Naxitamab

Based on its mechanism of action, naxitamab may cause fetal harm when administered to pregnant women. There are no available data on the use of naxitamab in pregnant women and no animal reproduction studies have been conducted with naxitamab. IgG1 monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. Advise pregnant women of 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 is 2% to 4% and 15% to 20%, respectively.

There are no data on the presence of naxitamab-gqgk in human milk or its effects on the breastfed child, or on milk production, however, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed child from naxitamab, advise women not to breastfeed during treatment and for 2 months after the final dose of naxitamab.

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.

Naxitamab has major influence on ability to drive and use machines. Patients should not use or drive machines at the day of infusion with naxitamab.

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 naxitamab in combination with GM-CSF was evaluated in patients with refractory or relapsed high-risk 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 naxitamab 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.

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.

Study 201

In Study 201, among 25 patients who received naxitamab in combination with GM-CSF, 12% were exposed for 6 months or longer and none were exposed for greater than one year.

Serious adverse reactions occurred in 32% of patients who received naxitamab in combination with GM-CSF. Serious adverse reactions in more than one patient included anaphylactic reaction (12%) and pain (8%). Permanent discontinuation of naxitamab due to an adverse reaction occurred in 12% of patients. Adverse reactions resulting in permanent discontinuation of naxitamab included anaphylactic reaction (8%) and respiratory depression (4%).

Dosage interruptions of naxitamab due to an adverse reaction occurred in 84% of patients. Adverse reactions requiring dosage interruption in >10% of patients included hypotension and bronchospasm.

Table 1 summarizes adverse reactions in Study 201.

Table 1. Adverse Reactions (>10%) in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received naxitamab with GM-CSF in Study 201:

^* Adverse reactions were graded using CTCAE version 4.0.
^† Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, and musculoskeletal pain.
^‡ Infusion-related reaction includes hypotension, bronchospasm, flushing, wheezing, stridor, urticaria, dyspnea, pyrexia, infusion-related reaction, face edema, edema mouth, tongue edema, lip edema, respiratory tract edema, chills, hypoxia, pruritis and rash occurring on the day of infusion or the day following an infusion.
^§ Fatigue includes fatigue, asthenia.
^¶ Pyrexia not occurring on the day of infusion or the day following an infusion
^# Urticaria, not occurring on the day of infusion or the day following an infusion
^Þ Tachycardia includes sinus tachycardia and tachycardia
^ß Peripheral neuropathy includes peripheral sensory neuropathy, paresthesia, neuralgia.
^à Neurological disorders of the eye includes unequal pupils, blurred vision, and mydriasis.

Clinically relevant adverse reactions occurring in ≤10% of patients who received naxitamab with GM-CSF included peripheral edema (8%).

Table 2 summarizes the laboratory abnormalities in Study 201.

Table 2. Selected Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received naxitamab with GM-CSF in Study 201:

^* The table presents laboratory parameters with available grading according to CTCAE version 4.0. Baseline evaluation was the last non-missing value prior to first naxitamab dosing. Each test incidence is based on the number of patients who had both a baseline value and at least one on-study laboratory measurement (range: 23 to 24 patients).

Study 12-230

In Study 12-230, among 72 patients who received naxitamab in combination with GM-CSF, 32% were exposed for 6 months or longer and 8% were exposed for greater than one year.

Serious adverse reactions occurred in 40% of patients who received naxitamab in combination with GM-CSF. Serious adverse reactions in >5% of patients included hypertension (14%), hypotension (11%), and pyrexia (8%). Permanent discontinuation of naxitamab due to an adverse reaction occurred in 8% of patients. Four (6%) patients permanently discontinued naxitamab due to hypertension and one (1.4%) patient discontinued due to RPLS.

Table 3 summarizes adverse reactions in Study 12-230.

Table 3. Adverse Reactions (>10%) in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received naxitamab with GM-CSF in Study 12-230:

^* In Study 12-230, all adverse reactions occurring in Cycle 1 and 2, and adverse reactions of ≥ Grade 3 severity occurring in subsequent cycles were reported. In the dose finding phase, Grade 2 unexpected adverse reactions were also reported for Cycles 3 and later.
^† Adverse reactions were graded using CTCAE version 4.0.
^‡ Infusion-related reaction includes hypotension, bronchospasm, flushing, wheezing, stridor, urticaria, dyspnea, pyrexia, face edema, periorbital edema, lip swelling, swollen tongue, chills, hypoxia, pruritis, rash maculopapular and rash erythematous occurring on the day of infusion or the day following an infusion.
^§ Pain includes pain, abdominal pain, pain in extremity, bone pain, neck pain, back pain, non-cardiac chest pain, flank pain, and musculoskeletal pain.
^¶ Fatigue includes fatigue, asthenia.
^# Pyrexia not occurring on the day of infusion or the day following an infusion.
^Þ Peripheral neuropathy includes peripheral sensory neuropathy, peripheral motor neuropathy, paresthesia, neuralgia.
^ß Neurological disorders of the eye includes unequal pupils, blurred vision, accommodation disorder, visual impairment and photophobia.

Clinically relevant adverse reactions in ≤10% of patients who received naxitamab with GM-CSF included apnea (4.2%), hypopnea (2.8%), generalized edema (2.8%), peripheral edema (8.3%), and device related infection (4.2%).

Table 4 summarizes the laboratory abnormalities in Study 12-230.

Table 4. Selected Laboratory Abnormalities (>20%) Worsening from Baseline in Patients with Refractory or Relapsed High-Risk Neuroblastoma in Bone or Bone Marrow Who Received naxitamab with GM-CSF in Study 12-230:

^* The table presents laboratory parameters with available grading according to CTCAE version 4.0. Baseline evaluation was the last non-missing value prior to first naxitamab dosing. Each test incidence is based on the number of patients who had both a baseline value and at least one on-study laboratory measurement (range 19 to 72 patients).

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 naxitamab.

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

Postmarketing Experience

The following adverse reactions have been identified from expanded access reports with use of naxitamab. 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: Transverse myelitis