Ciltacabtagene autoleucel

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

Patients with clinically significant active infection should not start ciltacabtagene autoleucel treatment until the infection is controlled.

There is currently no experience with manufacturing ciltacabtagene autoleucel for patients testing positive for HIV, active HBV, or active HCV. Screening for HBV, HCV and HIV and other infectious agents must be performed before collection of cells for manufacturing.

There are no available data on the use of ciltacabtagene autoleucel in pregnant women. No reproductive and developmental toxicity animal studies have been conducted with ciltacabtagene autoleucel. It is not known whether ciltacabtagene autoleucel has the potential to be transferred to the foetus and cause foetal toxicity.

Therefore, ciltacabtagene autoleucel is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised there may be risks to the foetus. Pregnancy after ciltacabtagene autoleucel therapy should be discussed with the treating physician.

Pregnant women who have received ciltacabtagene autoleucel may have hypogammaglobulinaemia. Assessment of immunoglobulin levels in newborns of mothers treated with ciltacabtagene autoleucel should be considered.

It is unknown whether ciltacabtagene autoleucel is excreted in human milk. Women who are breast-feeding should be advised of the potential risk to the breast-fed infant. Following administration of ciltacabtagene autoleucel, the decision to consider breast-feeding should be discussed with the treating physician.

Women of childbearing potential/Contraception in males and females

Pregnancy status for females of childbearing potential should be verified prior to starting treatment with ciltacabtagene autoleucel. There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with ciltacabtagene autoleucel.

In clinical trials, female patients of childbearing potential were advised to practice a highly effective method of contraception, and male patients with partners of childbearing potential or whose partners were pregnant were instructed to use a barrier method of contraception, until one year after the patient has received ciltacabtagene autoleucel.

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

Fertility

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

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

Due to the potential for neurologic events, patients receiving ciltacabtagene autoleucel are at risk for altered or decreased consciousness or coordination in the 8 weeks following ciltacabtagene autoleucel infusion. Patients should be advised to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurological symptoms.

Summary of the safety profile

The safety of ciltacabtagene autoleucel was evaluated in 179 adult patients with multiple myeloma infused with ciltacabtagene autoleucel in two open label clinical trials: Study MMY2001 (N=106), which included patients from the main Phase 1b/2 cohort (United States; n=97,) and an additional cohort (Japan; n=9), and Study MMY2003 (n=73).

The most common ciltacabtagene autoleucel adverse reactions (≥20%) were neutropenia (91%), CRS (88%), pyrexia (88%), thrombocytopenia (73%), anaemia (72%), leukopenia (54%), lymphopenia (45%), musculoskeletal pain (43%), hypotension (41%), fatigue (40%), transaminase elevation (37%), upper respiratory tract infection (32%), diarrhoea (28%), hypocalcaemia (27%), hypophosphataemia (26%), nausea (26%), headache (25%), cough (25%), tachycardia (23%), chills (23%), encephalopathy (22%), decreased appetite (22%), oedema (22%), and hypokalaemia (20%).

Serious adverse reactions occurred in 46% of patients; serious adverse reactions reported in ≥2% of patients were CRS (15%), neutropenia (6%), ICANS (4%), sepsis (3%), thrombocytopenia (3%), febrile neutropenia (3%) and pneumonia (3%).

The most common (≥5%) Grade ≥3 non-haematological adverse reactions was transaminase elevation (16%), hypotension (8%), hypophosphataemia (8%), Gamma-glutamyltransferase increased (7%), pneumonia (7%), sepsis (6%), pyrexia (6%), fatigue (6%), hypocalcaemia (5%) and hypoxia (5%).

The most frequent (≥20%) Grade ≥3 haematological abnormalities were neutropenia (90%), anaemia (58%), leukopenia (53%), thrombocytopenia (52%) and lymphopenia (43%).

Tabulated list of adverse reactions

Table 1 summarises the adverse reactions that occurred in patients receiving ciltacabtagene autoleucel. Within each system organ class, the adverse reactions are ranked by frequency. Within each frequency grouping, where relevant, adverse reactions are presented in order of decreasing seriousness. using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1. Adverse reaction in patients with multiple myeloma treated with ciltacabtagene autoleucel (N=179):

Adverse reactions are reported using MedDRA version 23.0

^# Contains fatal outcome(s).
^* Based on grouped term.
¹ Sepsis includes bacteraemia, septic shock.
² Coagulopathy includes activated partial thromboplastin time prolonged, coagulopathy, disseminated intravascular coagulation, fibrin D dimer increased, international normalised ratio increased, prothrombin level increased, and prothrombin time prolonged.
³ Delirium includes agitation, delirium, hallucination, irritability, and restlessness.
⁴ Personality changes includes apathy, flat affect, and reduced facial expression.
⁵ Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, lethargy, noninfective encephalitis, psychomotor retardation and sleep disorder.
⁶ Motor dysfunction includes bradykinesia, cogwheel rigidity, dysgraphia, micrographia, muscle rigidity, myoclonus, parkinsonism, posture abnormal, and stereotypy.
⁷ Aphasia includes dysarthria, slow speech, and speech disorder.
⁸ Paresis includes cranial nerve paralysis.
⁹ Ataxia includes ataxia, balance disorder, and gait disturbance.
¹⁰ Neuropathy peripheral includes peripheral motor/sensory neuropathy.
¹¹ Cardiac arrhythmias includes supraventricular/ventricular tachycardia.
¹² Haemorrhage includes conjunctival haemorrhage, epistaxis, haemoptysis, post procedural haemorrhage, pulmonary haemorrhage, retinal haemorrhage, and subarachnoid haemorrhage.
¹³ Dyspnoea includes dyspnoea, respiratory distress and respiratory failure.
¹⁴ Renal failure includes acute kidney injury, blood creatinine increased, and chronic kidney disease.
¹⁵ Oedema includes oedema generalised, peripheral and localised

Description of selected adverse reactions

Cytokine release syndrome

CRS was reported in 88% of patients (n=157); 83% (n=149) of patients had CRS events that were Grade 1 or Grade 2, 4% (n=7) of patients had Grade 3 or Grade 4 CRS events and <1% (n=1) of patients had a Grade 5 CRS event. Ninety-nine percent of patients (n=155) recovered from CRS. The duration of CRS was ≤14 days for all but one patient, who had a duration of CRS of 97 days, complicated by secondary HLH with a subsequent fatal outcome. The most frequent (≥10%) signs or symptoms associated with CRS included pyrexia (85%), hypotension (34%), Aspartate aminotransferase (AST) increased (18%), and Alanine aminotransferase (ALT) increased (13%).

Neurologic toxicities

Neurologic toxicity occurred in 20% of patients (n=35); 7% (n=12) of patients had Grade 3 or Grade 4 neurologic toxicity and <1% (n=1) of patients had Grade 5 neurologic toxicity. ICANS occurred in 13% of patients (n=24), with 2% (n=4) experiencing Grade 3 or 4 ICANS. Symptoms included aphasia, slow speech, dysgraphia, encephalopathy, depressed level of consciousness and confusional state.

Adverse reactions of neurologic toxicity after recovery from CRS and/or ICANS occurred in 11% of patients (n=20). A variety of symptoms with varying severity were observed, including disturbances in consciousness, coordination and balance disturbances, movement disorders, mental impairment disorders, cranial nerve disorders, and peripheral neuropathies. Nine of these 20 patients had also previously experienced ICANS.

Three percent of patients (n=6; all male) experienced a cluster of movement and neurocognitive adverse reactions including movement (e.g., micrographia, tremors), cognitive (e.g., memory loss, disturbance in attention), and personality change (e.g., reduced facial expression, flat affect), often with subtle onset (e.g., micrographia, flat affect), that in some patients progressed to an inability to work or care for oneself. The median time to first symptom onset was 33 days (range: 14 to 108 days). These patients all presented a combination of two or more factors such as high tumour burden at baseline (bone marrow plasma cell ≥80% or serum M-spike ≥5 g/dL or serum free light chain ≥5,000 mg/L), prior Grade 2 or higher CRS, prior ICANS, and high CAR-T cell expansion and persistence. Treatment with levodopa/carbidopa (n=2), was not effective in improving symptomatology in these patients. One of these six patients experienced a fatal outcome attributed to neurotoxicity, and two patients had ongoing neurotoxicity at the time of death; the deaths were due to infection. Of the remaining patients who reported adverse reactions of neurologic toxicity after recovery from CRS and/or ICANS, two patients had a fatal outcome with ongoing neurotoxicity at the time of death; the deaths were due to respiratory failure and sepsis respectively.

Prolonged cytopenia

Grade 3 or 4 cytopenias at Day 1 after dosing, not resolved to Grade 2 or lower by Day 30 following ciltacabtagene autoleucel infusion, included, thrombocytopenia (37%), neutropenia (35%), and lymphopenia (22%). After Day 60 following ciltacabtagene autoleucel, 26%, 13%, and 3% of patients had an occurrence of Grade 3 or 4 lymphopenia, neutropenia, and thrombocytopenia respectively, after initial recovery of their Grade 3 or 4 cytopenia.

Table 2 lists the incidences of Grade 3 or Grade 4 cytopenias occurring after dosing not resolved to Grade 2 or lower by Day 30 and Day 60, respectively.

Table 2. Incidences of prolonged cytopenias following treatment with ciltacabtagene autoleucel (N=179):

^a The laboratory result with the worst toxicity grade is used for a calendar day. Recovery definition: must have 2 consecutive Grade ≤2 results on different days if recovery period ≤10 days.
Notes: Lab results assessed after Day 1 until Day 100 are included in the analysis.
Thrombocytopenia: Grade ¾ – Platelets count <50,000 cells/µL.
Neutropenia: Grade ¾ - Neutrophil count <1,000 cells/µL.
Lymphopenia: Grade ¾ - Lymphocytes count <0.5×10⁹ cells/L.
Percentages are based on the number of treated patients.

Serious infections

Infections occurred in 45% of patients (n=80); 14% of patients (n=25) experienced Grade 3 or Grade 4 infections, and fatal infections occurred in 3% of patients (n=5)-lung abscess, sepsis, septic shock, COVID-19 pneumonia and Clostridium difficile colitis. The most frequently reported (≥2%) Grade 3 or higher infections were pneumonia and sepsis. Febrile neutropenia was observed in 9% of patients with 3% experiencing serious febrile neutropenia.

Hypogammaglobulinaemia

Hypogammaglobulinaemia occurred in 9% of patients, with 1% of patients experiencing Grade 3 or Grade 4 hypogammaglobulinaemia.

Immunogenicity

The immunogenicity of ciltacabtagene autoleucel has been evaluated using a validated assay for the detection of binding antibodies against ciltacabtagene autoleucel pre-dose, and at multiple timepoints post-infusion. In the pooled studies (N=179), 37 of 175 (21.1%) patients with appropriate samples were positive for treatment-emergent anti-CAR antibodies. There was no clear evidence that the observed anti-CAR antibodies had an impact on the safety of ciltacabtagene autoleucel. Further, analysis in Study MMY2001 (n=97) showed no clear evidence to suggest that the observed anti-CAR antibodies impact ciltacabtagene autoleucel kinetics of initial expansion and persistence, efficacy or safety.