any ongoing grade >1 ICANS should be ensured prior to initiating the second split infusion/dose (see section 4.2).

Table 3. ICANS adverse reaction grading and management guidance (all grades):

ASTCT = American Society for Transplantation and Cellular Therapy; ASBMT = American Society for Blood and Marrow Transplantation; CAT = chimeric antigen receptor; CRS = cytokine release syndrome; CT=computerized tomography; ICE = immune effector cell‑associated encephalopathy; EEG = electroencephalogram; ICANS = immune effector cell-associated neurotoxicity syndrome; ICP = intracranial pressure; ICU = intensive care unit; IL = interleukin; IV = intravenous; MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network.
^a Adapted from ASTCT/ASBMT ICANS Consensus and NCCN Guidelines v1.2025 on Management of CAR T-Cell-Related Toxicities. ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral oedema) not attributable to any other cause.
^b Depressed level of consciousness should be attributable to no other cause (e.g., no sedating medicinal product).
^c Repeat tocilizumab every 8 hours as needed if not responsive to IV fluids or increasing supplemental oxygen. Limit to a maximum of 3 doses in a 24-hour period; maximum total of 4 doses. In the case of tocilizumab unavailability suitable alternative anti-IL-6 therapy (e.g., siltuximab) must be administered.

Prolonged cytopenias

In the FELIX study, grade 3 or higher prolonged cytopenias following Aucatzyl infusion occurred very commonly and included thrombocytopenia and neutropenia (see section 4.8). Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and Aucatzyl infusion. The majority of patients who experienced cytopenias grade 3 at month 1 following Aucatzyl treatment resolved to grade 2 or below at month 3.

Patient blood counts should be monitored after Aucatzyl infusion. Prolonged cytopenias should be managed according to institutional guidelines.

Severe infections

Aucatzyl should not be administered to patients with clinically significant active systemic infections. Patients should be monitored for signs and symptoms of infection before, during and after Aucatzyl infusion and treated appropriately. Appropriate prophylactic and therapeutic treatment for infections should be provided (see section 4.2) and complete resolution of severe intercurrent infection should be ensured prior to initiating the second dose.

Severe infections, including life-threatening or fatal infections occurred in patients after receiving Aucatzyl. Grade 3 or higher febrile neutropenia was observed in patients after Aucatzyl infusion (see section 4.8) and may be concurrent with CRS. In the event of febrile neutropenia, the infection should be evaluated and managed 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) 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., HBV reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure, and death.

Hypogammaglobulinaemia

Hypogammaglobulinaemia is caused by B cell aplasia and has been seen as a consequence of depletion of normal B cells by CD19 CAR T therapy. Hypogammaglobulinaemia was reported in patients treated with Aucatzyl (see section 4.8).

Hypogammaglobulinaemia predisposes patients to become more susceptible to infections. Immunoglobulin levels should be monitored after treatment with Aucatzyl and managed per institutional guidelines including infection precautions, antibiotics or antiviral prophylaxis and immunoglobulin replacement.

Haemophagocytic lymphohistiocytosis and macrophage activation syndrome

HLH/MAS syndrome was reported following treatment with Aucatzyl (see section 4.8). Treatment should be administered per institutional standards.

Prior stem cell transplantation (GvHD)

It is not recommended that patients receive Aucatzyl within 3 months of undergoing an allogeneic haematopoietic stem cell transplantation (HSCT) because of the risk of Aucatzyl worsening GvHD.

Leukapheresis for Aucatzyl manufacturing should be performed at least 3 months after allogeneic HSCT.

Secondary malignancies including of T cell origin

Patients treated with Aucatzyl may develop secondary malignancies. T cell malignancies have been reported following treatment of haematological malignancies with a BCMA- or CD19-directed CAR T cell therapy. T cell malignancies, including CAR-positive malignancies, have been reported within weeks and up to several years following administration of a CD19- or BCMA-directed CAR T-cell therapy. There have been fatal outcomes.

Patients should be monitored life-long for signs of secondary malignancies. In the event that a secondary malignancy occurs, the company should be contacted to obtain instructions on the collection of patient samples for testing.

Tumour lysis syndrome (TLS)

TLS, which may be severe, has been observed in the FELIX trial. To minimise the risk of TLS, patients with high tumour burden should receive TLS prophylaxis as per standard guidelines prior to Aucatzyl infusion. Signs and symptoms of TLS after Aucatzyl infusions must be monitored, and events managed according to standard guidelines.

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis, may occur due to DMSO in Aucatzyl.

Transmission of an infectious agent

Although Aucatzyl is tested for sterility and mycoplasma, a risk of transmission of infectious agents exists. Healthcare professionals administering Aucatzyl must therefore, monitor patients for signs and symptoms of infection after treatment and treat appropriately, if needed.

Interference with virological testing

Due to limited and short spans of identical genetic information between the lentiviral vector used to create Aucatzyl and HIV, some HIV nucleic acid tests may give a false positive result.

Serological testing

Screening for HBV, HCV, HIV and other infectious agents must be performed in accordance with clinical guidelines before collection of cells for manufacturing (see section 4.2). Leukapheresis material from patients with active HIV, active HBV, or active HCV infection will not be accepted for manufacturing.

Blood, organ, tissue and cell donation

Patients treated with Aucatzyl must not donate blood, organs, tissues and cells for transplantation. This information is provided in the Patient Card which must be given to the patient after treatment.

Active CNS lymphoma

There is limited experience of use of this medicinal product in patients with active CNS lymphoma defined as brain metastases confirmed by imaging. 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 Aucatzyl, however, data are limited in this population. Therefore, the benefit/risk of Aucatzyl 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.

Prior treatment with anti-CD19 therapy

Aucatzyl is not recommended if the patient has CD19-negative disease or an unconfirmed CD19 status.

Long-term follow-up

Patients are expected to be enrolled in a long-term follow-up study or registry in order to better understand the long-term safety and effectiveness of Aucatzyl.

Sodium content

This medicinal product contains 1 131 mg sodium per target dose, equivalent to 57% of the World Health Organization (WHO) recommended maximum daily intake of 2 g sodium for an adult.

Potassium content

This medicinal product contains 39 mg potassium per target dose, equivalent to 1% of the WHO recommended minimum daily intake of 3.51 g potassium for an adult.

No interaction studies have been performed.

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

Administration of tocilizumab or corticosteroids for the treatment of CRS and ICANS did not affect the rate or extent of expansion and persistency.

Live vaccines

The safety of immunisation with live viral vaccines during or following treatment with Aucatzyl has not been studied. As a precautionary measure, vaccination with live vaccines is not recommended for at least 6 weeks prior to the start of lymphodepletion chemotherapy, during Aucatzyl treatment, and until immune recovery following treatment.

Women of childbearing potential / Contraception in males and females

The pregnancy status of women of childbearing potential must be verified before starting Aucatzyl treatment. Aucatzyl is not recommended for women of childbearing potential who are not using contraception.

See the prescribing information for lymphodepleting therapy for information on the need for effective contraception in patients who receive the lymphodepleting chemotherapy.

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

Pregnancy

There is a limited amount of data from the use of obecabtagene autoleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with Aucatzyl to assess whether it can cause foetal harm when administered to a pregnant woman (see section 5.3).

It is not known if obecabtagene autoleucel 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, Aucatzyl is not recommended for women who are pregnant. Pregnant women must be advised on the potential risks to the foetus.

Pregnancy after Aucatzyl therapy must be discussed with the treating physician.

Assessment of immunoglobulin levels and B cells in newborn infants of mothers treated with Aucatzyl must be considered.

Breast-feeding

It is unknown whether obecabtagene autoleucel cells are excreted in human milk or transferred to the breast-feeding child. A risk to the breast-fed infant cannot be excluded. Breast-feeding women must be advised by the treating physician of the potential risk to the breast-fed child.

Fertility

There are no clinical data on the effect of Aucatzyl on fertility. Effects on male and female fertility have not been evaluated in animal studies.

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

Due to the potential for neurological events, including altered mental status or seizures, patients should refrain from driving or operating heavy or potentially dangerous machines until at least 8 weeks after infusion or until resolution of the neurological event by the treating physician.

Summary of the safety profile

The most common non-laboratory adverse reactions of any grade included CRS (68.5%), infections - pathogen unspecified (44.9%), musculoskeletal pain (31.5%), pyrexia (29.1%), pain (27.6%), nausea (26.0%), diarrhoea (25.2%), headache (23.6%), fatigue (22.0%), and haemorrhage (21.3%).

The most common non-laboratory grade 3 or higher adverse reactions were infections - pathogen unspecified (24.4%), febrile neutropenia (23.6%), viral infections (13.4%), and bacterial infectious disorders (11.0%).

The most common serious adverse reactions of any grade included infections - pathogen unspecified (20.5%), febrile neutropenia (13.4%), ICANS (9.4%), CRS (7.9%), sepsis (7.9%) and pyrexia (7.1%).

The most common grade 3 or 4 laboratory abnormalities included neutropenia (98.4%), leucocytes decreased (97.6%), lymphocytes decreased (95.3%), thrombocytopenia (77.2%), and anaemia (65.4%).

The lymphodepleting chemotherapy prior to Aucatzyl administration also contributes to the laboratory abnormalities.

Tabulated list of adverse reactions

Table 4 summarises the adverse reactions in a total of 127 patients exposed to Aucatzyl in the Phase Ib and Phase II FELIX study. These reactions are presented by Medical Dictionary for Regulatory Activities system organ class and by frequency. Frequencies are defined as: very common (≥1/10), and common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 4. Adverse drug reactions identified with Aucatzyl:

^a Frequency based on grade 3 or higher laboratory parameter.
^b Delirium includes agitation, delirium, disorientation, hallucination, irritability.
^c Encephalopathy includes aphasia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dysarthria, dysgraphia, encephalopathy, lethargy, memory impairment, mental status changes, posterior reversible encephalopathy syndrome, somnolence.

Description of selected adverse reactions

Cytokine release syndrome

CRS was reported in 68.5% of patients, including grade 3 CRS in 2.4% of patients. The median time to onset of CRS of any grade was 8 days following the first infusion (range: 1-23 days) with a median duration of 5 days (range: 1-21 days).

In the FELIX study, 80% of patients who experienced CRS had ≥5% blasts in their BM at the time of lymphodepletion, with 39% of patients presenting with >75% blast in their BM. The most common manifestations of CRS among patients who experienced CRS included fever (68.5%), hypotension (25.2%) and hypoxia (11.8%).

The majority of patients experienced CRS after the first but prior to the second infusion of Aucatzyl. Of the 87 patients who experienced CRS, for 64.3% CRS occurred after the first, but prior to the second infusion of Aucatzyl with a median time to onset of 6 days (range: 3-9 days). Median time to onset after the second infusion was 2 days (range: 1-2 days). The primary treatment for CRS was tocilizumab (75.9%), with patients also receiving corticosteroids (22.9%) and other anti-cytokine therapies (13.8%), see section 4.4.

Haemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS)

HLH/MAS, including severe and life-threatening reactions may occur following treatment with Aucatzyl. HLH/MAS was reported in 1.6% of patients and included grade 3 and grade 4 events with a time of onset at day 22 and day 41, respectively. One patient experienced a concurrent ICANS event after Aucatzyl infusion (see section 4.4).

Immune effector cell-associated neurotoxicity syndrome

ICANS was reported in 29 patients (22.8%). Grade ≥ 3 ICANS occurred in 9 patients (7.1%) following treatment with Aucatzyl. One patient (1.1%) experienced grade 4 ICANS. The most common symptoms included confusional state (9.4%) and tremor (4.7%).

In the FELIX study, most patients who experienced ICANS (89.7%) and all patients who experienced grade ≥3 ICANS had >5% blasts in their BM at the time of lymphodepleting treatment. Among the patients who experienced grade ≥3 ICANS, 5 patients presented with >75% blasts in their BM.

The median time to onset for ICANS events was 12 days (range: 1-31 days) with a median duration of 8 days (range: 1-53 days). The median time to onset for ICANS events after the first infusion and before the second infusion was 8 days (range: 1-10 days) and 6.5 days (range: 2-22 days) after the second infusion. Onset of ICANS after the second infusion occurred in the majority of patients (62.1%).

Twenty-four patients received treatment for ICANS. All treated patients received high-dose corticosteroids and 12 patients received anti-epileptics prophylactically (see section 4.4).

Prolonged cytopenia

Among the safety set (N=127), median time from day of Aucatzyl infusion to neutrophil recovery to ≥0.5 × 10⁹/L and ≥1 × 10⁹/L (based on counts at screening) was 0.8 months and 1.9 months, respectively.

Grade ≥3 cytopenias at month 1 following infusion were observed in 68.5% of patients and included neutropenia (57.5%) and thrombocytopenia (52.0%). Grade 3 or higher cytopenias at month 3 following Aucatzyl infusion was observed in 21.3% of patients and included neutropenia (13.4%) and thrombocytopenia (13.4%) (see section 4.4).

Infections

Infections following Aucatzyl infusion (all grades) occurred in 70.9% of patients. Grade 3 or 4 non-COVID-19 infections occurred in 44.9% of patients including unspecified pathogen (24.4%), bacterial (11.0%), sepsis (10.2%), viral (5.5%), and fungal (4.7%) infections.

Fatal infections of unspecified pathogen were reported in 0.8% of patients. Fatal sepsis occurred in 3.9% of patients.

Grade 3 or higher febrile neutropenia was observed in 23.6% of patients after Aucatzyl infusion and may be concurrent with CRS (see section 4.4).

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 9.4% of patients, treated with Aucatzyl including 2 cases (1.6%) of grade 3 hypogammaglobulinaemia (see section 4.4).

Immunogenicity

The humoral immunogenicity of Aucatzyl was measured using an assay for the detection of anti-drug antibodies against Aucatzyl. In the FELIX study, 8.7% of patients tested positive for anti-CD19 CAR antibodies pre-infusion. Treatment induced anti-CD19 CAR antibodies were detected in 1.6% of patients. There is no evidence that the presence of pre-existing or post-infusion anti-CD19 CAR antibodies affect the effectiveness, safety, initial expansion and persistency of Aucatzyl.

The cellular immunogenicity of Aucatzyl was measured using an enzyme-linked immunosorbent spot assay for the detection of T cell responses, measured by production of interferon gamma (IFN-γ), to the full length anti-CD19 CAR. Only 3.1% (3/96) of patients tested positive in the cellular immunogenicity readout (IFN-γ) post-infusion. There is no evidence that the cellular immunogenicity affects the kinetics of initial expansion and persistence of Aucatzyl, or the safety or effectiveness of Aucatzyl.

Secondary malignancies

There have been cases of the following adverse reaction(s) reported after treatment with other CAR T cell products, which might also occur after treatment with Aucatzyl: secondary malignancy of T cell origin.

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 the national reporting system listed in Appendix V.

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