Dosing & Uses
Dosage Forms & Strengths
injection, suspension
- 2.68-10 x 109 MAGE-A4 TCR-positive T cells in 1 or more patient-specific infusion bag(s)
- Each 250-mL infusion bag contained in a protective metal cassette
Synovial Sarcoma
Indicated for unresectable or metastatic melanoma-associated antigen A4 (MAGE-A4)-positive synovial sarcoma in adults who are HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, or HLA-A*02:06P positive and have received prior chemotherapy
2.68-10 x 109 MAGE-A4 T-cell receptor (TCR)-positive T cells IV as a single dose
Premedicate with acetaminophen and H1-antihistamine ∼30-60 min before infusion
Administer on Day 1 following lymphodepleting therapy
Lymphodepleting chemotherapy
- Fludarabine 30 mg/m2 IV qDay for 4 days (on Days -7, -6, -5, and -4) AND
- Cyclophosphamide 600 mg/m2 IV qDay for 3 days (on Days -7, -6, and -5)
- Granulocyte-colony stimulating factors may be considered ≥24 hr after last dose of lymphodepleting chemotherapy
Dosage Modifications
Renal or hepatic impairment: not studied
Dosing Considerations
For autologous use only
Ensure patient is euvolemic before starting infusion
Administer at a healthcare facility with access to medications and resuscitative equipment to manage cytokine release syndrome (CRS)
Monitor signs/symptoms of CRS and neurologic toxicities at least daily for 7 days following infusion
Instruct patients to remain close to healthcare facility for at least 4 weeks following infusion
Patient selection
- Use FDA-approved or cleared companion diagnostic devices
- Test patients for HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, and HLA-A*02:06P alleles
- Test tumor samples for MAGE-A4 expression
Safety and efficacy not established
Adverse Effects
>50%
All grades
- Lymphocyte count decreased (98%)
- Neutrophil count decreased (96%)
- White blood cell decreased (96%)
- Red blood cell decreased (96%)
- Platelet count decreased (82%)
- Cytokine release syndrome (75%)
- Nausea (66%)
Grade 3 or 4
- Lymphocyte count decreased (98%)
- Neutrophil count decreased (91%)
- White blood cell decreased (86%)
>10-50%
All grades
- Alanine aminotransferase increased (46%)
- Vomiting (36%)
- Fatigue (34%)
- Constipation (32%)
- Infection (32%)
- Pyrexia (32%)
- Abdominal pain (25%)
- Dyspnea (25%)
- Non-cardiac chest pain (23%)
- Decreased appetite (23%)
- Diarrhea (21%)
- Edema (21%)
- Back pain (21%)
- Hypotension (21%)
- Sinus tachycardia/tachycardia (21%)
- Headache (18%)
- Cough (18%)
- Asthenia (16%)
- Chills (16%)
- Hypertension (16%)
- Chest pain (14%)
- Pain in extremity (14%)
- Alopecia (14%)
- Dizziness (11%)
- Weight decreased (11%)
Grade 3 or 4
- Red blood cell decreased (32%)
- Platelet count decreased (21%)
- Infection (14%)
- Back pain (5%)
- Dyspnea (5%)
- Abdominal pain (5%)
- Alanine aminotransferase increased (5%)
- Pyrexia (5%)
- Weight decreased (2%)
- Nausea (2%)
- Non-cardiac chest pain (2%)
- Asthenia (2%)
- Cytokine release syndrome (2%)
- Headache (2%)
- Decreased appetite (2%)
- Hypertension (2%)
Other Clinically Important ADRs
- Pleural effusion (7%)
- Immune effector cell-associated neurotoxicity syndrome, grade 1 (2%)
Warnings
Black Box Warnings
Cytokine release syndrome (CRS)
- Severe or life-threatening CRS can occur
- Consider need for hospitalization and institute treatment with supportive care at first sign of CRS
- Ensure healthcare providers have immediate access to medications and resuscitative equipment to manage CRS
Contraindications
Heterozygous or homozygous for HLA-A*02:05P
Cautions
CRS
- Common symptoms include fever, tachycardia, hypotension, nausea/vomiting, and headache
- Median time to onset, 2 days (range, 1-5); median time to resolution, 3 days (range, 1-14)
- Ensure patients are euvolemic before starting infusion
- Monitor for signs and symptoms of CRS during infusion, at a healthcare facility daily for at least 7 days following infusion, and then for at least 4 weeks after infusion
- Start supportive care and manage per current practice guidelines if CRS develops; hospitalization may be necessary
- Tocilizumab was used for CRS management in some patients
Immune effector cell-associated neurotoxicity syndrome (ICANS)
- ICANS reported
- Symptoms may include mild mental status changes, drowsiness, or inattention
- Severe symptoms may also occur (eg, disorientation to time and place, altered consciousness, seizures, cerebral edema, cognitive impairment, progressive, aphasia, or motor weakness)
- Ensure healthcare providers have immediate access to medications and resuscitative equipment to manage ICANS
- Monitor for signs and symptoms of ICANS during infusion, at a healthcare facility daily for at least 7 days following infusion, and then for at least 4 weeks after infusion
- Start supportive care and manage per current practice guidelines if ICANS develops; hospitalization may be necessary
Driving or machine use
- Neurologic effects (eg, dizziness, presyncope, altered or decreased coordination) may occur
- Advise patients to not drive or engage in hazardous occupations or activities (eg, operating heavy or potentially dangerous machinery) for 4 weeks after infusion
Prolonged severe cytopenia
- Anemia, neutropenia, and thrombocytopenia lasting 4 weeks or longer can occur
- Monitor blood counts after infusion
- Manage with growth factors and transfusions per local institutional guidelines or clinical practice
Infection
- Infections reported; febrile neutropenia may occur concurrently with CRS
- Monitor for signs and symptoms of infection before and after infusion
- Avoid in patients with active infections or inflammatory disorders
- Treat infection and manage febrile neutropenia as medically indicated (eg, broad-spectrum antibiotics, fluids, other supportive care)
- Viral reactivation may occur; screen for Epstein-Barr virus, cytomegalovirus, hepatitis B and C viruses, human immunodeficiency virus (HIV), and other infectious agents as clinically indicated
- Consider antiviral prophylaxis to prevent viral reactivation
Secondary malignancies
- Secondary malignancies or cancer recurrence may occur
- Monitor for secondary malignancies
- Contact Adaptimmune at 1-855-246-9232 for instructions on patient sample collection and testing if a secondary malignancy develops
Hypersensitivity reactions
- Product contains dimethyl sulfoxide; serious hypersensitivity reactions (eg, anaphylaxis) may occur
- Premedicate with acetaminophen and H1-antihistamine ∼30-60 min before infusion
- Monitor for hypersensitivity reactions during infusion
HIV nucleic acid tests
- HIV and the lentivirus used to make afamitresgene autoleucel have limited, short spans of identical genetic material
- Commercial HIV nucleic acid tests may yield false-positive results
Pregnancy & Lactation
Pregnancy
No data available in pregnant women or from animal reproductive and developmental toxicity studies
Perform pregnancy test prior to therapy in females of reproductive potential
Not recommended in pregnancy; unknown if afamitresgene autoleucel can be transferred to fetus and cause fetal toxicity
Report pregnancy following infusion to Adaptimmune at 1-855-246-9232
Lactation
No data available on presence in human milk, effects on breastfed infants, or effects on milk production
Consider developmental and health benefits of breastfeeding and potential adverse effects on breastfed infant from therapy or underlying maternal condition along with patient’s clinical need for therapy
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Melanoma-associated antigen A4 (MAGEA4)-directed genetically modified autologous T-cell immunotherapy
Prepared from a patient's own peripheral blood mononuclear cells (PBMCs); obtained via standard leukapheresis procedure
Patient-specific product consists of CD4- and CD8-positive T cells transduced with a self-inactivating lentiviral vector (LV) expressing an affinity-enhanced T-cell receptor (TCR) specific for human MAGE-A4
MAGE-A4 is an intracellular antigen that is expressed in synovial sarcoma cells
TCR recognizes HLA-A*02-restricted MAGE-A4 peptide and forms a TCR-peptide-HLA-A*02 complex
Antigen-specific activation of this complex leads to T cell proliferation, cytokine secretion, and MAGE-A4/HLA-A*02-expressing tumor cell death
Pharmacodynamics
Peak serum concentrations occurred on Days 3-8 for cytokines and other soluble factors involved in cellular homeostasis, T cell activation, and inflammation (eg, IFNγ, IL-6, IL-8, IL-15, and IL-2Rα)
Absorption
Initial engraftment and expansion phase followed by contraction and then persistence
Peak plasma concentration (Cmax), mean: 189,269 DNA copies/mcg
Peak plasma time (Tmax), median: 7 days (range, 1-89)
AUC
- 0-7 days: mean, 729,653 day⋅DNA copies/mcg
- 0-28 days: mean, 3,074,205 day⋅DNA copies/mcg
- 0-3 mo: mean, 4,988,965 day⋅DNA copies/mcg
- 0-6 mo: mean, 6,784,047 day⋅DNA copies/mcg
Pharmacogenomics
HLA-A*02 genotype: HLA-A*02:01P, HLA-A*02:02P, HLA-A*02:03P, HLA-A*02:06P
Administration
Inspect Product
Ensure product arrives prior to beginning lymphodepleting chemotherapy
Follow universal precautions and local biosafety guidelines for handling and disposal to avoid potential transmission of infectious diseases
Contact Adaptimmune at 1-855-246-9232 for
- Visible signs of damage or anomalies of product upon receipt
- Labels or patient identifiers on cassette(s) or infusion bag(s) that do not match patient name
- Breaks, cracks, or otherwise compromised infusion bag(s) upon removal from cassette(s)
- Improper product storage at any time prior to thaw
- Presence of cellular clumps that do not disperse with gentle manual massaging after infusion bag(s) thaw
Preparation
Confirm infusion time in advance; adjust start time for thaw so that autologous suspension is available for infusion when recipient is ready
If more than 1 infusion bag is needed for dose, administer content of each infusion bag completely before thawing next infusion bag
Place infusion bag inside a second sealable and sterile bag per standard practice
Thaw infusion bag at 37ºC using either a water bath or dry thaw method until there is no visible ice
Gently mix contents with manual massaging to disperse visible cell clumps; do not infuse if clumps do not disperse
Do not pre-filter into a different container or wash, spin down, or resuspend autologous product in new media
Administer infusion bag within 1 hr of thawing
Premedication
Premedicate with acetaminophen and H1-antihistamine ∼30-60 min before infusion
Avoid prophylactic systemic corticosteroids
IV Administration
Do not use a leukodepleting filter
Prime tubing of infusion set with 0.9% NaCl solution prior to infusion
Administer entire contents of infusion bag via IV infusion within 1 hr
Rinse infusion bag with ∼50 mL 0.9% NaCl solution and infuse to ensure complete product delivery
Repeat thaw and administration for next infusion bag if more than 1 infusion bag is needed for dose
Storage
Frozen product
- Keep in original packaging
- Store in vapor phase of liquid nitrogen at -130ºC or colder
Thawed infusion bag
- Store at ambient temperature (20-25ºC) for up to 1 hr
Formulary
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