Capillary Leak Syndrome (CLS) which may be life-threatening or fatal, can occur in patients receiving ELZONRIS. Monitor for signs and symptoms of CLS and take actions as recommended [see Warnings and Precautions ].
ELZONRIS is indicated for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and in pediatric patients 2 years and older.
Monitor vital signs and check albumin, transaminases, and creatinine prior to preparing each dose of ELZONRIS. See Table 1 for recommended dose modifications and Table 2 for CLS management guidelines.
| Parameter | Severity Criteria | Dosage Modification |
| Serum albumin | Serum albumin < 3.5 g/dL or reduced ≥ 0.5 g/dL from value measured prior to initiation of the current cycle | See CLS Management Guidelines |
| Body weight | Body weight increase ≥ 1.5 kg over pretreatment weight on prior treatment day | See CLS Management Guidelines |
| Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) | ALT or AST increase > 5 times the upper limit of normal | Withhold ELZONRIS until transaminase elevations are ≤ 2.5 times the upper limit of normal. |
| Serum creatinine | Serum creatinine > 1.8 mg/dL (159 micromol/L) or creatinine clearance < 60 mL/minute | Withhold ELZONRIS until serum creatinine resolves to ≤ 1.8 mg/dL (159 micromol/L) or creatinine clearance ≥ 60 mL/minute. |
| Systolic blood pressure | Systolic blood pressure ≥ 160 mmHg or ≤ 80 mmHg | Withhold ELZONRIS until systolic blood pressure is < 160 mmHg or > 80 mmHg. |
| Heart rate | Heart rate ≥ 130 bpm or ≤ 40 bpm | Withhold ELZONRIS until heart rate is < 130 bpm or > 40 bpm. |
| Body temperature | Body temperature ≥ 38°C | Withhold ELZONRIS until body temperature is < 38°C. |
| Hypersensitivity reactions | Mild or moderate | Withhold ELZONRIS until resolution of any mild or moderate hypersensitivity reaction. Resume ELZONRIS at the same infusion rate. |
| Severe or life-threatening | Discontinue ELZONRIS permanently. |
1If ELZONRIS dose is held:
| |||
| Time of Presentation | CLS Sign/Symptom | Recommended Action | ELZONRIS Dosing Management |
| Prior to first dose of ELZONRIS in cycle 1 | Serum albumin < 3.2 g/dL | Administer ELZONRIS when serum albumin ≥ 3.2 g/dL. | |
| During ELZONRIS dosing | Serum albumin < 3.5 g/dL | Administer 25g intravenous albumin (q12h or more frequently as practical) until serum albumin is ≥ 3.5 g/dL AND not more than 0.5 g/dL lower than the value measured prior to dosing initiation of the current cycle. | Interrupt ELZONRIS dosing until the relevant CLS sign/symptom has resolved1. |
| Serum albumin reduced by ≥ 0.5 g/dL from the albumin value measured prior to ELZONRIS dosing initiation of the current cycle | |||
| A predose body weight that is increased by ≥ 1.5 kg over the previous day’s predose weight | Administer 25g intravenous albumin (q12h or more frequently as practical), and manage fluid status as indicated clinically (e.g., generally with intravenous fluids and vasopressors if hypotensive and with diuretics if normotensive or hypertensive), until body weight increase has resolved (i.e. the increase is no longer ≥ 1.5 kg greater than the previous day’s predose weight). | ||
| Edema, fluid overload and/or hypotension | Administer 25g intravenous albumin (q12h, or more frequently as practical) until serum albumin is ≥ 3.5 g/dL. Administer 1 mg/kg of methylprednisolone (or an equivalent) per day, until resolution of CLS sign/symptom or as indicated clinically. Aggressive management of fluid status and hypotension if present, which could include intravenous fluids and/or diuretics or other blood pressure management, until resolution of CLS sign/symptom or as clinically indicated. | ||
Assure the following components required for dose preparation and administration are available prior to thawing ELZONRIS:
Injection: 1,000 mcg in 1 mL clear colorless solution in a single-dose vial.
Risk Summary
Based on its mechanism of action, ELZONRIS has the potential for adverse effects on embryo-fetal development [see Clinical Pharmacology ]. There are no available data on ELZONRIS use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Animal reproduction or developmental toxicity studies have not been conducted with tagraxofusp-erzs. Advise pregnant women of the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively.
Risk Summary
No data are available regarding the presence of ELZONRIS in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children from ELZONRIS, breast feeding is not recommended during treatment and for 1 week after the last dose.
Based on its mechanism of action, ELZONRIS may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ]
Pregnancy Testing:
Conduct pregnancy testing in females of reproductive potential within 7 days prior to initiating ELZONRIS treatment.
Contraception:
Advise females to use acceptable contraceptive methods during ELZONRIS treatment and for 1 week after the last dose of ELZONRIS.
The safety and effectiveness of ELZONRIS for treatment of BPDCN have been established in pediatric patients 2 years of age and older (no data for pediatric patients less than 2 years of age). Use of ELZONRIS in these age groups is supported by evidence from an adequate and well-controlled study of ELZONRIS in adults with BPDCN and additional safety data from three pediatric patients with BPDCN, including 1 child (2 years to < 12 years old) and 2 adolescents (12 years to < 17 years old), treated with ELZONRIS at the recommended dosage. The safety profile of ELZONRIS in the pediatric patients was similar to that seen in the adults. Efficacy for pediatric patients is extrapolated from the results of STML-401-0114 [see Clinical Studies 14.1, 14.2]. Safety and effectiveness have not been established in pediatric patients younger than 2 years of age.
Of the 86 patients who received ELZONRIS for BPDCN at the labeled dose in STML-401-0114, 63% were 65 years and older and 22% were 75 years and older. Patients 75 years or older experienced a higher incidence of altered mental status (including confusional state, delirium, mental status changes, dementia, and encephalopathy) than patients under 75 years of age.
None.
Capillary leak syndrome (CLS), including life-threatening and fatal cases, has been reported among patients treated with ELZONRIS. In patients receiving ELZONRIS in clinical trials, the overall incidence of CLS was 53% (65/122), including Grade 1 or 2 in 43% (52/122) of patients, Grade 3 in 7% (8/122) of patients, Grade 4 in 1% (1/122) of patients, and four fatalities (3%) [see Adverse Reactions (6.1)]. The median time to onset was 4 days (range - 1 to 46 days), and all but 5 patients experienced an event in Cycle 1.
Before initiating therapy with ELZONRIS, ensure that the patient has adequate cardiac function and serum albumin is greater than or equal to 3.2 g/dL. During treatment with ELZONRIS, monitor serum albumin levels prior to the initiation of each dose of ELZONRIS and as indicated clinically thereafter, and assess patients for other signs or symptoms of CLS, including weight gain, new onset or worsening edema, including pulmonary edema, hypotension or hemodynamic instability [see Dosage and Administration (2.2)].
ELZONRIS can cause severe hypersensitivity reactions. In patients receiving ELZONRIS in clinical trials, hypersensitivity reactions were reported in 43% (53/122) of patients treated with ELZONRIS and were Grade ≥ 3 in 7% (9/122) [see Adverse Reactions (6.1)]. Manifestations of hypersensitivity reported in ≥ 5% of patients include rash, pruritus, and stomatitis. Monitor patients for hypersensitivity reactions during treatment with ELZONRIS. Interrupt ELZONRIS infusion and provide supportive care as needed if a hypersensitivity reaction should occur [see Dosage and Administration (2.2)].
Treatment with ELZONRIS was associated with elevations in liver enzymes. In patients receiving ELZONRIS in clinical trials, elevations in ALT occurred in 79% (96/122) and elevations in AST occurred in 76% (93/122) [see Adverse Reactions (6.1)]. Grade 3 ALT elevations were reported in 26% (32/122) of patients. Grade 3 AST elevations were reported in 30% (36/122) and Grade 4 AST elevations were reported in 3% (4/122) of patients. Elevated liver enzymes occurred in the majority of patients in Cycle 1 and were reversible following dose interruption.
Monitor alanine aminotransferase (ALT) and aspartate aminotransferase (AST) prior to each infusion with ELZONRIS. Withhold ELZONRIS temporarily if the transaminases rise to greater than 5 times the upper limit of normal and resume treatment upon normalization or when resolved [see Dosage and Administration (2.2)].
The following serious adverse drug reactions are described elsewhere in the labeling:
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.
Safety of ELZONRIS was assessed in a single-arm clinical trial that included 122 adults with newly diagnosed or relapsed/refractory myeloid malignancies, including 86 with BPDCN, treated with ELZONRIS 12 mcg/kg daily for 5 days of a 21-day cycle. The overall median number of cycles started was 2.5 (range, 1-76), and 4 in patients with BPDCN (range, 1-76).
Four (3%) patients (4/122) had fatal adverse reactions, all of which were related to capillary leak syndrome. Overall, 8% (10/122) of patients discontinued treatment with ELZONRIS due to an adverse reaction; the most common adverse reactions resulting in treatment discontinuation were hepatic toxicities, hypoalbuminemia and CLS (2% each).
Table 3 summarizes the common (≥ 10%) adverse reactions with ELZONRIS in patients with myeloid malignancies. The rate of any given adverse reaction or lab abnormality was derived from all the reported events of that type.
1 Capillary leak syndrome defined as any event reported as CLS during treatment with ELZONRIS or the occurrence of at least 2 of the following CLS manifestations within 7 days of each other: hypoalbuminemia (including albumin value less than 3.0 g/dL), edema (including weight increase of 5 kg or more), hypotension (including systolic blood pressure less than 90 mmHg). | ||
| N=122 | ||
| All Grades % | Grade ≥ 3 % | |
| Vascular disorders | ||
| Capillary leak syndrome1 | 53 | 11 |
| Hypotension | 25 | 7 |
| Hypertension | 14 | 6 |
| General disorders and administration site conditions | ||
| Fatigue | 45 | 7 |
| Pyrexia | 43 | 0 |
| Peripheral edema | 39 | 1 |
| Chills | 26 | 1 |
| Gastrointestinal disorders | ||
| Nausea | 45 | 0 |
| Constipation | 24 | 0 |
| Diarrhea | 21 | 0 |
| Vomiting | 19 | 0 |
| Investigations | ||
| Weight increase | 31 | 0 |
| Nervous system disorders | ||
| Headache | 28 | 0 |
| Dizziness | 21 | 0 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 22 | 0 |
| Respiratory, thoracic and mediastinal disorders | ||
| Dyspnea | 20 | 3 |
| Epistaxis | 12 | 1 |
| Cough | 12 | 0 |
| Blood and lymphatic system disorders | ||
| Febrile neutropenia | 19 | 16 |
| Musculoskeletal and connective tissue disorders | ||
| Back pain | 19 | 2 |
| Pain in extremity | 10 | 2 |
| Cardiac disorders | ||
| Tachycardia | 17 | 0 |
| Psychiatric disorders | ||
| Insomnia | 16 | 0 |
| Anxiety | 15 | 0 |
| Skin and subcutaneous tissue disorders | ||
| Pruritus | 10 | 0 |
Clinically relevant adverse reactions occurring in less than 10% of patients treated with ELZONRIS included tumor lysis syndrome.
Table 4 summarizes the clinically important laboratory abnormalities that occurred in ≥ 10% patients with myeloid malignancies treated with ELZONRIS.
| Treatment-Emergent Laboratory Abnormalities | ||
| All Grades % | Grade ≥ 3 % | |
| Hematology | ||
| Platelets decrease | 68 | 49 |
| Hemoglobin decrease | 61 | 30 |
| Neutrophils decrease | 38 | 29 |
| Chemistry | ||
| Glucose increase | 89 | 21 |
| ALT increase | 79 | 26 |
| AST increase | 76 | 33 |
| Albumin decrease | 72 | 1 |
| Calcium decrease | 57 | 2 |
| Sodium decrease | 52 | 9 |
| Potassium decrease | 36 | 6 |
| Phosphate decrease | 32 | 10 |
| Creatinine increase | 26 | 0 |
| Magnesium decrease | 25 | 0 |
| Alkaline phosphatase increase | 22 | 1 |
| Potassium increase | 20 | 3 |
| Magnesium increase | 13 | 4 |
| Bilirubin increase | 11 | 0 |
| Glucose decrease | 10 | 0 |
Tagraxofusp-erzs, a CD123-directed cytotoxin, is a fusion protein comprised of a recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT). Tagraxofusp-erzs has an approximate molecular weight of 57,695 Daltons. Tagraxofusp-erzs is constructed by recombinant DNA technology and produced in Escherichia coli cells.
ELZONRIS (tagraxofusp-erzs) injection is a preservative-free, sterile, clear, colorless solution that may contain a few white to translucent particles and requires dilution prior to intravenous infusion. ELZONRIS is supplied at a concentration of 1,000 mcg/mL in a single-dose vial. Each mL of ELZONRIS contains 1,000 mcg tagraxofusp-erzs, sodium chloride (4.38 mg), sorbitol (50 mg), tromethamine (2.42 mg) and Water for Injection, USP and pH is 7.5.
Tagraxofusp-erzs is a CD123-directed cytotoxin composed of recombinant human interleukin-3 (IL-3) and truncated diphtheria toxin (DT) fusion protein that inhibits protein synthesis and causes cell death in CD123-expressing cells.
The exposure-response relationships and the time course of pharmacodynamic response for ELZONRIS have not been fully characterized.
Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with BPDCN, the mean (SD) area under the plasma drug concentration over time curve (AUC) was 231 (123) hr·mcg/L and maximum plasma concentration (Cmax) was 162 (58.1) mcg/L.
Distribution
Mean (SD) volume of distribution of tagraxofusp-erzs is 5.1 (1.9) L in patients with BPDCN.
Elimination
Mean (SD) clearance is 7.1 (7.2) L/hr in patients with BPDCN. Mean (SD) terminal half-life of tagraxofusp-erzs is 0.7 (0.3) hours.
Specific Population
No clinically significant differences in the pharmacokinetics of tagraxofusp-erzs were observed based on age (22 to 84 years), sex, mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2, estimated by MDRD), mild (total bilirubin ≤ ULN and AST >ULN, or total bilirubin 1 to 1.5 times ULN and any AST) or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic impairment or body weight after adjusting dose by body weight. The effect of severe renal impairment (eGFR 15 to 29 mL/min/1.73 m2), or severe hepatic impairment (total bilirubin >3 times ULN and any AST) on tagraxofusp-erzs pharmacokinetics is unknown.
Drug Interaction Studies
No drug-drug interaction studies have been conducted with ELZONRIS.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ELZONRIS with the incidences of antibodies to other products may be misleading. Immune response to ELZONRIS was evaluated by assessment of serum binding reactivity against ELZONRIS (anti-drug antibodies; ADA) and neutralizing antibodies by inhibition of functional activity. Immune response to ELZONRIS was assessed using two immunoassays. The first assay detected reactivity directed against ELZONRIS (ADA), and the second assay detected reactivity against the interleukin-3 (IL-3) portion of ELZONRIS. Two cell-based assays were used to investigate the presence of neutralizing antibodies by inhibition of a cell-based functional activity.
In 130 patients treated with ELZONRIS in 4 clinical trials:
Anti-Product Antibody Effects on Pharmacokinetics
The presence of ADA had a clinically significant effect on the pharmacokinetics of tagraxofusp-erzs. Pharmacokinetic data obtained following doses given in Cycle 3 showed increased titers of anti-drug antibodies and reduced free ELZONRIS concentration in most plasma samples. Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with pre-existing anti-drug antibodies, the mean (SD) volume of distribution of tagraxofusp-erzs is 21.2 (25.4) L, clearance is 13.9 (19.4) L/hr, AUC is 151 (89.2) hr·mcg/L and Cmax is 80.0 (82.2) mcg/L.
No studies have been conducted to assess the carcinogenic or genotoxic potential of tagraxofusp. Animal fertility studies have not been conducted with tagraxofusp-erzs.
At human equivalent doses greater than or equal to 1.6 times the recommended dose based on body surface area, severe kidney tubular degeneration/necrosis was observed in cynomolgus monkeys. At human equivalent doses equal to the recommended dose, degeneration/necrosis of the choroid plexus in the brain was observed in cynomolgus monkeys. The reversibility of this finding was not assessed at lower doses, but the finding was irreversible and became progressively more severe at a human equivalent dose 1.6 times the recommended dose, 3 weeks after dosing stopped.
STML-401-0114 (NCT 02113982; Study 0114) was a multicenter, open-label, single-arm, clinical trial that included a prospective cohort of 13 patients with treatment-naive BPDCN. Treatment consisted of ELZONRIS 12 mcg/kg intravenously over 15 minutes once daily on days 1 to 5 of a 21-day cycle. Patient baseline characteristics are presented in Table 5.
| Parameter | N=13 |
| Gender, N (%) | |
| Male | 11 (84.6) |
| Female | 2 (15.4) |
| Age (years), N (%) | |
| Median | 65.0 |
| Minimum, Maximum | 22, 84 |
| ECOG, N (%) | |
| 0 | 8 (61.5) |
| 1 | 5 (38.5) |
| BPDCN at Baseline, N (%) | |
| Skin | 13 (100.0) |
| Bone Marrow | 7 (53.8) |
| Peripheral Blood | 3 (23.1) |
| Lymph Nodes | 6 (46.2) |
| Viscera | 2 (15.4) |
The efficacy of ELZONRIS in patients with treatment-naive BPDCN was based on the rate of complete response or clinical complete response (CR/CRc). Key efficacy measures are presented in Table 6. The median time to CR/CRc was 57 days (range: 14 to 107).
* CRc is defined as complete response with residual skin abnormality not indicative of active disease. | |
| Parameter | N=13 |
| CR/CRc* Rate, N (%) | 7 (53.8) |
| (95% CI) | (25.1, 80.8) |
| Duration of CR/CRc (months) | |
| Median | Not reached |
| Minimum, Maximum | 3.9, 12.2 |
| Duration of follow up (months) | |
| Median | 11.5 |
| Minimum, Maximum | 0.2, 12.7 |
STML-401-0114 (NCT02113982; Study 0114) was a multicenter, open-label, single-arm, clinical trial that included 15 patients with relapsed or refractory BPDCN. Treatment consisted of ELZONRIS 12 mcg/kg on days 1 to 5 of each 21-day cycle. Patient baseline characteristics are presented in Table 7.
| Parameter | N=15 |
| Gender, N (%) | |
| Male | 13 (86.7) |
| Female | 2 (13.3) |
| Age (years) | |
| Median | 72 |
| Minimum, Maximum | 44, 80 |
| ECOG, N (%) | |
| 0 | 5 (33.3) |
| 1 | 10 (66.7) |
| BPDCN at Baseline, N (%) | |
| Skin | 13 (86.7) |
| Bone marrow | 9 (60.0) |
| Lymph node | 8 (53.3) |
| Visceral | 4 (26.7) |
| Peripheral blood | 1 (6.7) |
In the 15 patients with relapsed/refractory BPDCN, one patient achieved a CR (duration: 111 days) and one patient achieved a CRc (duration: 424 days).
How Supplied
ELZONRIS (tagraxofusp-erzs) injection is a preservative-free, sterile, clear, colorless, 1,000 mcg in 1 mL solution supplied in a single-dose glass vial. Each carton contains one vial (NDC 72187-0401-1).
Storage and Handling
Store in freezer between -25°C and -15°C (-13°F and 5°F). Protect ELZONRIS from light by storing in the original package until time of use. Thaw vials at room temperature between 15°C and 25°C (59°F and 77°F) prior to preparation [see Dosage and Administration ]. Do not refreeze the vial once thawed. Do not use beyond expiration date on container.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ELZONRIS with the incidences of antibodies to other products may be misleading. Immune response to ELZONRIS was evaluated by assessment of serum binding reactivity against ELZONRIS (anti-drug antibodies; ADA) and neutralizing antibodies by inhibition of functional activity. Immune response to ELZONRIS was assessed using two immunoassays. The first assay detected reactivity directed against ELZONRIS (ADA), and the second assay detected reactivity against the interleukin-3 (IL-3) portion of ELZONRIS. Two cell-based assays were used to investigate the presence of neutralizing antibodies by inhibition of a cell-based functional activity.
In 130 patients treated with ELZONRIS in 4 clinical trials:
Anti-Product Antibody Effects on Pharmacokinetics
The presence of ADA had a clinically significant effect on the pharmacokinetics of tagraxofusp-erzs. Pharmacokinetic data obtained following doses given in Cycle 3 showed increased titers of anti-drug antibodies and reduced free ELZONRIS concentration in most plasma samples. Following administration of tagraxofusp-erzs 12 mcg/kg via 15-minute infusion in patients with pre-existing anti-drug antibodies, the mean (SD) volume of distribution of tagraxofusp-erzs is 21.2 (25.4) L, clearance is 13.9 (19.4) L/hr, AUC is 151 (89.2) hr·mcg/L and Cmax is 80.0 (82.2) mcg/L.
