Carvykti

Description of Carvykti

CARVYKTI (ciltacabtagene autoleucel) is a BCMA-directed genetically modified autologous T cell immunotherapy. CARVYKTI is prepared from the patient’s peripheral blood mononuclear cells, which are obtained via a standard leukapheresis procedure. The mononuclear cells biology are enriched for T cells and genetically modified ex vivo by transduction with a replication-incompetent lentiviral vector to express a chimeric antigen receptor (CAR) comprising an anti-BCMA targeting domain, which consists of two single-domain antibodies linked to a 4-1BB costimulatory domain and a CD3-zeta signaling domain.

The transduced anti-BCMA CAR T cells are expanded in cell culture, washed, formulated into a suspension and cryopreserved. The product must pass a sterility test before release for shipping as a frozen suspension in a patient-specific infusion bag. The product is thawed and then infused back into the patient, where the anti-BCMA CAR T cells can recognize and eliminate BCMA-expressing target cells. [see DOSAGE AND ADMINISTRATION, HOW SUPPLIED/Storage And Handling].

In addition to T cells, CARVYKTI may contain Natural Killer (NK) cells. The formulation contains 5% dimethyl sulfoxide (DMSO).

CARVYKTI is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Dosage And Administration of Carvykti

For autologous use only. For intravenous use only.

Dose

CARVYKTI is provided as a single dose for infusion containing a suspension of chimeric antigen receptor (CAR)-positive viable T cells in one infusion bag.

The recommended dose range is 0.5-1.0×10⁶ CAR-positive viable T cells per kg of body weight, with a maximum dose of 1×10⁸ CAR-positive viable T cells per single infusion.

Administration

CARVYKTI is for autologous use only. The patient’s identity must match the patient identifiers on the CARVYKTI cassette and infusion bag. Do not infuse CARVYKTI if the information on the patient-specific labels does not match the intended patient.

Preparing The Patient For CARVYKTI Infusion

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

Pretreatment

Administer the lymphodepleting chemotherapy regimen: cyclophosphamide 300 mg/m² intravenously (IV) and fludarabine 30 mg/m² IV daily for 3 days.

See the prescribing information of cyclophosphamide and fludarabine for information on dose adjustment in renal impairment.

Lymphodepleting regimen must be delayed if a patient has serious adverse reactions from preceding bridging therapies (including clinically significant active infection, cardiac toxicity, and pulmonary toxicity) or active graft versus host disease in patient with prior allogeneic stem cell transplant. Consider repeating lymphodepleting regimen if CARVYKTI dosing is delayed by more than 14 days and patient has recovered from toxicity of the first lymphodepleting regimen.

Administer CARVYKTI infusion 2 to 4 days after the completion of the lymphodepleting chemotherapy regimen.

CARVYKTI infusion should be delayed if a patient has any of the following conditions:

• Clinically significant active infection or inflammatory disorders.
• Grade ≥3 non-hematologic toxicities of cyclophosphamide and fludarabine conditioning, except for Grade 3 nausea, vomiting, diarrhea, or constipation. CARVYKTI infusion should be delayed until resolution of these events to Grade ≤1.

Premedication

Administer the following pre-infusion medications to all patients 30 – 60 minutes prior to CARVYKTI infusion:

• Antipyretics (oral or intravenous acetaminophen 650 to 1000 mg).
• Antihistamine (oral or intravenous diphenhydramine 25 to 50 mg or equivalent).

Avoid prophylactic use of systemic corticosteroids, because their use may interfere with the activity of CARVYKTI.

Receipt Of CARVYKTI

• All sites approved for infusion will support required storage conditions for vapor phase of liquid nitrogen.
• CARVYKTI is shipped directly to the cell laboratory or clinical pharmacy associated with the infusion center in the vapor phase of a liquid nitrogen shipper.
• Confirm the patient’s identity with the patient identifiers on the shipper.
• If the patient is not expected to be ready for same-day administration, before the shipper expires, transfer CARVYKTI to onsite vapor phase of liquid nitrogen storage.

Preparation Of CARVYKTI For Infusion

Do not thaw the product until it is ready to be used. Coordinate the timing of CARVYKTI thaw and infusion. Confirm the infusion time in advance and adjust the start time for thaw so that CARVYKTI is available for infusion when the patient is ready. Once thawed, the CARVYKTI infusion must be completed within 2.5 hours at room/ambient temperature (20°C to 25°C).

Prior to thawing the product, confirm that tocilizumab and emergency equipment are available prior to the infusion and during the recovery period.

1. Confirm patient identity: Prior to CARVYKTI preparation, match the patient’s identity with the patient identifiers on the CARVYKTI cassette. Do not remove the CARVYKTI infusion bag from the cassette if the information on the patient-specific label does not match the intended patient. Contact Janssen Biotech, Inc. at 1-800-526-7736 if there are any discrepancies between the labels and the patient identifiers.
2. Once patient identification is confirmed, remove the CARVYKTI product bag from the cassette and check that the patient information on the cassette label matches the patient information on the bag label.
3. Inspect the product bag for any breaches of container integrity, such as breaks or cracks before thawing. Do not administer if the bag is compromised, and contact Janssen Biotech, Inc. at 1-800-526-7736.
4. Place the infusion bag inside a sealable plastic bag (preferably sterile) prior to thawing.
5. Thaw CARVYKTI at 37°C±2°C using either a water bath or dry thaw method until there is no visible ice in the infusion bag. Total time from start of thaw until completion of thawing should be no more than 15 minutes.
6. Remove the infusion bag from the sealable plastic bag and wipe dry. 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 pre-filter into a different container, wash, spin down, or resuspend CARVYKTI in new media prior to infusion.
7. Do not re-freeze or refrigerate thawed product.

Administration

• For autologous infusion only.
• Do NOT use a leukocyte-depleting filter.
• Ensure that a minimum of two doses of tocilizumab and emergency equipment are available prior to infusion and during the recovery period.
• Central venous access may be utilized for the infusion of CARVYKTI and is encouraged in patients with poor peripheral access.

1. Confirm the patient’s identity with the patient identifiers on the infusion bag. Do not infuse CARVYKTI if the information on the patient-specific label does not match the intended patient.
2. Prime the tubing of the infusion set with normal saline prior to infusion.
3. Once thawed, administer the entire contents of the CARVYKTI bag by intravenous infusion within 2.5 hours using infusion sets fitted with an in-line filter.
4. Gently mix the contents of the bag during CARVYKTI infusion to disperse cell clumps.
5. After the entire content of the product bag is infused, flush the administration line, inclusive of the in-line filter, with normal saline with a volume equal or greater to the total hold up volume of the primary administration set used inclusive of the drip tube, to ensure that all product is delivered.

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

Monitoring After Infusion

Administer CARVYKTI at a REMS-certified healthcare facility.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a certified healthcare facility for signs and symptoms of cytokine release syndrome (CRS) and neurologic toxicities. Monitor periodically for 4 weeks for signs and symptoms of delayed neurologic toxicity.

Instruct patients to remain within proximity of a certified healthcare facility for at least 4 weeks following infusion.

Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.

Management Of Severe Adverse Reactions

Cytokine Release Syndrome

Identify CRS based on clinical presentation [see WARNINGS AND PRECAUTIONS]. Evaluate for and treat other causes of fever, hypoxia and hypotension. Consider laboratory testing to monitor for disseminated intravascular coagulation, hematology parameters, as well as pulmonary, cardiac, renal, and hepatic function. If CRS is suspected, manage according to the recommendations in Table 1.

Patients who experience CRS should be closely monitored for cardiac and other organ function until resolution of symptoms. Consider anti-seizure prophylaxis with levetiracetam in patients who experience CRS.

Patients who experience Grade 2 or higher CRS (e.g., hypotension not responsive to fluids, or hypoxia requiring supplemental oxygenation) should be monitored with continuous telemetry and pulse oximetry.

For severe or life-threatening CRS, consider intensive care unit level monitoring and supportive therapy.

For CRS refractory to first line interventions such as tocilizumab or tocilizumab and corticosteroids, consider alternate treatment options (i.e., higher corticosteroid dose, alternative anti-cytokine agents, e.g., anti-IL1 and/or anti-TNFα, anti-T cell therapies). Refractory CRS is characterized by fevers, end-organ toxicity (e.g., hypoxia, hypotension) not improving within 12 hours of first line interventions or development of HLH/MAS.

If concurrent neurologic toxicity is suspected during CRS, administer:

• Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
• Tocilizumab according to the CRS grade in Table 1
• Anti-seizure medication according to the neurologic toxicity in Table 2

Table 1: CRS Grading and Management Guidance

CRS Gradea	Tocilizumabb	Corticosteroidsf
Grade 1 Temperature ≥38°Cc	In patients with: Early onset of fever (if onset less than 72 hours after infusion) Tocilizumab 8 mg/kg intravenously (IV) over 1 hour (not to exceed 800 mg) may be considered	N/A
Grade 2 Symptoms require and respond to moderate intervention. Temperature ≥38°Cc with: Hypotension not requiring vasopressors, and/or, Hypoxia requiring oxygen via canulae or blow-by, or, Grade 2 organ toxicity.g	Administer tocilizumab 8 mg/kg IV over 1 hour (not to exceed 800 mg). Repeat tocilizumab every 8 hours as needed if not responsive to intravenous fluids up to 1 liter or increasing supplemental oxygen.	Consider dexamethasone 10 mg IV every 12-24 hours.
	If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents.d Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.
Grade 3 Symptoms require and respond to aggressive intervention. Temperature >38°Cc with: Hypotension requiring one vasopressor with or without vasopressin, and/or, Hypoxia requiring oxygen via high-flow nasal canulae, facemask, nonrebreather mask, or Venturi mask, or, Grade 3 organ toxicity or Grade 4 transaminitis.	Per Grade 2	Administer dexamethasone 10 mg IV every 12 hours.
	If no improvement within 24 hours or rapid progression, repeat tocilizumab and escalate dose and frequency of dexamethasone (20 mg IV every 6 to 12 hours). If no improvement within 24 hours or continued rapid progression, switch to methylprednisolone 2 mg/kg IV every 12 hours. After 2 doses of tocilizumab, consider alternative anti-cytokine agents.d Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total.
Grade 4 Life-threatening symptoms. Requirements for ventilator support, continuous veno-venous hemodialysis (CVVHD). Temperature ≥38°Cc with: Hypotension requiring multiple vasopressors (excluding vasopressin), and/or, Hypoxia requiring positive pressure (e.g., CPAP, BiPAP, intubation, and mechanical ventilation), or, Grade 4 organ toxicity (excluding transaminitis).	Per Grade 2	Administer dexamethasone 20 mg IV every 6 hours.
	After 2 doses of tocilizumab, consider alternative anti-cytokine agentsd. Do not exceed 3 doses of tocilizumab in 24 hours, or 4 doses in total. If no improvement within 24 hours, consider methylprednisolone (1-2 g IV, repeat every 24 hours if needed; taper as clinically indicated) or other immunosuppressants (e.g. other anti-T cell therapies).
a Based on ASTCT 2019 grading system (Lee et.al, 2019), modified to include organ toxicity. b Refer to tocilizumab prescribing information for details. c Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia, as it may be masked by interventions such as antipyretics or anti-cytokine therapy (e.g., tocilizumab or steroids). Absence of fever does not impact CRS management decision. In this case, CRS management is driven by hypotension and/or hypoxia and by the more severe symptom not attributable to any other cause. d Monoclonal antibodies targeting cytokines may be considered based on institutional practice for unresponsive CRS. e Low-flow nasal cannula is ≤6 L/min; high-flow nasal cannula is >6 L/min. f Continue corticosteroids use until the event is Grade 1 or less; taper steroids if total corticosteroid exposure is greater than 3 days. g Organ toxicity grading based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

 

Neurologic Toxicities

Monitor patients for signs and symptoms of neurologic toxicities (ICANS and other neurologic toxicities) (Table 2). Rule out other causes of neurologic signs or symptoms. Provide intensive care and supportive therapy for severe or life-threatening neurologic toxicities. Please see section 5.2 for non ICANS neurologic toxicities. If ICANS is suspected, manage according to the recommendations in Table 2.

If concurrent CRS is suspected during the neurologic toxicity event, administer:

• Corticosteroids according to the more aggressive intervention based on the CRS and neurologic toxicity grades in Tables 1 and 2
• Tocilizumab according to CRS grade in Table 1
• Anti-seizure medication according to neurologic toxicity in Table 2

Table 2: Guideline for management of ICANS

ICANS Gradea	Corticosteroids
Grade 1 ICE score 7-9b or depressed level of consciousness: awakens spontaneously.	Consider dexamethasonec 10 mg IV every 12 to 24 hours for 2 to 3 days. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 2 ICE score-3-6b or depressed level of consciousness: awakens to voice	Administer dexamethasonec 10 mg IV every 12 hours for 23 days, or longer for persistent symptoms. Consider steroid taper if total corticosteroid exposure is greater than 3 days. If no improvement after 24 hours or worsening of neurologic toxicity, increase the dose and/or frequency of dexamethasone up to a maximum of 20 mg IV every 6 hours. Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis.
Grade 3 ICE score-0-2b (If ICE score is 0, but the patient is arousable (e.g., awake with global aphasia) and able to perform assessment) or depressed level of consciousness: awakens only to tactile stimulus, or seizures, either: any clinical seizure, focal or generalized, that resolves rapidly, or non-convulsive seizures on EEG that resolve with intervention, or raised intracranial pressure (ICP): focal/local edema on neuroimagingd.	Administer dexamethasonec 10 mg-20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate dexamethasonec dose to at least 20 mg IV every 6 hours, OR escalate to high-dose methylprednisolone (1-2 g/day, repeat every 24 hours if needed; taper as clinically indicated) Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g, repeat every 24 hours if needed; taper as clinically indicated).
Grade 4 ICE score-0b (Patient is unarousable and unable to perform ICE assessment) or depressed level of consciousness either: patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma, or seizures, either: life-threatening prolonged seizure (>5 min), or repetitive clinical or electrical seizures without return to baseline in between, or motor findingse: deep focal motor weakness such as hemiparesis or paraparesis, or raised ICP/cerebral edema, with signs/symptoms such as: diffuse cerebral edema on neuroimaging, or decerebrate or decorticate posturing, or cranial nerve VI palsy, or papilledema, or Cushing’s triad	Administer dexamethasonec 20 mg IV every 6 hours. If no improvement after 24 hours or worsening of neurologic toxicity, escalate to high-dose methylprednisolone (1-2 g/day, repeated every 24 hours if needed; taper as clinically indicated). Consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis. If raised ICP/cerebral edema is suspected, consider hyperventilation and hyperosmolar therapy. Give high-dose methylprednisolone (1-2 g/day, repeat every 24 hours if needed; taper as clinically indicated), and consider neurology and/or neurosurgery consultation.
Note: ICANS grade and management is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema), not attributable to any other cause. a ASTCT 2019 criteria for grading Neurologic Toxicity (Lee et.al, 2019). b If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen, button = 3 points); Following Commands (e.g., “show me 2 fingers” or “close your eyes and stick out your tongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from 100 by ten = 1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS) = 0 points. c All references to dexamethasone administration are dexamethasone or equivalent. d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It may be graded according to NCI CTCAE v5.0. e Tremors and myoclonus associated with immune effector cell therapies may be graded according to NCI CTCAE v5.0, but they do not influence ICANS grading.

How Supplied

Dosage Forms And Strengths

CARVYKTI is a cell suspension for intravenous infusion.

A single dose of CARVYKTI contains a cell suspension of 0.5-1.0×10⁶ CAR-positive viable T cells per kg body weight in one infusion bag up to a maximum of 1×10⁸ CAR-positive viable T cells [see HOW SUPPLIED/Storage And Handling].

Storage And Handling

CARVYKTI is supplied in one infusion bag containing a frozen suspension of genetically modified autologous T cells in 5% DMSO, either as a:

70 mL suspension in an infusion bag and metal cassette (NDC 57894-111-01) or
30 mL suspension in an infusion bag and metal cassette (NDC 57894-111-02)

Each CARVYKTI infusion bag is individually packed in an aluminum cryo-cassette.

Match the identity of the patient with the patient identifiers on the cassette and infusion bag upon receipt.

Store and transport below -120°C, e.g., in a container for cryogenic storage in the vapor phase of liquid nitrogen.

Store CARVYKTI in the original packaging containing the cassette protecting the infusion bag.

Thaw CARVYKTI prior to infusion [see DOSAGE AND ADMINISTRATION].

Manufactured/Marketed by: Janssen Biotech, Inc., Horsham, PA 19044, USA. Marketed by: Legend Biotech, Somerset, NJ 08873, USA.  Revised: Feb 2022

The following clinically significant adverse reactions are also described elsewhere in the labeling:

• Cytokine Release Syndrome [see WARNINGS AND PRECAUTIONS].
• Neurologic Toxicities [see WARNINGS AND PRECAUTIONS].
• Hemophagocytic Lymphohistiocytosis(HLH)/MacrophageActivation Syndrome (MAS)[see WARNINGS AND PRECAUTIONS].
• Prolonged and Recurrent Cytopenias[see WARNINGS AND PRECAUTIONS].
• Infections[see WARNINGS AND PRECAUTIONS].
• Hypogammaglobulinemia[see WARNINGS AND PRECAUTIONS].
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinicaltrials of a drug cannot be directly compared o rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety data described in this section reflect the exposure of 97 adult patients with relapsed/refractory multiple myeloma in the CARTITUDE-1 study (USA cohort) to ciltacabtagene autoleucel and includes 17 patients (18%) with manufacturing failures either because they received ciltacabtagene autoleucel that did not meet product release specifications or there were insufficient data to confirm product release specifications for CARVYKTI. Patients received ciltacabtagene autoleucel across a dose range of 0.51 to 0.95×10⁶ CAR-positive viable T cells/kg body weight [see Clinical Studies]. Patients with a history of CNS disease (such as seizure or cerebrovascular ischemia) or requiring ongoing treatment with chronic immunosuppression were excluded. The median duration of follow-up was 18 months. The median age of the study population was 61 years (range: 43 to 78 years); 36% were 65 years or older, and 59% were men. The Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 in 40%, 1 in 56%, and 2 in 4% of patients. Three of the patients treated with ciltacabtagene autoleucel had a creatinine clearance of <45 mL/min at baseline. For the details about the study population, see Clinical Studies.

The safety data in the Warnings and Precautions section also reflects exposure to ciltacabtagene autoleucel in two ongoing, open-label studies, including patients with previously untreated and relapsed/refractory multiple myeloma in a non-randomized, multi-cohort study (CARTITUDE-2) and patients with relapsed/refractory multiple myeloma in a randomized controlled study (CARTITUDE-4).

The most common (greaterorequalto 10%)Grade3 or4 nonlaboratory adversereactionswere infections-pathogen unspecified(17%), pneumonia (11%), febrile neutropenia (10%), and hypotension (10%).

The most common nonlaboratory adverse reactions (incidence greater than or equal to 20%) included pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting.

Serious adverse reactions occurred in 55% of patients. The most common non-laboratory (greater than or equal to 5%) serious adverse reactions included CRS (21%), sepsis (7%), encephalopathy (10%), and pneumonia (7%). Fatal adverse reactions occurred in 9% of patients.

Table 3 summarizes the adverse reactions that occurred in at least 10% of patients treated with ciltacabtagene autoleucel.

Table 4 describes the most common Grade 3 or 4 laboratory abnormalities.

Table 3: Adverse reactions observed in at least 10% of patients treated with ciltacabtagene autoleucel in CARTITUDE-1 Study (N=97)

System Organ Class (SOC) Preferred term	Any Grade (%)	Grade 3 or higher (%)
Blood and lymphatic system disorders
Coagulopathya	22	2.1
Febrile Neutropenia	10	10
Cardiac disorders
Tachycardiab	27	1
Gastrointestinal disorders
Diarrheac	33	1
Nausea	31	1
Constipation	22	0
Vomiting	20	0
General disorders and administrative site conditions
Pyrexia	96	5
Fatigued	47	7
Chills	33	0
Edemae	23	0
Immune system disorders
Cytokine release syndromef	95	5
Hypogammaglobulinemiag	94	2
Infections and infestationsh
Infections-pathogen unspecifiedi	41	17
Upper respiratory tract infectionj	28	3
Viral infectionsk	23	7
Pneumonial	12	11
Sepsism	10	7
Bacterial infectionsn	10	3
Metabolism and nutrition disorders
Decreased appetite	29	1
Musculoskeletal and connective tissue disorders
Musculoskeletal paino	48	2
Nervous system disorders
Encephalopathyp	30	6
Headache	27	0
Dizzinessq	23	1
Motor dysfunctionr	16	3
Psychiatric disorders
Insomnia	13	0
Respiratory, thoracic and mediastinal disorders
Coughs	39	0
Dyspneat	23	3
Nasal congestion	15	0
Hypoxia	12	4
Vascular disorders
Hypotensionu	51	10
Hypertension	19	6
Hemorrhagev	15	4
Adverse reactions are reported using MedDRA version 23.0 a Coagulopathy includes Activated partial thromboplastin time prolonged, Coagulopathy, Disseminated intravascular coagulation, Hypofibrinogenemia, International normalized ratio increased, and Prothrombin time prolonged. Also includes terms reported under investigation SOC. b Tachycardia includes Sinus tachycardia, and Tachycardia. c Diarrhea includes Colitis, and Diarrhea. d Fatigue includes Asthenia, Fatigue, and Malaise. e Edema includes Face edema, Generalized edema, Localized edema, Edema peripheral, Periorbital edema, Peripheral swelling, Pulmonary edema, and Scrotal edema. f Cytokine release syndrome includes Cytokine release syndrome, and Systemic inflammatory response syndrome. g Hypogammaglobulinemia includes subjects with adverse event of hypogammaglobulinemia (12%) and/or laboratory IgG levels that fell below 500 mg/dL following CARVYKTI infusion (92%). h Infections and infestations System Organ Class Adverse Events are grouped by pathogen type and selected clinical syndromes. i Infections – pathogen unspecified includes Abscess limb, Atypical pneumonia, Bacteremia, Bronchitis, Conjunctivitis, Enterocolitis infectious, Folliculitis, Gastroenteritis, Lung abscess, Lung opacity, Osteomyelitis, Otitis media, Parotitis, Perirectal abscess, Pneumonia, Rash pustular, Rhinitis, Sepsis, Septic shock, Sinusitis, Skin infection, Soft tissue infection, Tooth infection, Upper respiratory tract infection, and Urinary tract infection. j Upper respiratory tract infection includes Human rhinovirus test positive, Rhinitis, Rhinovirus infection, Sinusitis, Upper respiratory tract infection, and Viral upper respiratory tract infection. Also includes terms reported under investigation SOC. Upper respiratory tract infections may also be included under pathogen categories. k Viral infection includes Adenovirus test positive, Coronavirus infection, Cytomegalovirus syndrome, Cytomegalovirus viremia, Enterovirus infection, Gastroenteritis viral, Herpes zoster, Herpes zoster disseminated, Influenza, Influenza like illness, Oral herpes, Parainfluenza virus infection, Rhinovirus infection, Urinary tract infection viral, and Viral upper respiratory tract infection. l Pneumonia includes Atypical pneumonia, Lung abscess, Lung opacity, Pneumocystis jirovecii pneumonia, Pneumonia, and Pneumonia aspiration. m Sepsis includes Bacteremia, Bacterial sepsis, Pseudomonal bacteremia, Sepsis, Septic shock, and Staphylococcal bacteremia. n Bacterial infection includes Abscess limb, Cholecystitis, Cholecystitis acute, Clostridium difficile colitis, Clostridium difficile infection, Enterocolitis bacterial, Osteomyelitis, Perirectal abscess, Soft tissue infection, Staphylococcal infection, and Tooth infection. o Musculoskeletal pain includes Arthralgia, Back pain, Bone pain, Joint stiffness, Muscle strain, Musculoskeletal chest pain, Musculoskeletal discomfort, Musculoskeletal pain, Musculoskeletal stiffness, Myalgia, Neck pain, Non-cardiac chest pain, and Pain in extremity. p Encephalopathy includes Amnesia, Bradyphrenia, Confusional state, Depressed level of consciousness, Disturbance in attention, Encephalopathy, Immune effector cell-associated neurotoxicity syndrome, Lethargy, Memory impairment, Mental impairment, Mental status changes, Noninfective encephalitis, and Somnolence. q Dizziness includes Dizziness, Presyncope, and Syncope. r Motor dysfunction includes Motor dysfunction, Muscle spasms, Muscle tightness, Muscular weakness, and Myoclonus. s Cough includes Cough, Productive cough, and Upper-airway cough syndrome. t Dyspnea includes Acute respiratory failure, Dyspnea, Dyspnea exertional, Respiratory failure, and Tachypnea. u Hypotension includes Hypotension, and Orthostatic hypotension. v Hemorrhage includes Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eye contusion, Hematochezia, Hemoptysis, Infusion site hematoma, Oral contusion, Petechiae, Post procedural hemorrhage, Pulmonary hemorrhage, Retinal hemorrhage, and Subdural hematoma.

Other clinically important adverse reactions that occurred in less than 10% of patients treated with ciltacabtagene autoleucel include the following:

• • Cardiac disorders: cardiac arrhythmias^a (8%), chest pain^b (7%)
  • Eye disorders: diplopia (1%)
  • Gastrointestinal disorders: dysphagia (1%)
  • Immune system disorders: hemophagocytic lymphohistiocytosis (1%), hypersensitivity reaction (5%)
• Infections and Infestations: urinary tract infection^c (4.1%)
• Injury, Poisoning and Procedural complications: fall (3.1%)
• Metabolism and Nutrition Disorders: tumor lysis syndrome (1%)
• Musculoskeletal and Connective tissue disorders: posture abnormal (1%)
• Nervous system disorders: aphasia^d (8%), ataxia^e (8%), tremor (6%), paresis^f (4.1%), parkinsonism (4.1%), peripheral neuropathy (6%), micrographia (4.1%), dysgraphia (3.1%), reduced facial expression (3.1%), bradykinesia (2.1%), cogwheel rigidity (1%), cerebrovascular accident (1%), seizure 1%, low speech (1%), nystagmus (1%)
• Psychiatric disorders: delirium^g (5%) depression^h (4.1%), psychomotor retardation (1%)
• Renal and urinary disorders: renal failureⁱ (7%)
• Skin and subcutaneous tissues: rash^j (8%)
• Vascular Disorders: thrombosis^k (5%)

^a Cardiac arrhythmias includes atrial fibrillation, atrial flutter, supraventricular tachycardia, ventricular extrasystoles, ventricular tachycardia.
^b Chest pain includes Angina pectoris, Chest discomfort, and Chest pain.
_c Urinary tract infection includes Urinary tract infection, and Urinary tract infection viral.
_d Aphasia includes Aphasia, Dysarthria, and Speech disorder.
_e Ataxia includes Ataxia, Balance disorder, and Gait disturbance.
_f Paresis includes Cranial nerve paralysis, Facial paralysis, and Peroneal nerve palsy.
_g Delirium includes Agitation, Hallucination, Irritability, Personality change, and Restlessness.
_h Depression includes Depression, and Flat affect.
_i Renal failure includes Acute kidney injury, Blood creatinine increased, Chronic kidney disease, and Renal impairment.
_j Rash includes Erythema, Rash, Rash maculo-papular, and Rash pustular.
_k Thrombosis includes Deep vein thrombosis, and Device related thrombosis.

Laboratory Abnormalities

Table 4 presents the most common Grade 3 or 4 laboratory abnormalities based on laboratory data, occurring in at least 10% of patients.

Table 4: Grade 3 or 4 laboratory abnormalities in at least 10% of patients treated with

Laboratory Abnormality	Grade 3 or 4 (%)
Lymphopenia	99
Neutropenia	98
White blood cell decreased	98
Anemia	72
Thrombocytopenia	63
Aspartate aminotransferase increased	21
Laboratory abnormalities graded using NCI Common Terminology Criteria for Adverse Events version 5.0. Laboratory abnormalities are sorted by decreasing frequency in the Grade column.

Other clinically important Grade 3 or 4 laboratory abnormalities (based on laboratory data) that occurred in less than 10% of patients treated with ciltacabtagene autoleucel include the following: fibrinogen decreased, hypoalbuminemia, alanine aminotransferase increased, hyponatremia, hypocalcemia, gamma glutamyl transferase increased, alkaline phosphatase increased, hypokalemia, blood bilirubin increased.

Immunogenicity

The immunogenicity of CARVYKTI has been evaluated using a validated assay for the detection of binding antibodies against the extracellular portion of the anti-BCMA CAR pre-dose, and at multiple timepoints post-infusion. In Study CARTITUDE-1, 19 of 97 (19.6%) patients were positive for anti-product antibodies.

There was no clear evidence that the observed anti-product antibodies impact CARVYKTI kinetics of initial expansion and persistence, efficacy, or safety.

Drug Interactions

HIV and the lentivirus used to make CARVYKTI have limited, short spans of identical genetic material (RNA). Therefore, some commercial HIV nucleic acid tests (NATs) may yield false-positive results in patients who have received CARVYKTI.

Included as part of the PRECAUTIONS section.

Precautions

Cytokine Release Syndrome

Cytokine release syndrome, including fatal or life-threatening reactions, occurred following treatment with CARVYKTI. CRS occurred in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade)¹ occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 1 to 12 days). The median duration of CRS was 4 days (range:1 to 40 days) in all but one patient who had a duration of CRS of 97 days with a subsequent fatal outcome. In patients who experienced CRS, the most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased-C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase [see ADVERSE REACTIONS].

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Please see Section 5.3; Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS).

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received tocilizumab without corticosteroids, of whom 33 (34%) received a single dose and 11 (11%) received more than 1 dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids.

Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids, as indicated in Table 1 [see DOSING AND ADMINISTRATION].

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling information].

Neurologic Toxicities

Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, peripheral neuropathies and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time [see Patient Counseling Information].

Overall, one or more subtypes of neurologic toxicity² described below occurred following ciltacabtagene autoleucel infusion in 26% (25/97) of patients of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in 2 ongoing studies [see ADVERSE REACTIONS].

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

Patients receiving CARVYKTI may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS.

ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). Two patients had ongoing Grade 3 and Grade 1 ICANS at last known alive date and one patient had Grade 1 ICANS ongoing at time of death from neurologic toxicity with parkinsonian features. The median time to onset of ICANS was 8 days (range: 1 to 28 days). ICANS resolved in 17 of 22 patients (77%), and the median time to resolution was 6 days (range: 2 to 143 days). Median duration of ICANS in all patients, including those with fatal ICANS, ICANS ongoing at time of death from other causes or ongoing at last known alive date, was 7.5 days (range: 2 to 927 days). All 22 patients with ICANS had CRS. The onset of ICANS occurred during CRS in 16 patients, before the onset of CRS in 3 patients, and after the CRS event in 3 patients.

The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed [see DOSAGE AND ADMINISTRATION].

Parkinsonism

Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, five male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from ICANS. Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism and frontal lobe release signs. Symptoms did not respond to one or more of the following treatments attempted in one or more patients – systemic chemotherapy, intrathecal chemotherapy and steroids, dopaminergic agents, systemic corticosteroids, plasmapheresis, and intravenous immunoglobulin and dasatinib. One patient experienced partial resolution with residual gait disturbance without treatment for parkinsonism, immunosuppressants or chemotherapy. The median onset of parkinsonism in the 5 patients in CARTITUDE-1 was 43 days (range: 15 to 108 days) from infusion of ciltacabtagene autoleucel. One patient died of neurologic toxicity with parkinsonism 247 days after administration of ciltacabtagene autoleucel; two patients with ongoing parkinsonism died of infectious causes 162 and 119 days after administration of ciltacabtagene autoleucel; in the remaining 2 patients, symptoms of parkinsonism were ongoing up to 530 days after administration of ciltacabtagene autoleucel. Maximum toxicity grade was 2, 3, 4 and 5 in 1, 2, 1 and 1 patient respectively. All 5 patients had a history of prior CRS (n=4 Grade 2; n=1 Grade 3), while 4 of 5 patients had prior ICANS (n=3 Grade 1; n=1 Grade 2).

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome

A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulins. Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.

Peripheral Neuropathy

Six patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor or sensorimotor neuropathies. Median time of onset of symptoms was 62 days (range: 4 to 136 days), median duration of peripheral neuropathies was 256 days (range: 2 to 465 days) including those with ongoing neuropathy. Of these six patients, two patients experienced Grade 3 peripheral neuropathy, and 3 had resolution of neuropathy. Treatment with corticosteroids in one patient was not associated with improvement of peripheral neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel.

Cranial Nerve Palsies

Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All 3 patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range: 21 to 101 days) following infusion of ciltacabtagene autoleucel. All three patients received systemic corticosteroids and had resolution of symptoms; one patient received valacyclovir in addition to corticosteroids. Median time to resolution was 70 days (range: 1 to 79 days) following onset of symptoms. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel infusion. The HLH event was preceded by prolonged CRS lasting 97 days.

The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia and multi-organ dysfunction, including renal dysfunction.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS

Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. The required components of the CARVYKTI REMS are:

• Healthcare facilities that dispense and administer CARVYKTI must be enrolled and comply with the REMS requirements.
• Certified healthcare facilities must have on-site, immediate access to tocilizumab.
• Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after CARVYKTI infusion, if needed for treatment of CRS.
• Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense or administer CARVYKTI are trained in the management of CRS and neurologic toxicities.

Further information is available at www.carvyktirems.com or 1-844-672-0067.

Prolonged And Recurrent Cytopenias

Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. In Study CARTITUDE-1 (N=97), 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion. In 31% (29/95) of patients who recovered from Grade 3 or 4 neutropenia after 1 month, the median time to recovery from ciltacabtagene autoleucel infusion was 1.8 months (range: 1.0 to 3.7 months). In 52% (32/61) of patients who recovered from Grade 3 or 4 thrombocytopenia after 1 month, the median time to recovery from ciltacabtagene autoleucel infusion was 1.9 months (range: 1.1 to 8.5 months).

One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia, and anemia were seen in 63% (61/97), 18% (17/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following ciltacabtagene autoleucel infusion. After Day 60 following ciltacabtagene autoleucel, 31%, 12%, and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia, and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia [see ADVERSE REACTIONS]. Eighty-seven percent (84/97) of patients had one, two or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Six and 11 patients had Grade 3 or 4 neutropenia and thrombocytopenia respectively at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

Infections

CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections, occurred in patients after CARVYKTI infusion [see ADVERSE REACTIONS].

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 23% (22/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 17%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, 4 patients had Grade 5 infections: lung abscess (n=1), sepsis (n=2) and pneumonia (n=1).

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion 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.

Viral Reactivation

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia.

Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing.

Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

Hypogammaglobulinemia

Hypogammaglobulinemia can occur in patients receiving treatment with CARVYKTI. Hypogammaglobulinemia was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients treated with ciltacabtagene autoleucel. Hypogammaglobulinemia either as an adverse reaction or a laboratory IgG level below 500 mg/dL, after infusion occurred in 94% (91/97) of patients treated with ciltacabtagene autoleucel. Thirty-eight percent of patients received intravenous immunoglobulin (IVIG) post ciltacabtagene autoleucel for either an adverse reaction or prophylaxis.

Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use Of Live Vaccines

The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

Hypersensitivity Reactions

Hypersensitivity reactions have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. All reactions were Grade 1 and symptoms included flushing (n=4), chest discomfort (n=2), tachycardia (n=1), wheezing (n=1), tremor (n=1), and burning sensation (n=1). Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction.

Secondary Malignancies

Patients treated with CARVYKTI may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc. at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples for testing of secondary malignancy of T cell origin.

Effects On Ability To Drive And Use Machines

Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline or neuropathy, patients receiving CARVYKTI are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI 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, and in the event of new onset of any neurologic toxicities.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Ensure that patients understand the risk of manufacturing failure [18%, (17/97 in the clinical study)]. In case of a manufacturing failure, a second manufacturing of CARVYKTI may be attempted. In addition, while the patient awaits the product, additional anticancer treatment (other than lymphodepletion) may be necessary and may increase the risk of adverse reactions during the pre-infusion period, which could delay or prevent the administration of CARVYKTI.

Advise patients that they will be monitored daily for the first 10 days following the infusion at a REMS-certified healthcare facility, and instruct patients to remain within proximity of a certified healthcare facility for at least 4 weeks following the infusion.

Prior to infusion, advise patients of the following risks and to seek immediate medical attention in the event of the following signs or symptoms:

Cytokine Release Syndrome (CRS)

Signs or symptoms of CRS, including fever, chills, fatigue, headache, tachycardia, hypotension, hypoxia, dizziness/lightheadedness or organ toxicities [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Neurologic Toxicities

Signs or symptoms associated with neurologic events, some of which occur days, weeks or months following the infusion including [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS]:

ICANS: e.g., aphasia, encephalopathy, depressed level of consciousness, seizures, delirium, dysgraphia

Parkinsonism: e.g., tremor, micrographia, bradykinesia, rigidity, shuffling gait, stooped posture, masked facies, apathy, flat affect, lethargy, somnolence

Guillain Barré Syndrome: e.g., motor weakness and polyradiculoneuritis

Peripheral neuropathy: e.g., peripheral motor and/or sensory nerve dysfunction

Cranial Nerve Palsies: e.g., facial paralysis, facial numbness

Prolonged And Recurrent Cytopenias

Signs or symptoms associated with bone marrow suppression including neutropenia, thrombocytopenia, anemia, or febrile neutropenia for several weeks or months. Signs or symptoms associated with bone marrow suppression may recur [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Infections

Signs or symptoms associated with infection [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS].

Hypersensitivity Reactions

Signs or symptoms associated with hypersensitivity reactions including flushing, chest tightness, tachycardia, and difficulty breathing [see WARNINGS AND PRECAUTIONS].

Advise patients of the need to:

• Have periodic monitoring of blood counts before and after CARVYKTI infusion [see WARNINGS AND PRECAUTIONS].
• Contact Janssen Biotech, Inc. at 1-800-526-7736 if they are diagnosed with a secondary malignancy [see WARNINGS AND PRECAUTIONS].
• Refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, for at least 8 weeks after treatment and in the event of any new onset of neurologic toxicities [see WARNINGS AND PRECAUTIONS].
• Tell their physician about their treatment with CARVYKTI before receiving a live virus vaccine [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No genotoxicity or carcinogenicity studies have been performed with CARVYKTI as they were not indicated. In vitro studies with CARVYKTI manufactured from healthy donors and patients with multiple myeloma showed no evidence of cytokine independent growth and no preferential integration near genes associated with oncogenic transformation.

No studies have been conducted to evaluate the effects of CARVYKTI on fertility.

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data on the use of CARVYKTI in pregnant women. No reproductive and developmental toxicity studies in animals have been conducted with CARVYKTI to assess whether it can cause fetal harm when administered to a pregnant woman. It is not known whether CARVYKTI has the potential to be transferred to the fetus and cause fetal toxicity. Based on the mechanism of action, if the transduced cells cross the placenta, they may cause fetal toxicity, including B-cell lymphocytopenia and hypogammaglobulinemia. Therefore, CARVYKTI is not recommended for women who are pregnant, or for women of childbearing potential not using contraception. Pregnant women should be advised that there may be risks to the fetus. Pregnancy after CARVYKTI therapy should be discussed with the treating physician.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Lactation

Risk Summary

There is no information regarding the presence of CARVYKTI 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 CARVYKTI and any potential adverse effects on the breastfed infant from CARVYKTI or from the underlying maternal condition.

Females And Males Of Reproductive Potential

Pregnancy Testing

Pregnancy status for females of child-bearing age should be verified prior to starting treatment with CARVYKTI.

Contraception

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

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 CARVYKTI infusion.

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

Infertility

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

Pediatric Use

Safety and effectiveness of CARVYKTI in pediatric patients have not been established.

Geriatric Use

Of the 97 patients in Study CARTITUDE-1 that received ciltacabtagene autoleucel, 28% were 65 to 75 years of age, and 8% were 75 years of age or older. CARTITUDE-1 did not include sufficient numbers of patients aged 65 and older to determine whether the effectiveness differs compared with that of younger patients. In 62 patients less than 65 years of age, all grade and Grade 3 and higher neurologic toxicities occurred in 19% (12/62) and 6% (4/62) respectively. Of the 35 patients ≥65 years of age, all grade and Grade 3 and higher neurologic toxicities occurred in 37% (13/35) and 20% (7/35) respectively.

REFERENCES

1 Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 2019; 25: 625-638.

2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v 5.0; 2017.

No Information provided

Contraindications

None.

Mechanism Of Action

CARVYKTI is a BCMA-directed, genetically modified autologous T cell immunotherapy, which involves reprogramming a patient’s own T cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. The CARVYKTI CAR protein features two BCMA-targeting single-domain antibodies designed to confer high avidity against human BCMA, a 4-1BB co-stimulatory domain and a CD3-zeta (CD3ζ) signaling cytoplasmic domain. Upon binding to BCMA-expressing cells, the CAR promotes T cell activation, expansion, and elimination of target cells.

Pharmacodynamics

After a single infusion of ciltacabtagene autoleucel, expansion of CAR-positive T cells coincided with decreases of serum soluble BCMA, serum M-protein, and/or free light chains. Across all patients, levels of IL-6, IL-10, IFN-γ and IL-2 receptor alpha increased post-infusion and peaked at Days 7–14. The serum levels of all cytokines generally returned to baseline levels within 2–3 months post-infusion.

Pharmacokinetics

The pharmacokinetics (PK) of ciltacabtagene autoleucel was assessed in 97 patients with multiple myeloma receiving a single infusion at the median dose of 0.71×10⁶ CAR positive viable T cells/kg (range: 0.51×10⁶ to 0.95×10⁶ cells/kg).

Following a single infusion, ciltacabtagene autoleucel exhibited an initial expansion phase followed by a rapid decline, and then a slower decline. However, high inter-individual variability was observed.

Table 5: Pharmacokinetic parameters of ciltacabtagene autoleucel in patients with multiple myeloma

Parameter	Summary Statistics	N=97
Cmax (copies/μg genomic DNA)	Median (range), n	47806 (7189 – 115234), 97
tmax (day)	Median (range), n	12.7 (8.7 – 329.8), 97
AUC0-28d (copies *day/μg genomic DNA)	Median (range), n	371569 (58691 – 2024126), 97
t½ (day)	Median (range), n	15.3 (3.0 – 95.4), 42

After the cell expansion, the persistence phase of ciltacabtagene autoleucel was observed for all patients. At the time of analysis (n=65), the median time for CAR transgene levels in peripheral blood to return to the pre-dose baseline level was approximately 100 days (range: 28 to 365 days) post-infusion.

Detectable ciltacabtagene autoleucel exposures in bone marrow indicate a distribution of ciltacabtagene autoleucel from systemic circulation to bone marrow. Similar to blood transgene levels, bone marrow transgene levels declined over time and exhibited high inter-individual variability.

Some patients required tocilizumab, corticosteroids, and anakinra for the management of CRS. Ciltacabtagene autoleucel continues to expand and persist following administration of tocilizumab, corticosteroids, and anakinra. Ciltacabtagene autoleucel median Cmax and AUC0-28d in patients treated with tocilizumab (n=68) for CRS were 168% and 209% of those in patients (n=29) who did not receive tocilizumab for CRS, respectively. The median Cmax and AUC0-28d of ciltacabtagene autoleucel in patients who received corticosteroids (n=21) for CRS were 186% and 307% of those in patients who did not receive corticosteroids (n=76) for CRS, respectively. In addition, the median Cmax and AUC0-28d of ciltacabtagene autoleucel in patients who received anakinra (n=18) for CRS were 139% and 232% of those in patients who did not receive anakinra (n=79) for CRS, respectively.

Specific Populations

The pharmacokinetics of ciltacabtagene autoleucel (Cmax and AUC0-28d) were not impacted by age (43 to 78 years), gender, body weight, race, mild hepatic dysfunction [(total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase > ULN) or (ULN < total bilirubin ≤1.5 times ULN)] or aspartate aminotransferase > ULN), or mild renal dysfunction (60 mL/min ≤ creatinine clearance [CRCL] <90 mL/min). Formal renal and hepatic impairment studies of CARVYKTI were not conducted.

Clinical Studies

The efficacy of ciltacabtagene autoleucel was evaluated in CARTITUDE-1 (NCT03548207), an open-label, single-arm, multicenter trial in adult patients with relapsed or refractory multiple myeloma, who previously received at least 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody [see ADVERSE REACTIONS].

Patients with known active or prior history of significant central nervous system (CNS) disease, including CNS multiple myeloma, plasma cell leukemia, allogeneic stem cell transplant within 6 months before apheresis or ongoing treatment with immunosuppressants, creatinine clearance <40 mL/min, absolute lymphocyte concentration <300/μL, absolute neutrophil count <750 cells/mm³, platelet count <50,000/mm³, hepatic transaminases >3 times the upper limit of normal, cardiac ejection fraction <45%, or with active serious infection were excluded from the trial.

Of the 113 patients who underwent leukapheresis, 16 patients did not receive ciltacabtagene autoleucel due to progressive disease (n=2), death (n=9), or withdrawal from study (n=5). There were 97 patients in the efficacy evaluable population who received ciltacabtagene autoleucel, including 17 patients (18%) with manufacturing failures either because they received ciltacabtagene autoleucel that did not meet product release specifications for CARVYKTI or received ciltacabtagene autoleucel for which there were insufficient data to confirm product release specifications for CARVYKTI.

Of the 97 efficacy-evaluable patients, the median age was 61 years (range: 43 to 78 years), 59% were male, 71% were white, and 18% were black. Most patients (86%) were International Staging System (ISS) Stage I or II. Of the 91 patients for whom baseline cytogentic data were available, high-risk cytogenetics (presence of t(4:14), t(14:16), or 17p13 del) were present in 24% of patients. Thirteen percent of the patients had extramedullary disease.

The median number of prior lines of therapy was 6 (range: 3 to 18), with 82% of patients receiving 4 or more prior lines of therapy, 90% of patients had received prior autologous stem cell transplantation (ASCT) and 8% of patients received an allogeneic transplant. Ninety-nine percent of patients were refractory to their last line of prior therapy, and 88% were refractory to a proteasome inhibitor (PI), immunomodulatory agent, and anti-CD38 antibody.

Most patients (75%) treated with ciltacabtagene autoleucel received bridging therapy for control of their multiple myeloma during the manufacturing process. The median time from leukapheresis to product availability was 32 days (range: 27 to 66 days).

The most commonly used agents as bridging therapies (≥20% of patients) included dexamethasone: 62 patients (64%), bortezomib: 26 patients (27%), cyclophosphamide: 22 patients (23%), and pomalidomide: 21 patients (22%).

Efficacy was established on the basis of overall response rate, complete response rate and duration of response as assessed by the Independent Review Committee (IRC) using International Myeloma Working Group (IMWG) criteria (see Table 6). The median time to first response was 1 month (range: 0.9 to 10.7 months).

Table 6: Summary of efficacy results for CARTITUDE-1 based on IRC using IMWG criteria

	Ciltacabtagene autoleucel treated (N=97)
Overall Response Rate (sCRa + VGPR + PR) n (%)	95 (97.9)
95% CI (%)	(92.7, 99.7)
Stringent complete response (sCR)a n (%)	76 (78.4)
95% CIb (%)	(68.8, 86.1)
Very good partial response (VGPR) n (%)	16 (16.5)
95% CIb (%)	(9.7, 25.4)
Partial response (PR) n (%)	3 (3.1)
95% CIb (%)	(0.6, 8.8)
Duration of Response (DOR)
Number of responders	95
DOR (Months) :Median (95% CI)c	21.8 (21.8, NE)
Number of responders with sCRa	76
DOR if best response is sCRa (Months):Median (95% CI)c	NE (21.8, NE)
Number of responders with VGPR or better	92
DOR if best response is VGPR or better (Months):Median (95% CI)c	21.8 (21.8, NE)
Notes: Based on a median duration of follow- up of 18 months a All complete responses were stringent CRs. b Exact 95% confidence interval. c Kaplan-Meier estimate. CI=confidence interval; IRC=Independent Review Committee; IMWG=International Myeloma Working Group; NE=not estimable.

The IRC assessed overall response in the 113 patients that underwent leukapheresis was 84% (95% CI: 76, 90) with stringent CR rate of 67% (95% CI: 58, 76), VGPR rate of 14% (95% CI: 8, 22) and PR rate of 3% (95% CI: 1, 8).