Loncastuximab tesirine-lpyl

Loncastuximab tesirine-lpyl
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Parth Vikram Singh, MBBS[2]

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Overview

Loncastuximab tesirine-lpyl is a CD19-directed antibody and alkylating agent that is FDA approved for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.. Common adverse reactions include thrombocytopenia, increased gamma-glutamyltransferase, neutropenia, anemia, hyperglycemia, transaminase elevation, fatigue, hypoalbuminemia, rash, edema, nausea, and musculoskeletal pain..

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

There is limited information regarding Loncastuximab tesirine-lpyl FDA-Labeled Indications and Dosage (Adult) in the drug label.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Loncastuximab tesirine-lpyl in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Loncastuximab tesirine-lpyl in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Loncastuximab tesirine-lpyl FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Loncastuximab tesirine-lpyl in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Loncastuximab tesirine-lpyl in pediatric patients.

Contraindications

There is limited information regarding Loncastuximab tesirine-lpyl Contraindications in the drug label.

Warnings

There is limited information regarding Loncastuximab tesirine-lpyl Warnings' in the drug label.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Loncastuximab tesirine-lpyl Clinical Trials Experience in the drug label.

Postmarketing Experience

There is limited information regarding Loncastuximab tesirine-lpyl Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Loncastuximab tesirine-lpyl Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Loncastuximab tesirine-lpyl in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Loncastuximab tesirine-lpyl in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Loncastuximab tesirine-lpyl during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl in geriatric settings.

Gender

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl with respect to specific gender populations.

Race

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Loncastuximab tesirine-lpyl in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Loncastuximab tesirine-lpyl in patients who are immunocompromised.

Immunogenicity

• As with all therapeutic proteins, there is potential for 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 in the studies described below with the incidence of antibodies to loncastuximab tesirine-lpyl in other studies or to other products may be misleading.

• In LOTIS-2, 0 of 134 patients tested positive for antibodies against loncastuximab tesirine-lpyl after treatment. The potential effect of anti-drug antibodies to ZYNLONTA on pharmacokinetics, efficacy, or safety is unknown.

Administration and Monitoring

Administration

There is limited information regarding Loncastuximab tesirine-lpyl Administration in the drug label.

Monitoring

There is limited information regarding Loncastuximab tesirine-lpyl Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Loncastuximab tesirine-lpyl and IV administrations.

Overdosage

There is limited information regarding Loncastuximab tesirine-lpyl overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Loncastuximab tesirine-lpyl Pharmacology in the drug label.

Mechanism of Action

• Loncastuximab tesirine-lpyl is an antibody-drug conjugate (ADC) targeting CD19. The monoclonal IgG1 kappa antibody component binds to human CD19, a transmembrane protein expressed on the surface of cells of B-lineage origin. The small molecule component is SG3199, a PBD dimer and alkylating agent.

• Upon binding to CD19, loncastuximab tesirine-lpyl is internalized followed by release of SG3199 via proteolytic cleavage. The released SG3199 binds to the DNA minor groove and forms highly cytotoxic DNA interstrand crosslinks, subsequently inducing cell death. Loncastuximab tesirine-lpyl had anticancer activity in animal models of lymphoma.

Structure

There is limited information regarding Loncastuximab tesirine-lpyl Structure in the drug label.

Pharmacodynamics

• Higher loncastuximab tesirine-lpyl exposure in Cycle 1 was associated with higher incidence of some Grade ≥2 adverse reactions, including skin and nail reactions,
• liver function test abnormalities and increased gamma-glutamyltransferase. Lower loncastuximab tesirine-lpyl exposure in Cycle 1 was associated with lower efficacy over the dose range of 0.015-0.2 mg/kg (0.1 to 1.33 times the maximum recommended dose).

Cardiac Electrophysiology

• At the maximum recommended therapeutic dose of 0.15 mg/kg during Cycle 1 and Cycle 2, loncastuximab tesirine-lpyl does not cause large mean increases (i.e., >20 msec) in the QTc interval.

Pharmacokinetics

• The exposure of loncastuximab tesirine-lpyl at the approved recommended dosage in Cycle 2 and at steady state is shown in Table 3. Loncastuximab tesirine-lpyl steady state Cmax was 28.2% lower than the Cmax after the first dose. The time to reach steady state was 105 days.

Loncastuximab Tesirine-lpyl Exposure Parameters

Distribution

• The mean (CV%) of loncastuximab tesirine-lpyl volume of distribution was 7.11 (26.6%) L.

Elimination

• The mean (CV%) of loncastuximab tesirine-lpyl clearance decreased with time from 0.499 L/day (89.3%) after a single dose to 0.275 L/day (38.2%) at steady state. The mean (standard deviation) half-life of loncastuximab tesirine-lpyl was 20.8 (7.06) days at steady state.

Metabolism

• The monoclonal antibody portion of loncastuximab tesirine-lpyl is expected to be metabolized into small peptides by catabolic pathways. The small molecule cytotoxin, SG3199, is metabolized by CYP3A4/5 in vitro.

Excretion

• The major excretion pathways of SG3199 have not been studied in humans. SG3199 is expected to be minimally renally excreted.

Specific Populations

• No clinically significant differences in the pharmacokinetics of loncastuximab tesirine-lpyl were observed based on age (20-94 years), sex, race (White vs. Black), body weight (42.1 to 160.5 kg), *ECOG status (0 to 2) or mild to moderate renal impairment (CLcr 30 to <90 mL/min using the Cockcroft-Gault equation).
• The effect of severe renal impairment (CLcr 15 to 29 mL/min), and end-stage renal disease with or without hemodialysis on loncastuximab tesirine-lpyl pharmacokinetics is unknown.

Patients with Hepatic Impairment

• Mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1 to 1.5 × ULN and any AST) may increase the exposure of unconjugated SG3199, however there was no clinically significant effect on loncastuximab tesirine-lpyl pharmacokinetics.
• The effect of moderate (total bilirubin >1.5 to ≤3 × ULN and any AST) or severe (total bilirubin >3 ULN and any AST) hepatic impairment on loncastuximab tesirine-lpyl pharmacokinetics is unknown.

Drug Interaction Studies

In Vitro Studies

• Cytochrome P450 (CYP) Enzymes: SG3199 does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4/5 at clinically relevant unconjugated SG3199 concentrations.

Transporter Systems:

• SG3199 is a substrate of P-glycoprotein (P-gp), but not a substrate of breast cancer resistance protein (BCRP), organic anion-transporting polypeptide (OATP)1B1, or organic cation transporter (OCT)1.
• SG3199 does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT)1, OAT3, OCT2, OCT1, multi-antimicrobial extrusion protein (MATE)1, MATE2-K, or bile salt export pump (BSEP) at clinically relevant unconjugated SG3199 concentrations.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

• Carcinogenicity studies have not been conducted with loncastuximab tesirine-lpyl or SG3199.

• SG3199 was genotoxic in an in vitro micronucleus test and a chromosome aberration assay using human lymphocytes through a clastogenic mechanism. These results are consistent with the pharmacological effect of SG3199 as a covalent DNA crosslinking agent. Results of a bacterial reverse mutation assay (Ames test) were inconclusive due to cytotoxicity.

• Fertility studies have not been conducted with loncastuximab tesirine-lpyl. Results from repeat-dose toxicity studies with intravenous administration of loncastuximab tesirine-lpyl in cynomolgus monkeys indicate the potential for impaired male reproductive function and fertility. Administration of loncastuximab tesirine-lpyl to cynomolgus monkeys every 3 weeks at 0.6 mg/kg for a total of 2 doses, or every 3 weeks at 0.3 mg/kg for 13 weeks resulted in adverse findings that included decreased weight and/or size of the testes and epididymis, atrophy of the seminiferous tubules, germ cell degeneration, and/or reduced sperm content. The dose of 0.3 mg/kg in animals results in an exposure (AUC) that is approximately 3 times the exposure at the maximum recommended human dose [MRHD] of 0.15 mg/kg. Findings were not reversible at the end of the 12-week recovery period following 4 or 13 weeks of dosing.

Animal Toxicology and/or Pharmacology

• Inflammatory-mediated toxicities associated with PBDs have been observed at low incidence in animals. In repeat-dose toxicity studies in cynomolgus monkeys, administration of loncastuximab tesirine-lpyl was associated with potential inflammatory mediated-toxicities, including in the lungs and kidneys.
• Renal toxicity including increased kidney weights and nephropathy with variable inflammation and fibrosis that was reversible was observed in monkeys. Black skin spots potentially related to phototoxicity were observed and were still present after the 12-week treatment-free period.

Clinical Studies

Relapsed or Refractory Diffuse Large B-cell Lymphoma

• The efficacy of ZYNLONTA was evaluated in LOTIS-2 (NCT03589469), an open-label, single-arm trial in 145 adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after at least 2 prior systemic regimens. The trial excluded patients with bulky disease and active central nervous system lymphoma. Patients received ZYNLONTA 0.15 mg/kg every 3 weeks for 2 cycles, then 0.075 mg/kg every 3 weeks for subsequent cycles and received treatment until progressive disease, or unacceptable toxicity.
• Of the 145 patients enrolled, the median age was 66 years (range 23 to 94), 59% male, and 94% had an ECOG performance status of 0 to 1. Race was reported in 97% of patients; of these patients, 90% were White, 3% were Black, and 2% were Asian. The diagnosis was DLBCL not otherwise specified (NOS) in 88% (including 20% with DLBCL arising from low-grade lymphoma) and high-grade B-cell lymphoma in 7%. The median number of prior therapies was 3 (range 2 to 7), 63% with refractory disease, 17% with prior stem cell transplant, and 9% with prior chimeric antigen receptor (CAR) T-cell therapy.
• Efficacy was established on the basis of overall response rate (ORR) as assessed by an Independent Review Committee (IRC) using Lugano 2014 criteria (Table 4). The median follow-up time was 7.3 months (range 0.3 to 20.2).

Efficacy Results in Patients with Relapsed or Refractory DLBCL

The median time to response was 1.3 months (range 1.1 to 8.1).

How Supplied

ZYNLONTA (loncastuximab tesirine-lpyl) for injection is a sterile, preservative-free, white to off-white lyophilized powder, which has a cake-like appearance, supplied in a single-dose vial for reconstitution and further dilution. Each carton (NDC 79952-110-01) contains one 10 mg single-dose vial.

Storage

• Store refrigerated at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not use beyond the expiration date shown on the carton. Do not freeze. Do not shake.

Special Handling

• ZYNLONTA is a hazardous drug. Follow applicable special handling and disposal procedures.1

Any unused drug product or waste material should be disposed in accordance with local requirements.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Loncastuximab tesirine-lpyl Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Loncastuximab tesirine-lpyl interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Loncastuximab tesirine-lpyl Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Loncastuximab tesirine-lpyl Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.