2.1 Recommended Dosage

The recommended dosage of DANYELZA is 3 mg/kg/day (up to 150 mg/day) on Days 1, 3, and 5 of each treatment cycle, administered as an intravenous infusion after dilution [see Dosage and Administration (2.4 and 2.5)] in combination with GM-CSF subcutaneously as shown in Table 1. Refer to the GM-CSF Prescribing Information for recommended dosing information.

Treatment cycles are repeated every 4 weeks until complete response or partial response, followed by 5 additional cycles every 4 weeks. Subsequent cycles may be repeated every 8 weeks. Discontinue DANYELZA and GM-CSF for disease progression or unacceptable toxicity.

Administer pre-infusion medications and supportive treatment, as appropriate, during infusion. [see Dosage and Administration (2.2)]

The recommended dosage regimen for each treatment cycle is described below and in Table 1:

• Days -4 to 0: administer GM-CSF 250 µg/m2/day by subcutaneous injection, beginning 5 days prior to DANYELZA infusion.
• Days 1 to 5: administer GM-CSF 500 µg/m2/day by subcutaneous injection. Administer at least 1 hour prior to DANYELZA administration on Days 1, 3, and 5.
• Days, 1, 3, and 5: administer DANYELZA 3 mg/kg/day (up to 150 mg/day) by intravenous infusion.

2.2 Premedications and Supportive Medications

2.3 Dosage Modifications for Adverse Reactions

The recommended dosage modifications for DANYELZA for adverse reactions are presented in Table 2.

2.4 Preparation

• Use appropriate aseptic technique.
• Visually inspect vial for particulate matter and discoloration prior to administration. Discard vial if solution is discolored, cloudy, or contains particulate matter.
• Add appropriate quantities of 5% Albumin (Human), USP and 0.9% Sodium Chloride Injection, USP to an empty, sterile intravenous infusion bag large enough to hold the volume needed for the relevant dose as indicated in Table 3. Allow for 5-10 minutes of passive mixing.
• Withdraw the required dose of DANYELZA and inject into the infusion bag containing the 5% Albumin (Human), USP and 0.9% Sodium Chloride Injection, USP. Discard any unused portion of DANYELZA left in the vial.

Preparation instructions for DANYELZA are described in Table 3.

If not used immediately, store the diluted DANYELZA infusion solution at room temperature (15°C to 25°C [59°F to 77°F]) for up to 8 hours or refrigerate (2°C to 8°C [36°F to 46°F]) for up to 24 hours. Once removed from refrigeration, initiate infusion within 8 hours.

2.5 Administration

• Administer DANYELZA as a diluted intravenous infusion as recommended. Do not administer DANYELZA as an intravenous push or bolus [see Dosage and Administration (2.4)].
• For the first infusion (Cycle 1, Day 1), administer DANYELZA intravenously over 60 minutes.
  For subsequent infusions, administer DANYELZA intravenously over 30 to 60 minutes, as tolerated. [see Dosage and Administration (2.1, 2.3)].
• Observe patients for a minimum of 2 hours following each infusion.

5.1 Serious Infusion-Related Reactions

DANYELZA can cause serious infusion reactions requiring urgent intervention including fluid resuscitation, administration of bronchodilators and corticosteroids, intensive care unit admission, infusion rate reduction or interruption of DANYELZA infusion. Infusion-related reactions included hypotension, bronchospasm, hypoxia, and stridor [see Adverse Reactions (6.1)].

Serious infusion-related reactions occurred in 4% of patients in Study 201 and in 18% of patients in Study 12-230. Infusion-related reactions of any Grade occurred in 100% of patients in Study 201 and 94% of patients in Study 12-230. Hypotension of any grade occurred in 100% of patients in Study 201 and 89% of patients in Study 12-230.

In Study 201, 68% of patients experienced Grade 3 or 4 infusion reactions; and in Study 12-230, 32% of patients experienced Grade 3 or 4 infusion reactions. Anaphylaxis occurred in 12% of patients and 2 patients (8%) permanently discontinued DANYELZA due to anaphylaxis in Study 201. One patient in Study 12-230 (1.4%) experienced a Grade 4 cardiac arrest 1.5 hours following completion of DANYELZA infusion.

In Study 201, infusion reactions generally occurred within 24 hours of completing a DANYELZA infusion, most often within 30 minutes of initiation. Infusion reactions were most frequent during the first infusion of DANYELZA in each cycle. Eighty percent of patients required reduction in infusion rate and 80% of patients had an infusion interrupted for at least one infusion-related reaction.

Caution is advised in patients with pre-existing cardiac disease, as this may exacerbate the risk of severe hypotension.

Premedicate with an antihistamine, acetaminophen, an H2 antagonist and corticosteroid as recommended [see Dosage and Administration (2.2)]. Monitor patients closely for signs and symptoms of infusion reactions during and for at least 2 hours following completion of each DANYELZA infusion in a setting where cardiopulmonary resuscitation medication and equipment are available.

Reduce the rate, interrupt infusion, or permanently discontinue DANYELZA based on severity and institute appropriate medical management as needed [see Dosage and Administration (2.3) and Contraindications (4)].

5.2 Neurotoxicity

DANYELZA can cause severe neurotoxicity, including severe neuropathic pain, transverse myelitis, and reversible posterior leukoencephalopathy syndrome.

5.3 Myocarditis

Myocarditis has occurred in adolescent patients receiving DANYELZA in clinical trials and expanded access programs. Myocarditis occurred within days of receiving DANYELZA requiring drug interruption. Monitor for signs and symptoms of myocarditis during treatment with DANYELZA. Withhold, reduce the dose, or permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.3)].

5.4 Hypertension

Hypertension occurred in 44% of patients in Study 201 and 28% of patients in Study 12-230 who received DANYELZA. Grade 3 or 4 hypertension occurred in 4% of patients in Study 201 and 7% of patients in Study 12- 230. Four patients (6%) in Study 12-230 permanently discontinued DANYELZA due to hypertension. In both studies, most events occurred on the day of DANYELZA infusion and occurred up to 9 days following an infusion of DANYELZA.

Do not initiate DANYELZA in patients with uncontrolled hypertension. Monitor blood pressure during infusion, and at least daily on Days 1 to 8 of each cycle of DANYELZA and evaluate for complications of hypertension including RPLS [see Warnings and Precautions (5.2)]. Interrupt DANYELZA infusion and resume at a reduced rate, or permanently discontinue DANYELZA based on the severity [see Dosage and Administration (2.3) and Adverse Reactions (6.1)].

5.5 Orthostatic Hypotension

Orthostatic hypotension has occurred in patients receiving DANYELZA in clinical trials and expanded access programs. Severe orthostatic hypotension, including cases requiring hospitalization, have occurred. Cases occurred within hours to 6 days of DANYELZA infusions in any cycle.

In patients with symptoms of orthostatic hypotension, monitor postural blood pressure prior to initiating treatment with DANYELZA and as clinically indicated with subsequent dosing. Withhold, reduce dose, or permanently discontinue DANYELZA based on severity [see Dosage and Administration (2.3)].

5.6 Embryo-Fetal Toxicity

Based on its mechanism of action, DANYELZA may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential, including pregnant women, of the potential risk to a fetus. Advise females of reproductive potential to use effective contraceptive during treatment with DANYELZA and for two months after the last dose. [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 safety of DANYELZA in combination with GM-CSF was evaluated in patients with refractory or relapsed highrisk neuroblastoma in bone or bone marrow who had demonstrated a partial response, minor response, or stable disease following initial or subsequent therapy, and in patients who were in second complete remission, from two open-label, single arm studies, Study 201 (n=25) and Study 12-230 (n=72). Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (Day 1, 3 and 5) in the first week of each cycle. Patients also received GM-CSF 250 μg/m2/day subcutaneously on Days -4 to 0 and GM-CSF 500 μg/m2/day subcutaneously on Days 1 to 5 [see Clinical Studies (14)].

The most common adverse reactions in Studies 201 and 12-230 (≥25% in either study) were infusion-related reaction, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema and irritability. The most common Grade 3 or 4 laboratory abnormalities (≥5% in either study) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium and decreased phosphate.

6.2 Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of anti-drug antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of anti-drug 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 anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies or to other naxitamab products may be misleading.

In Study 201, 2 of 24 (8%) patients tested positive for anti-drug antibodies (ADA) after treatment with DANYELZA.

In Study 12-230, 27 of 117 patients (23%) tested positive for ADA after treatment with DANYELZA by an assay that was not fully validated; therefore, the incidence of ADA may not be reliable.

6.3 Postmarketing Experience/Spontaneous Reports

The following adverse reactions have been identified during expanded access and post-approval use of DANYELZA. 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.

Neurological: Orthostatic hypotension, Transverse myelitis
Cardiac disorders: Myocarditis

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

DANYELZA may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and effectiveness of DANYELZA, in combination with GM-CSF for the treatment of relapsed or refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response or stable disease following prior therapy, have been established in pediatric patients 1 year of age and older.

Safety and effectiveness have not been established in pediatric patients younger than 1 year of age.

8.5 Geriatric Use

Neuroblastoma is largely a disease of pediatric and young adult patients. Clinical studies of DANYELZA in combination with GM-CSF did not include patients 65 years of age and older.

12.1 Mechanism of Action

Naxitamab-gqgk binds to the glycolipid GD2. GD2 is a disialoganglioside that is overexpressed on neuroblastoma cells and other cells of neuroectodermal origin, including the central nervous system and peripheral nerves. In vitro, naxitamab-gqgk was able to bind to cell surface GD2 and induce complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC).

12.2 Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of naxitamab-gqgk have not been fully characterized.

12.3 Pharmacokinetics

The geometric mean (CV%) maximum plasma concentration (Cmax) of naxitamab-gqgk was 57.4 μg/mL (49%) following DANYELZA 3 mg/kg intravenous infusion over 30 minutes.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of naxitamab-gqgk.

Dedicated studies evaluating the effects of naxitamab-gqgk on fertility in animals have not been conducted.

13.2 Animal Toxicology and/or Pharmacology

Non-clinical studies suggest that naxitamab-gqgk-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of immunemediated cytotoxic activity.

In a nude rat model, slight-moderate hyperplasia and erosion of the glandular mucosa of the stomach occurred, occasionally accompanied by diffuse inflammation. Complete recovery of all histopathological findings in the stomachs of male rats was observed; however, only partial recovery was observed in the stomachs of female rats during the four week off-drug period.

Study 201

The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 201 (NCT03363373), a multicenter open-label, single arm trial, in a subpopulation of patients who had refractory or relapsed high-risk neuroblastoma in the bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg on Days 1, 3 and 5 of each cycle. Patients received GM-CSF subcutaneously at 250 μg/m2/day on Days -4 to 0 and at 500 μg/m2/day on Days 1 to 5. Preplanned radiation to the primary site was allowed.

The major efficacy outcome measure was overall response rate (ORR) according to the revised International Neuroblastoma Response Criteria (INRC), as determined by independent pathology and imaging review and confirmed by at least one subsequent assessment. An additional efficacy outcome measure was duration of response (DOR).

Of the 22 patients included in the efficacy analysis, 64% had refractory disease and 36% had relapsed disease; the median age was 5 years (range 3 to 10 years), 59% were male; 45% were White, 50% were Asian and 5% were Black. MYCN amplification was present in 14% of patients and 86% of patients were International Neuroblastoma Staging System (INSS) stage 4 at time of diagnosis. Disease sites included 59% in the bone only, 9% in bone marrow only, and 32% in both. Prior therapies included surgery (91%), chemotherapy (95%), radiation (36%), autologous stem cell transplant (ASCT) (18%), and anti-GD2 antibody treatment (18%).

Efficacy results for Study 201 are described in Table 8.

In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=4), one patient demonstrated a confirmed complete response and no patients demonstrated a partial response.

Study 12-230

The efficacy of DANYELZA in combination with GM-CSF was evaluated in Study 12-230 (NCT01757626), a single center, open-label, single arm trial, in a subpopulation of patients who had relapsed or refractory high-risk neuroblastoma in bone or bone marrow and demonstrated a partial response, minor response, or stable disease to prior therapy. Patients with progressive disease were excluded. All patients received at least one systemic therapy to treat disease outside of the bone or bone marrow prior to enrollment. Patients were required to have received at least one dose of DANYELZA at a dose of 3 mg/kg or greater per infusion and have evaluable disease at baseline according to independent review per the revised INRC.

Patients received DANYELZA 9 mg/kg/cycle administered as three separate intravenous infusions of 3 mg/kg (on Days 1, 3 and 5) in the first week of each cycle. Patients received GM-CSF subcutaneously at 250 μg/m2/day on Days -4 to 0 and at 500 μg/m2/day on Days 1 to 5. Radiation to non-target bony lesions and soft tissue lesions was permitted at the investigator's discretion; assessment of response excluded sites that received radiation. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR), as determined by independent pathology and imaging review according to the revised INRC and confirmed by at least one subsequent assessment.

Of the 38 patients included in the efficacy analysis, 55% had relapsed neuroblastoma and 45% had refractory disease; 50% were male, the median age was 5 years (range 2 to 23 years), 74% were White, 8% Asian and 5% were Black, 5% Native American/American Indian/Alaska Native, 3% other races and 5% was not available. MYCN-amplification was present in 16% of patients and most patients were International Neuroblastoma Staging System (INSS) stage 4 (95%). Fifty percent (50%) of patients had disease involvement in the bone only, 11% only in bone marrow, and 39% in both. Prior therapies included surgery (100%), chemotherapy (100%), radiation (47%), autologous stem cell transplant (ASCT) (42%), and anti-GD2 antibody treatment (58%).

Efficacy results are provided in Table 9.

In an exploratory analysis in the subset of patients previously treated with an anti-GD2 antibody (n=22), the ORR was 18% (95% CI 5%, 40%), with no patients having a documented response of 6 months or greater.

Store DANYELZA vial refrigerated at 2°C to 8°C (36°F to 46°F) in the outer carton to protect from light until time of use.

Serious Infusion-Related Reactions

Advise patients and caregivers that DANYELZA can cause serious infusion-related reactions and anaphylaxis and to immediately report any signs or symptoms, such as facial or lip swelling, urticaria, or difficulty breathing, that occur during or following the infusion [see Warnings and Precautions (5.1)].

Neurotoxicity

Advise patients and caregivers that DANYELZA can cause neurotoxicity, including severe pain, peripheral neuropathy, neurological disorders of the eye, prolonged urinary retention, transverse myelitis, and reverse posterior leukoencephalopathy syndrome. Advise patients to contact their healthcare provider for any new or worsening neurological symptoms [see Warnings and Precautions (5.2)].

Myocarditis

Advise patients and caregivers that myocarditis has been seen in patients taking DANYELZA and to report any signs or symptoms, such as chest pain, shortness of breath or abnormal heart rhythms during treatment with DANYELZA [see Warnings and Precautions (5.3)].

Hypertension

Advise patients and caregivers that DANYELZA can cause hypertension and to immediately report signs or symptoms of hypertension [see Warnings and Precautions (5.4)].

Orthostatic Hypotension

Advise patients and caregivers that DANYELZA can cause severe low blood pressure when standing after sitting or lying down. Advise patients and caregivers to report any signs or symptoms, such as dizziness, lightheadedness or fainting during treatment with DANYELZA [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential, including pregnant women, of the potential risk to the fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy and to use effective contraception during treatment with and for 2 months after the last dose of DANYELZA.

Lactation

Advise women not to breastfeed during treatment with DANYELZA and for 2 months after the last dose [see Use in Specific Populations (8.2)].