Idecabtagene vicleucel

Patients with active central nervous system (CNS) disorder or inadequate renal, hepatic, pulmonary or cardiac function are likely to be more vulnerable to the consequences of the adverse reactions described below and require special attention.

There are no data from the use of idecabtagene vicleucel in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with idecabtagene vicleucel to assess whether it can cause foetal harm when administered to a pregnant woman.

It is not known if idecabtagene vicleucel 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 plasma cell aplasia or hypogammaglobulinaemia. Therefore, idecabtagene vicleucel 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 idecabtagene vicleucel therapy should be discussed with the treating physician.

Assessment of immunoglobulin levels in newborn infants of mothers treated with idecabtagene vicleucel should be considered.

It is unknown whether idecabtagene vicleucel cells are excreted in human milk or transferred to the breast-feeding child. A risk to the breast-fed infant cannot be excluded. Women who are breastfeeding should be advised of the potential risk to the breast-fed child.

Women of childbearing potential/Contraception in males and females

Pregnancy status for women of childbearing potential should be verified using a pregnancy test prior to starting treatment with idecabtagene vicleucel.

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 idecabtagene vicleucel.

Fertility

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

Idecabtagene vicleucel may have major influence on the ability to drive and use machines.

Due to the potential for neurologic adverse reactions, including altered mental status or seizures with idecabtagene vicleucel, patients receiving idecabtagene vicleucel should refrain from driving or operating heavy or potentially dangerous machines for at least 8 weeks after idecabtagene vicleucel infusion or until resolution of neurologic adverse reactions.

Summary of the safety profile

The safety data described in this section reflect the exposure to idecabtagene vicleucel in the KarMMa, CRB-401 and KarMMa-3 studies in which 409 patients with relapsed and refractory multiple myeloma received idecabtagene vicleucel. In KarMMa (N=128) and CRB-401 (N=56), the median duration of follow-up (from idecabtagene vicleucel infusion to data cutoff date) was 20.8 months. In KarMMa-3 (N=225), the median duration of follow-up was 29.3 months.

The most common adverse reactions (≥20%) included CRS (84.6%), neutropenia (80.0%), anaemia (63.6%), thrombocytopenia (55.0%), infections – pathogen unspecified (43.8%), hypophosphataemia (33.3%), diarrhoea (33.0%), leukopenia (32.8%), hypokalaemia (32.0%), fatigue (29.8%), nausea (28.1%), lymphopenia (26.9%), pyrexia (24.7%), infections – viral (23.2%), headache (22.5%), hypocalcaemia (22.0%), hypomagnesaemia (21.3%), and arthralgia (20.0%); other common adverse events occurring at lower frequency and considered clinically important included hypotension (18.6%), upper respiratory tract infection (15.6%), hypogammaglobulinemia (13.7%), febrile neutropenia (11.2%), pneumonia (11.0%), tremor (5.6%), somnolence (5.6%), encephalopathy (3.4%), syncope (3.2%), and aphasia (2.9%).

Serious adverse reactions occurred in 57.2% of patients. The most common serious adverse reactions (≥ 5%) included CRS (10.3%), and pneumonia (7.1%); other serious adverse events occurring at lower frequency and considered clinically important include febrile neutropenia (4.2%), pyrexia (3.7%), neutropenia (2.7%), sepsis (2.7%), confusional state (2.4%), haemophagocytic lymphohistiocytosis (1.7%), thrombocytopenia (1.5%), encephalopathy (1.5%), dyspnoea (1.5%), seizure (1.0%), mental status changes (1.0%), hypoxia (0.7%) and disseminated intravascular coagulation (0.5%).

The most common Grade 3 or 4 adverse reactions (≥5%) were neutropenia (77.3%), anaemia (50.9%), thrombocytopenia (42.5%), leukopenia (31.5%), lymphopenia (25.9%), hypophosphataemia (19.8%), infections – pathogen unspecified (15.2%), febrile neutropenia (10.5%), infections – viral (7.6%), pneumonia (6.8%), hypertension (6.6%), hypocalcaemia (5.6%) and infections – bacterial (5.4%).

Grade 3 or 4 adverse reactions were more often observed within the initial 8 weeks post-infusion (93.2%) compared to after 8 weeks post-infusion (58.1%). The most frequently reported Grade 3 or 4 adverse reactions reported within the first 8 weeks after infusion were neutropenia (75.8%), anaemia (47.4%), thrombocytopenia (38.6%), leukopenia (30.3%) lymphopenia (23.5%) and hypophosphataemia (18.3%).

Tabulated list of adverse reactions

The table below summarises the adverse reactions observed in the clinical studies of 409 patients treated with idecabtagene vicleucel within the allowed dose range of 150 to 540 × 10⁶ CAR-positive T cells. Adverse reactions are presented by MedDRA system organ class and by frequency. Frequencies are defined as: 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) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions observed in patients treated with idecabtagene vicleucel:

^* Event that has been reported as a manifestation of CRS.
^a Infections and infestations system organ class adverse events are grouped by pathogen type and selected clinical syndromes.
^b Delirium includes delirium, disorientation, agitation, hallucination, restlessness.
^^ Encephalopathy includes amnesia, bradyphrenia, cognitive disorder, confusional state, depressed level of consciousness, disturbance in attention, dyscalculia, dysgraphia, encephalopathy, incoherent, lethargy, memory impairment, mental impairment, mental status changes, metabolic encephalopathy, neurotoxicity, somnolence, stupor.
^d Dizziness includes dizziness, presyncope, syncope, vertigo.
^e Aphasia includes aphasia, dysarthria, slow speech, and speech disorder.
^f Ataxia includes ataxia, dysmetria, gait disturbance.
^g Motor dysfunction includes motor dysfunction, muscular spasms, muscular weakness, parkinsonism.
^h Hypotension includes hypotension, orthostatic hypotension.
ⁱ Gastrointestinal haemorrhage includes gastrointestinal haemorrhage, gingival bleeding, haematochezia, haemorrhoidal
haemorrhage, melaena, mouth haemorrhage.
^j Fatigue includes fatigue, malaise.
^k Oedema includes oedema, oedema peripheral, face oedema, generalised oedema, peripheral swelling.

Description of selected adverse reactions

Cytokine release syndrome

In the pooled studies (KarMMa, CRB-401 and KarMMa-3), CRS occurred in 84.6% of patients receiving idecabtagene vicleucel. Grade 3 or higher CRS (Lee et al, 2014) occurred in 5.1% of patients, with fatal (Grade 5) CRS reported in 0.7% of patients. The median time-to-onset, any grade, was 1 day (range: 1 to 17) and the median duration of CRS was 4 days (range: 1 to 63).

The most common manifestations of CRS (≥10%) included pyrexia (82.6%), hypotension (29.1%), tachycardia (24.7%), chills (18.8%), hypoxia (15.9%), headache (11.2%) and increased C-reactive protein (10.5%). Grade 3 or higher events that may be observed in association with CRS included atrial fibrillation, capillary leak syndrome, hypotension, hypoxia and HLH/MAS.

Of the 409 patients, 59.7% of patients received tocilizumab; 37.2% received a single dose while 22.5% received more than 1 dose of tocilizumab for treatment of CRS. Overall, 22.7% of patients received at least 1 dose of corticosteroids for treatment of CRS. Of the 92 patients in KarMMa and CRB-401 who received the target dose of 450 × 10⁶ CAR-positive T cells, 54.3% of patients received tocilizumab and 22.8% received at least 1 dose of corticosteroids for treatment of CRS. Of the 225 patients in KarMMa-3 who received idecabtagene vicleucel infusion, 71.6% of patients received tocilizumab and 28.4% received at least 1 dose of corticosteroids for the treatment of CRS.

Neurologic adverse reactions

In the pooled studies, of the 409 patients, independent of investigator attribution of neurotoxicity, the most frequent neurologic or psychiatric adverse reactions (≥5%) included headache (22.5%), dizziness (12.5%), confusional state (11.0%), insomnia (10.3%), anxiety (5.9%), tremor (5.6%), and somnolence (5.6%). Other neurological adverse reactions occurring at a lower frequency and considered clinically important included encephalopathy (3.4%) and aphasia (2.9%).

Neurotoxicity identified by the investigators, which was the primary method of assessing CAR T cell associated-neurotoxicity in the KarMMa and KarMMa-3 studies, occurred in 57 (16.1%) of the 353 patients receiving idecabtagene vicleucel, including Grade 3 or 4 in 3.1% of patients (with no Grade 5 events). The median time to onset of the first event was 3 days (range: 1 to 317; one patient developed encephalopathy at Day 317 as a result of worsening pneumonia and Clostridium difficile colitis). The median duration was 3 days (range: 1 to 252; one patient developed neurotoxicity [highest Grade 3] 43 days after ide-cel infusion which resolved after 252 days). Overall, 7.1% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity.

In KarMMa, across the target dose levels, 7.8% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity, while at the target dose of 450 × 10⁶ CAR-positive T cells, 14.8% of patients received at least 1 dose of corticosteroids.

In KarMMa-3, across all patients who received idecabtagene vicleucel infusion at the target dose range, 6.7% of patients received at least 1 dose of corticosteroid for treatment of CAR T cell-associated neurotoxicity.

Of the 353 patients in the KarMMa and KarMMa-3 studies, the most common manifestations of investigator identified neurotoxicity (≥2%) included confusional state (8.5%), encephalopathy (3.4%), somnolence (2.8%), aphasia (2.5%), tremor (2.3%), disturbance in attention (2.0%) and dysgraphia (2.0%).

Febrile neutropenia and infections

In the pooled studies, infections occurred in 62.8% of patients. Grade 3 or 4 infections occurred in 23.2% of patients. Grade 3 or 4 infections with an unspecified pathogen occurred in 15.2%, viral infections in 7.6%, bacterial infections in 4.6% and fungal infections in 1.2% of patients. Fatal infections of unspecified pathogen were reported in 2.0% of patients, 0.7% of patients had fatal fungal or viral infection and 0.2% of patients had fatal bacterial infection.

Febrile neutropenia (Grade 3 or 4) was observed in 10.8% of patients after idecabtagene vicleucel infusion. Febrile neutropenia may be concurrent with CRS.

Prolonged cytopenia

Patients may exhibit prolonged cytopenias following lymphodepleting chemotherapy and idecabtagene vicleucel infusion. In the pooled studies, 38.2% of the 395 patients who had Grade 3 or 4 neutropenia and 71.3% of the 230 patients who had Grade 3 or 4 thrombocytopenia during the first month following idecabtagene vicleucel infusion had not resolved by last assessment during the first month. Among the 151 patients with neutropenia not resolved by month 1, 88.7% recovered from Grade 3 or 4 neutropenia with a median time to recovery from idecabtagene vicleucel infusion of 1.9 months. Of the 164 patients with thrombocytopenia not resolved by month 1, 79.9% recovered from Grade 3 or 4 thrombocytopenia with the median time to recovery of 2.0 months.

Hypogammaglobulinaemia

Hypogammaglobulinaemia was reported in 13.7% of patients treated with idecabtagene vicleucel in the pooled studies with a median time to onset of 90 days (range 1 to 326).

Immunogenicity

Idecabtagene vicleucel has the potential to induce anti-CAR antibodies. In clinical studies, humoral immunogenicity of idecabtagene vicleucel was measured by determination of anti-CAR antibody in serum pre- and post-administration. In the pooled studies of KarMMa, CRB-401 and KarMMa-3, 3.2% of patients tested positive for pre-infusion anti-CAR antibodies and post-infusion anti-CAR antibodies were detected in 56.2% of the patients. There is no evidence that the presence of pre-existing or post-infusion anti-CAR antibodies impact the cellular expansion, safety or effectiveness of idecabtagene vicleucel.