2.1 Recommended Dosage

• Administer ELZONRIS at 12 mcg/kg intravenously over 15 minutes once daily on days 1 to 5 of a 21-day cycle. The dosing period may be extended for dose delays up to day 10 of the cycle. Continue treatment with ELZONRIS until disease progression or unacceptable toxicity. The dose is calculated based on the patient’s actual weight.
• Prior to the first dose of the first cycle, ensure serum albumin is greater than or equal to 3.2 g/dL before administering ELZONRIS.
• Premedicate patients with an H1-histamine antagonist (e.g., diphenhydramine hydrochloride), H2-histamine antagonist (e.g., famotidine), corticosteroid (e.g., 50 mg intravenous methylprednisolone or equivalent) and acetaminophen (or paracetamol) approximately 60 minutes prior to each ELZONRIS infusion.
• Administer Cycle 1 of ELZONRIS in the inpatient setting with patient observation through at least 24 hours after the last infusion.
• Administer subsequent cycles of ELZONRIS in the inpatient setting or in a suitable outpatient ambulatory care setting that is equipped with appropriate monitoring for patients with hematopoietic malignancies undergoing treatment. Observe patients for a minimum of 4 hours following each infusion.

2.2 Dosage Modifications

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.

2.3 Preparation for Administration

Assure the following components required for dose preparation and administration are available prior to thawing ELZONRIS:

 

• One infusion syringe pump
• One empty 10 mL sterile vial
• 0.9% Sodium Chloride Injection, USP
• Three 10 mL sterile syringes
• One 1 mL sterile syringe
• One mini-bifuse Y-connector
• Microbore tubing
• One 0.2 micron polyethersulfone in-line filter

• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Thawed ELZONRIS appearance should be a clear, colorless liquid that may contain a few white to translucent particles.
• Prior to dose preparation thaw at room temperature, between 15°C and 25°C (59°F and 77°F), for 15 to 30 minutes in original carton, and verify thaw visually. Thawed vials may be held at room temperature for approximately 1 hour prior to dosage preparation. Do not force thaw. Do not refreeze vial once thawed.
• Use aseptic technique for preparation of the ELZONRIS dose.
• A 2-step process is required for preparation of the final ELZONRIS dose:

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  Step 1 - Prepare 10 mL of 100 mcg/mL ELZONRIS

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  Using a sterile 10 mL syringe, transfer 9 mL of 0.9% Sodium Chloride Injection, USP to an empty sterile 10 mL vial.

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  Gently swirl the ELZONRIS vial to mix the contents, remove the cap, and using a sterile 1 mL syringe, withdraw 1 mL of thawed ELZONRIS from the product vial.

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  Transfer the 1 mL of ELZONRIS into the 10 mL vial containing the 0.9% Sodium Chloride Injection, USP. Gently invert the vial at least 3 times to mix the contents. Do not shake vigorously.

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  Following dilution the final concentration of ELZONRIS is 100 mcg/mL.

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  Step 2 – Prepare the ELZONRIS infusion set.

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  Calculate the required volume of diluted ELZONRIS (100 mcg/mL) according to patient’s weight.

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  Draw up the required volume into a new syringe (if more than 10 mL of diluted ELZONRIS (100 mcg/mL) is required for the calculated patient dose, repeat step 1 with a second vial of ELZONRIS). Label the ELZONRIS syringe.

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  Prepare a separate syringe with at least 3 mL of 0.9% Sodium Chloride Injection, USP to be used to flush the administration set once the ELZONRIS dose is delivered.

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  Label the 0.9% Sodium Chloride Injection, USP flush syringe.

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  Connect the 0.9% Sodium Chloride Injection, USP flush syringe to one arm of the Y-connector and ensure the clamp is closed.

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  Connect the product syringe to the other arm of the Y-connector and ensure the clamp is closed.

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  Connect the terminal end of the Y-connector to the microbore tubing.

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  Remove the cap from the supply side of the 0.2 micron filter and attach it to the terminal end of the microbore tubing.

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  Unclamp the arm of the Y-connector connected to the 0.9% Sodium Chloride Injection, USP flush syringe. Prime the Y-connector up to the intersection (do not prime the full infusion set with 0.9% Sodium Chloride Injection, USP). Re-clamp the Y-connector line on the 0.9% Sodium Chloride Injection, USP flush arm.

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  Remove the cap on the terminal end of the 0.2 micron filter and set it aside. Unclamp the arm of the Y-connector connected to the product syringe, and prime the entire infusion set, including the filter. Recap the filter, and re-clamp the Y-connector line on the product side. The infusion set is now ready for delivery for dose administration.

• Administer ELZONRIS within 4 hours. During this 4-hour window, the prepared dose should remain at room temperature.
• Do not reuse excess ELZONRIS. Any excess material should be thrown away immediately following infusion.

2.4 Administration

• Establish venous access and maintain with sterile 0.9% Sodium Chloride Injection, USP.
• Administer the prepared ELZONRIS dose via infusion syringe pump over 15 minutes. The total infusion time will be controlled using a syringe pump to deliver the entire dose and the 0.9% Sodium Chloride Injection, USP flush over 15 minutes.
• Insert the ELZONRIS syringe into the syringe pump, open the clamp on the ELZONRIS side of the Y-connector and deliver the prepared ELZONRIS dose.
• Once the ELZONRIS syringe has been emptied, remove it from the pump and place the 0.9% Sodium Chloride Injection, USP flush syringe in the syringe pump.
• Open the clamp on the 0.9% Sodium Chloride Injection, USP flush side of the Y-connector and resume infusion via the syringe pump at the pre-specified flow to push remaining ELZONRIS dose out of the infusion line to complete delivery.

5.1 Capillary Leak Syndrome

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)].

5.2 Hypersensitivity Reactions

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)].

5.3 Hepatotoxicity

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)].

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.

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.

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.

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, ELZONRIS has the potential for adverse effects on embryo-fetal development [see Clinical Pharmacology (12.1)]. 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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

Based on its mechanism of action, ELZONRIS may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]

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.

8.4 Pediatric Use

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.

8.5 Geriatric Use

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.

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

The exposure-response relationships and the time course of pharmacodynamic response for ELZONRIS have not been fully characterized.

12.3 Pharmacokinetics

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.

12.6 Immunogenicity

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:

• 96% (115/120) of patients evaluable for the presence of pre-existing ADA at baseline before treatment were confirmed positive with 21% being positive for the presence of neutralizing antibodies. The high prevalence of ADA at baseline was anticipated due to diphtheria immunization.
• 99% (107/108) of patients evaluable for treatment-emergent ADA tested positive with most patients showing an increase in ADA titer by the end of Cycle 2 of ELZONRIS.
• 85% (86/101) of ADA-positive patients evaluable for the presence of neutralizing antibodies were neutralizing antibody-positive.
• 68% (73/108) of patients evaluable for treatment-emergent anti-IL-3 antibodies tested positive with most patients testing positive by Cycle 3 of ELZONRIS.

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.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been conducted to assess the carcinogenic or genotoxic potential of tagraxofusp. Animal fertility studies have not been conducted with tagraxofusp-erzs.

13.2 Animal Toxicology and/or Pharmacology

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.

14.1 First-Line Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

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.

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).

14.2 Relapsed or Refractory Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

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.

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).