2.1 Important Dosing Instructions

Prior to starting each treatment cycle, assess hepatic and renal function. If serum albumin is less than 3 g/dL, delay administration of LYMPHIR until serum albumin is greater than or equal to 3 g/dL [see Warnings and Precautions ( 5.1)] .

2.2 Recommended Dosage

The recommended dosage of LYMPHIR is 9 mcg/kg/day actual body weight administered as an intravenous infusion over 60 minutes on Days 1 through 5 of a 21-day treatment cycle. Administer LYMPHIR until disease progression or unacceptable toxicity. 

2.3 Recommended Premedications

Administer premedications prior to starting a LYMPHIR infusion in Cycles 1 through 3, as outlined in Table 1, to reduce the risk of infusion-related reactions [see Warnings and Precautions ( 5.3)] .

If patients experience a Grade 2 or higher infusion reaction, premedicate at least 30 minutes prior to each subsequent infusion with a systemic steroid such as dexamethasone 4 mg (or equivalent) via slow intravenous push, for at least 3 cycles.

2.4 Dosage Modifications for Adverse Reactions

Dosage modifications for adverse reactions with LYMPHIR are shown in Table 2 below.

* Based on NCI CTCAE version 5.0

Restarting after Dosage Delay Due to Toxicity

2.5 Preparation and Administration

Reconstitute and further dilute LYMPHIR prior to administration. Administer as an intravenous infusion over 60 minutes. Use aseptic technique to prepare LYMPHIR.

LYMPHIR does not contain a preservative or anti-microbial agent. Care should be taken during preparation and administration of LYMPHIR to prevent inadvertent microbial contamination.

Reconstitution

• Calculate the dose (mcg), total volume (mL) of solution required, and number of vials of LYMPHIR needed based on the patient’s actual body weight (kg). More than one vial may be needed for a full dose.
• Remove the vial(s) of LYMPHIR from the refrigerator and allow to stand for approximately 30 minutes to reach to room temperature [20°C to 25°C (68°F to 77°F)].
• Reconstitute each LYMPHIR vial with 2.1 mL of Sterile Water for Injection to obtain a final concentration of 150 mcg/mL. If more than one vial is needed to make a complete dose, use a separate syringe and needle for each vial.
• Gently swirl the vial. Do not shake.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear and colorless. Discard if the solution is not clear, colorless, and contains particulate matter.
• Use the reconstituted LYMPHIR solution immediately to prepare the drug product. 

Dilution

• Use only plastic syringes or soft plastic intravenous bags. Do notuse glass containers.
• Maintain concentration of LYMPHIR at 15 mcg/mL or higher during all steps in the preparation of the solution for intravenous infusion.
• Withdraw the calculated dose from the vial(s) with a sterile syringe and inject it into an empty intravenous bag.
• Dilute with 0.9% Sodium Chloride Injection to final concentration of 15 mcg/mL or higher.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the prepared solution is cloudy or particulates are present.
• If not used immediately, store the diluted LYMPHIR solution at room temperature [20°C to 25°C (68°F to 77°F)] for up to 4 hours. Protect diluted solution from light.

Administration

• Administer infusion solution intravenously over 60 minutes through an intravenous line using a syringe pump or intravenous infusion bag. Do not administer through in-line filter.
• Do not mix LYMPHIR with other drugs or administer other drugs through the same infusion line.
• At the end of the infusion, discard any empty or unused portions of LYMPHIR immediately.

5.1 Capillary Leak Syndrome

LYMPHIR can cause capillary leak syndrome (CLS), including life-threatening or fatal reactions. CLS was defined in the clinical trials as the occurrence of at least 2 of the following symptoms at any time during LYMPHIR therapy: hypotension, edema, and serum albumin <3 g/dL. These symptoms were not required to occur simultaneously to be characterized as capillary leak syndrome.

As defined, CLS occurred in 27% of patients in the pooled population across 3 clinical trials, including 8% with Grade 3. There was one (0.8%) fatal occurrence of CLS. Of the patients with CLS, 22% had recurrence. The majority of CLS events (81%) occurred within the first 2 cycles of treatment. The median time to onset from Cycle 1, Day 1 was 6.5 days (range: 1 to 77), the median duration of CLS was 14 days (range: 2 to 40), and 75% of patients had resolution. The most common symptoms included edema, hypoalbuminemia, and hypotension. Pleural effusion, pericardial effusion, and dehydration also occurred.

Regularly assess patients for weight gain, new onset or worsening of edema, dyspnea, and hypotension (including orthostatic changes). Monitor serum albumin levels prior to the initiation of each cycle of therapy and more often as clinically indicated.

Withhold, reduce dose, or permanently discontinue based on severity. If LYMPHIR is withheld, resume LYMPHIR following resolution of CLS and when serum albumin is greater than or equal to 3 g/dL [see Dosage and Administration ( 2.1and 2.4)] .

5.2 Visual Impairment

LYMPHIR can cause serious visual impairment, including changes in visual acuity and color vision. In the pooled population across 3 clinical trials, visual impairment occurred in 9%, with Grade 1 in 8% and Grade 2 in 1%. The most commonly reported symptom was blurred vision. Of the patients with visual impairment, 67% had resolution of their visual impairment.

Perform baseline ophthalmic examination and monitor as clinically indicated. If patients experience symptoms of visual impairment, such as changes in visual acuity, changes in color vision, or blurred vision, refer for ophthalmologic evaluation.

Withhold LYMPHIR until visual impairment resolves or permanently discontinue based on severity [see Dosage and Administration ( 2.4)] .

5.3 Infusion-Related Reactions

LYMPHIR can cause serious infusion-related reactions. Infusion-related reactions were reported in 69% of patients in the pooled population across 3 clinical trials of patients who received LYMPHIR, with Grade 3 infusion-related reactions in 3.4% [see Adverse Reactions ( 6.1)] . Eighty-three percent of infusion-related reactions occurred in Cycles 1 and 2. The most common symptoms included nausea, fatigue, chills, musculoskeletal pain, vomiting, fever, and arthralgia.

Premedicate patients for the first three cycles prior to starting a LYMPHIR infusion [see Dosage and Administration ( 2.3)] . Monitor patients frequently during infusion. For Grade 2 or higher infusion reactions, premedicate at least 30 minutes prior to each subsequent infusion with a systemic steroid for at least 3 cycles [see Dosage and Administration ( 2.3)] .

Interrupt or discontinue LYMPHIR based on severity [see Dosage and Administration ( 2.4)]. Institute appropriate medical management.

5.4 Hepatotoxicity

LYMPHIR can cause hepatotoxicity. In the pooled safety population, elevated ALT occurred in 70% of patients, with Grade 3 ALT occurring in 22%; elevated AST occurred in 64% of patients, with Grade 3 AST elevation occurring in 9%. For Grade 3 events, median time to onset was 8 days (range: 1 to 15 days); median time to resolution was 15 days (range: 7 to 50 days); all cases of Grade 3 ALT or AST elevations resolved [see Adverse Reactions ( 6.1)]. Elevated total bilirubin occurred in 5% of patients, with Grade 3 occurring in 0.9%.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold, reduce dose, or permanently discontinue LYMPHIR based on severity [see Dosage and Administration ( 2.4)] .

5.5 Embryo-Fetal Toxicity

Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to the initiation of LYMPHIR. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 days following the last dose of LYMPHIR [see Use in Specific Populations ( 8.1, 8.3)] .

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.

The pooled safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to LYMPHIR as a single agent in 119 patients with CTCL across 3 clinical trials. Patients received treatment with LYMPHIR as an intravenous infusion at 9 mcg/kg daily from Day 1 through Day 5 of each 21-day cycle until disease progression or unacceptable toxicity. Among 119 patients who received LYMPHIR the median number of cycles received was 5 (range: 1 to 42), with 13% exposed for 6 months or longer.

In this pooled safety population, the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were increased transaminases (70%), albumin decreased (53%), nausea (40%), edema (35%), hemoglobin decreased (34%), fatigue (30%), musculoskeletal pain (26%), rash (23%), chills (22%), constipation (22%), pyrexia (21%), and capillary leak syndrome (20%).

Relapsed or Refractory Stage I-III CTCL

Study 302

The safety of LYMPHIR was evaluated in Study 302, an open-label, single-arm, multicenter trial that included 69 patients with relapsed or refractory Stage I-III CTCL [see Clinical Studies ( 14)] . Patients received treatment with LYMPHIR 9 mcg/kg daily from Day 1 through Day 5 of each 21-day cycle. Treatment was administered until disease progression or unacceptable toxicity. The median number of LYMPHIR cycles was 6 (range: 1 to 42).

The median age of patients was 64 years (range: 28 to 87 years), 49% were 65 years of age or older, 65% were men, 72% were White, 19% were Black or African American, 1.4% were Asian, and 14% were Hispanic or Latino.

Serious adverse reactions occurred in 38% of patients who received LYMPHIR. Serious adverse reactions in > 2% of patients included capillary leak syndrome (10%), infusion-related reaction (9%), sepsis (7%), skin infection (2.9%), pyrexia (2.9%), and rash (2.9%).

Permanent discontinuation of LYMPHIR due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of LYMPHIR included capillary leak syndrome, infusion-related reaction, renal insufficiency, respiratory failure, and sepsis.

Dosage interruptions of LYMPHIR due to an adverse reaction occurred in 38% of patients. Adverse reactions requiring dosage interruption of LYMPHIR included capillary leak syndrome, infusion-related reaction, weight increase, nausea, and tachycardia.

Table 3 summarizes the adverse reactions in Study 302.

#Only Grade 3 adverse reaction occurred
aIncludes fatigue, asthenia, and lethargy
bIncludes edema, edema peripheral, generalized edema, face edema, swelling face, peripheral swelling
cIncludes musculoskeletal pain, back pain, neck pain, pain in extremity, myalgia, bone pain
dIncludes headache, migraine
eIncludes amnesia, confusional state, delirium, memory impairment, disturbance in attention, somnolence, cognitive disorder
fIncludes rash, drug eruption, erythema, rash maculo-papular, rash papular, rash pustular, rash pruritic, dermatitis exfoliative generalized, acute generalized exanthematous pustulosis
gIncludes skin infection, skin bacterial infection, staphylococcal skin infection, impetigo
hIncludes acute kidney injury, blood creatinine increased

Clinically relevant adverse reactions in < 10% of patients who received LYMPHIR included sepsis and peripheral neuropathy.

Table 4 summarizes select laboratory abnormalities in Study 302.

aGraded according to NCI CTCAE version 5.0
bThe denominator used to calculate the rate was 67 based on the number of patients with a baseline value and at least one post-treatment value
cPercentage of patients with an increase of at least 1 CTCAE grade from baseline to the worst post-baseline value of any grade, or to the worst post-baseline value that is Grade 3 or 4
dThe denominator used to calculate the rate was based on 36 patients with a baseline value and at least one post-treatment value.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of denileukin diftitox. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Thyroid conditions: hyperthyroidism, thyroiditis, thyrotoxicosis, and hypothyroidism.

8.1 Pregnancy

Risk Summary

Based on its mechanism of action, LYMPHIR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1)]. There are no available data on the use of LYMPHIR in pregnant women to evaluate for a drug-associated risk. No animal reproductive and developmental toxicity studies have been conducted with denileukin diftitox.

Denileukin diftitox-cxdl causes depletion of regulatory T lymphocytes (Treg), immune activation, and capillary leak syndrome, compromising pregnancy maintenance. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. 

8.2 Lactation

Risk Summary

No data are available regarding the presence of denileukin diftitox-cxdl in human milk, the effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LYMPHIR and for 7 days after the last dose.

8.3 Females and Males of Reproductive Potential

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

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating LYMPHIR [see Use in Specific Populations ( 8.1)] .

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with LYMPHIR and for 7 days after the last dose.

Infertility

Males

Based on findings in rats, male fertility may be compromised by treatment with LYMPHIR [see Nonclinical Toxicology ( 13.1)] . The reversibility of the effect on fertility is unknown.

8.4 Pediatric Use

Safety and effectiveness of LYMPHIR in pediatric patients have not been established.

8.5 Geriatric Use

Of the 69 patients with Stage I-III relapsed or refractory CTCL who received LYMPHIR, 34 patients (49%) were 65 years of age and older and 10 patients (14%) were 75 years of age and older [see Clinical Studies ( 14)] . Clinical studies of LYMPHIR did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

12.1 Mechanism of Action

Denileukin diftitox-cxdl is a fusion protein designed to direct the cytocidal action of diphtheria toxin (DT) to cells which express the IL-2 receptor. After uptake into the cell, the DT fragment is cleaved and the free DT fragments inhibit protein synthesis, resulting in cell death. Denileukin diftitox-cxdl demonstrated the ability to deplete immunosuppressive regulatory T lymphocytes (Tregs) and antitumor activity through a direct cytocidal action on IL-2R-expressing tumors.

12.2Pharmacodynamics

Higher denileukin diftitox-cxdl exposures were associated with higher incidence of capillary leak syndrome, hepatotoxicity, treatment discontinuations due to adverse reactions, and adverse reactions Grade ≥3 following administration of LYMPHIR. Denileukin diftitox-cxdl time course of pharmacodynamic response is unknown.

12.3 Pharmacokinetics

Following a single dose of denileukin diftitox-cxdl 9 mcg/kg via 1-hr infusion on Cycle 1, Day 1 in patients with CTCL, the geometric mean (coefficient of variation [CV]%) maximum serum concentration (C max) was 94.4 ng/mL (77%) and area under the concentration over time curve (AUC 0-inf) was 20700 ng· min/L (60%). There is no accumulation after repeated daily dosing.

Distribution

The geometric mean (CV%) volume of distribution of denileukin diftitox-cxdl is 5.0 L (43%) on Cycle 1, Day 1.

Elimination

The geometric mean (CV%) clearance is 36.5 mL/min (73%) after the first dose of denileukin diftitox-cxdl at the recommended dose level. The arithmetic mean (CV%) denileukin diftitox-cxdl terminal half-life is 112 minutes (31%) on Cycle 1, Day 1.  

Metabolism

Denileukin diftitox-cxdl is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of LYMPHIR were observed based on age (23 to 86 years), body weight (39 kg to 148 kg), sex, race (White, African American/Black, Asian), ECOG status (0 to 2), mild to moderate renal impairment (estimated creatinine clearance [CLcr] by Cockcroft–Gault equation: 30 to 89 mL/min), or mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin 1 to 1.5 times ULN and any AST). The effect of moderate or severe hepatic impairment (total bilirubin greater than 1.5 times ULN with any AST) and severe renal impairment (CLcr 15 to 29 mL/min) on denileukin diftitox-cxdl pharmacokinetics is unknown.

12.6Immunogenicity

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the methods. Differences in ADA assay methods may preclude meaningful comparisons of the incidence of ADAs in the studies of denileukin diftitox-cxdl.

In Study 302, among patients with any stage CTCL who received LYMPHIR 9 mcg/kg/day (median duration of treatment: 6 cycles),

• Of the 90 subjects with immunogenicity results at baseline, 74% (67/90) of subjects had pre-existing antibodies to denileukin diftitox-cxdl and 7.8% (7/90) of the subjects had neutralizing anti-denileukin diftitox-cxdl antibodies. The high prevalence of ADA at baseline was anticipated due to vaccination against diphtheria toxin. Among these subjects, 5.6% (5/90) of the subjects had ADAs against IL-2 but none had neutralizing antibodies against IL-2.
• Of the 84 subjects evaluable for treatment-emergent (TE) ADA across all cycles after treatment with LYMPHIR, 88% (74/84) and 82% (69/84) of subjects developed treatment-emergent ADAs against denileukin diftitox-cxdl and IL-2, respectively. Among these subjects, 80% (67/84) developed neutralizing antibodies against denileukin diftitox-cxdl and 13% (11/84) developed neutralizing antibodies against the IL-2 domain of denileukin diftitox-cxdl.
• Treatment with LYMPHIR leads to an increase in anti-denileukin diftitox-cxdl and anti-IL-2 antibody titers. In subjects with treatment-emergent ADA during Study 302, the median anti-denileukin diftitox-cxdl antibody titers were 182, 260, 153, and 94 times higher than baseline at C2D1, C3D1, C5D1, and C8D1 and the anti-IL2 antibody titers were 2, 49, 437, and 1312 times higher than baseline at these same visits.

Anti-Drug Antibody Effects on Pharmacokinetics

The presence of ADA is associated with a reduction in the measured serum concentration. In a subset of patients with treatment-emergent anti-denileukin diftitox-cxdl and/or anti-IL-2 antibodies during Study 302, the geometric mean ratio for denileukin diftitox-cxdl C maxand AUC (0-t)is 37% and 19% in Cycle 3 compared to Cycle 1, and is 30% and 15% in Cycle 5 compared to Cycle 1. The decrease in denileukin diftitox-cxdl concentration does not appear to adversely impact safety and efficacy.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There have been no studies to assess the carcinogenic potential of denileukin diftitox-cxdl. Denileukin diftitox-cxdl showed no evidence of mutagenicity in the Ames test and the chromosomal aberration assay. There have been no studies to assess the effect of denileukin diftitox on fertility. In a 14-week repeat-dose toxicology study in rats, denileukin diftitox-cxdl caused toxicity to male reproductive organs including atrophy of the epididymis, prostate gland, and testes and single cell necrosis in the epididymis.