2.1 Dose

Each single infusion bag of TECARTUS contains a suspension of chimeric antigen receptor (CAR)-positive T cells in approximately 68 mL. The dose is 2 × 106 CAR-positive viable T cells per kg body weight, with a maximum of 2 × 108 CAR-positive viable T cells.

2.2 Administration

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

2.3 Management of Severe Adverse Reactions

5.1 Cytokine Release Syndrome

CRS, including life-threatening reactions, occurred following treatment with TECARTUS. In ZUMA-2, CRS occurred in 91% (75/82) of patients receiving TECARTUS, including ≥ Grade 3 (Lee grading system1) CRS in 18% of patients. Among the patients who died after receiving TECARTUS, one had a fatal CRS event. The median time to onset of CRS was three days (range: 1 to 13 days) and the median duration of CRS was ten days (range: 1 to 50 days). Among patients with CRS, key manifestations (>10%) included fever (99%), hypotension (60%), hypoxia (37%), chills (33%), tachycardia (37%), headache (24%), fatigue (19%), nausea (13%), alanine aminotransferase increased (13%), aspartate aminotransferase increased (12%), and diarrhea (11%). Serious events associated with CRS included hypotension, fever, hypoxia, acute kidney injury, and tachycardia [see Adverse Reactions (6)].

Ensure that a minimum of two doses of tocilizumab are available for each patient prior to infusion of TECARTUS. Monitor patients daily for at least seven days at the certified healthcare facility following infusion for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for four weeks after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [see Patient Counseling Information (17)]. At the first sign of CRS, institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated [see Dosage and Administration (2.3)].

5.2 Neurologic Toxicities

Neurologic events, including those that were life-threatening, occurred following treatment with TECARTUS. In ZUMA-2, neurologic events occurred in 81% of patients, 37% of whom experienced Grade 3 or higher (severe or life-threatening) adverse reactions. The median time to onset for neurologic events was six days (range: 1 to 32 days). Neurologic events resolved for 52 out of 66 (79%) patients with a median duration of 21 days (range: 2 to 454 days). Three patients had ongoing neurologic events at the time of death, including one patient with serious encephalopathy. The remaining unresolved neurologic events were either Grade 1 or Grade 2. Fifty-four (66%) patients experienced CRS before the onset of neurological events. Five (6%) patients did not experience CRS with neurologic events and eight patients (10%) developed neurological events after the resolution of CRS. Eighty-five percent of all treated patients experienced the first CRS or neurological event within the first seven days after TECARTUS infusion.

The most common neurologic events (>10%) included encephalopathy (51%), headache (35%), tremor (38%), aphasia (23%), and delirium (16%). Serious events including encephalopathy, aphasia, and seizures occurred after treatment with TECARTUS.

Monitor patients daily for at least seven days at the certified healthcare facility following infusion for signs and symptoms of neurologic toxicities. Monitor patients for signs or symptoms of neurologic toxicities for four weeks after infusion and treat promptly. [see Dosage and Administration (2.3)].

5.3 YESCARTA and TECARTUS REMS Program

Because of the risk of CRS and neurologic toxicities, TECARTUS is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the YESCARTA and TECARTUS REMS Program [see Boxed Warning and Warnings and Precautions (5.1 and 5.2)]. The required components of the YESCARTA and TECARTUS REMS Program are:

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

Further information is available at www.YescartaTecartusREMS.com or 1-844-454-KITE (5483).

5.4 Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, may occur due to dimethyl sulfoxide (DMSO) or residual gentamicin in TECARTUS.

5.5 Severe Infections

Severe or life-threatening infections occurred in patients after TECARTUS infusion. In ZUMA-2, infections (all grades) occurred in 56% of patients. Grade 3 or higher infections, including bacterial, viral, and fungal infections, occurred in 30% of patients. TECARTUS should not be administered to patients with clinically significant active systemic infections. Monitor patients for signs and symptoms of infection before and after TECARTUS infusion and treat appropriately. Administer prophylactic antimicrobials according to local guidelines.

Febrile neutropenia was observed in 6% of patients after TECARTUS 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.

In immunosuppressed patients, including those who have received TECARTUS, life-threatening and fatal opportunistic infections including disseminated fungal infections (e.g., candida sepsis and aspergillus infections) and viral reactivation (e.g., human herpes virus-6 [HHV-6] encephalitis and JC virus progressive multifocal leukoencephalopathy [PML]) have been reported. The possibility of HHV-6 encephalitis and PML should be considered in immunosuppressed patients with neurologic events and appropriate diagnostic evaluations should be performed.

5.6 Prolonged Cytopenias

Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and TECARTUS infusion. In ZUMA-2, Grade 3 or higher cytopenias not resolved by Day 30 following TECARTUS infusion occurred in 55% of patients and included thrombocytopenia (38%), neutropenia (37%), and anemia (17%). Monitor blood counts after TECARTUS infusion.

5.7 Hypogammaglobulinemia

B cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with TECARTUS. In ZUMA-2, hypogammaglobulinemia occurred in 16% of patients. Monitor immunoglobulin levels after treatment with TECARTUS and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement.

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

5.8 Secondary Malignancies

Patients treated with TECARTUS may develop secondary malignancies. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Kite at 1-844-454-KITE (5483) to obtain instructions on patient samples to collect for testing.

5.9 Effects on Ability to Drive and Use Machines

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

6.1 Clinical Trials Experience

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

6.2 Immunogenicity

TECARTUS has the potential to induce anti-product antibodies, which has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding antibodies against FMC63, the originating antibody of the anti-CD19 CAR. To date, no anti-CAR T-cell antibody immunogenicity has been observed. Based on an initial screening assay, 17 patients tested positive for antibodies; however, a confirmatory orthogonal cell-based assay demonstrated that all 17 patients were antibody negative at all time points tested. There is no evidence that the kinetics of initial expansion and persistence of TECARTUS, or the safety or effectiveness of TECARTUS, was altered in these patients.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of TECARTUS have not been established in pediatric patients.

8.5 Geriatric Use

Of the 82 patients treated with TECARTUS, 42 were ≥ 65 years of age and 40 were < 65 years of age. No overall differences in safety or effectiveness were observed between patients ≥ 65 years of age and younger patients.

12.1 Mechanism of Action

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

12.2 Pharmacodynamics

After TECARTUS infusion, pharmacodynamic responses were evaluated over a four-week interval by measuring transient elevation of cytokines, chemokines, and other molecules in blood. Levels of cytokines and chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and sIL2Rα were analyzed. Peak elevation was generally observed between four and eight days after infusion, and levels generally returned to baseline within 28 days.

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

12.3 Pharmacokinetics

Following infusion (target dose of 2 × 106 anti-CD19 CAR T cells/kg) of TECARTUS, anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by three months. Peak levels of anti-CD19 CAR T cells occurred within the first seven to 15 days after TECARTUS infusion.

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

Median peak anti-CD19 CAR T-cell and AUC0–28 levels in patients who received neither corticosteroids nor tocilizumab (peak: 24.7 cells/μL; AUC0–28: 360.4 cells/μL∙days, n = 18) was similar to patients who received corticosteroids alone (peak: 24.2 cells/μL; AUC0–28: 367.8 cells/μL∙days, n = 2); both groups were lower than patients who received tocilizumab alone (peak: 86.5 cells/μL; AUC0–28: 1188.9 cells/μL∙days, n = 10); the highest exposure was in patients who received both corticosteroids and tocilizumab (peak: 167.2 cells/μL; AUC0–28: 1996.0 cells/μL∙days, n = 37).

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

Gender had no significant impact on AUCDay 0–28 and Cmax of TECARTUS.

Hepatic and renal impairment studies of TECARTUS were not conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

14.1 Relapsed or Refractory Mantle Cell Lymphoma

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

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

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

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

The primary endpoint of objective response rate (ORR) per the Lugano Classification (2014) in patients treated with TECARTUS as determined by an independent review committee is provided in Table 5. The median time to response was 28 days (range: 24 to 92 days) with a median follow-up time for DOR of 8.6 months.

• Match the identity of the patient with the patient identifiers on the cassette and infusion bag upon receipt.
• Store TECARTUS frozen in the vapor phase of liquid nitrogen (less than or equal to minus 150°C).
• Thaw before using [see Dosage and Administration (2)].