Dinutuximab

Risk Summary

Based on its mechanism of action, dinutuximab may cause fetal harm when administered to a pregnant woman. There are no studies in pregnant women and no reproductive studies in animals to inform the drug-associated risk. 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 the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Risk Summary

There is no information available on the presence of dinutuximab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. However, human IgG is present in human milk. Because of the potential for serious adverse reactions in a breastfed infant, advise a nursing woman to discontinue breastfeeding during treatment with dinutuximab.

No animal studies have been conducted to evaluate the carcinogenic or mutagenic potential of dinutuximab.

Dedicated studies examining the effects of dinutuximab on fertility in animals have not been conducted. No clear effects on reproductive organs were observed in general toxicology studies conducted in rats.

• Serious Infusion Reactions
• Neurotoxicity, including Pain, Peripheral Neuropathy, Neurological Disorders of the Eye, Prolonged Urinary Retention, Transverse Myelitis, and Reversible Posterior Leukoencephalopathy Syndrome
• Capillary Leak Syndrome
• Hypotension
• Infection
• Bone Marrow Suppression
• Electrolyte Abnormalities
• Atypical Hemolytic Uremic Syndrome
• Embryo-Fetal Toxicity

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 rates observed in clinical practice.

The data described below reflect exposure to dinutuximab at the recommended dose and schedule in 1021 patients with high-risk neuroblastoma enrolled in an open-label, randomized (Study 1), or single-arm clinical trials (Study 2 and Study 3). Prior to enrollment, patients received therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients received dinutuximab in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA). Treatment commenced within 95 days post autologous stem cell transplant in Study 1, within 210 days of autologous stem cell transplant in Study 2, and within 110 days of autologous stem cell transplant in Study 3.

Study 1

In a randomized, open-label, multicenter study (Study 1), 134 patients received dinutuximab in combination with GM-CSF, IL-2, and RA (dinutuximab/RA group), including 109 randomized patients and 25 patients with biopsy-proven residual disease who were non-randomly assigned to receive dinutuximab. A total of 106 randomized patients received RA alone (RA group). Patients had a median age at enrollment of 3.8 years (range: 0.94 to 15.3 years), and were predominantly male (60%) and White (82%). In Study 1, adverse reactions of Grade 3 or greater severity were comprehensively collected, but adverse reactions of Grade 1 or 2 severity were collected sporadically and laboratory data were not comprehensively collected.

Approximately 71% of patients in the dinutuximab/RA group and 77% of patients in the RA group completed planned treatment. The most common reason for premature discontinuation of study therapy was adverse reactions in the dinutuximab/RA group (19%) and progressive disease (17%) in the RA group.

The most common adverse drug reactions (≥25%) in the dinutuximab/RA group were pain, pyrexia, thrombocytopenia, lymphopenia, infusion reactions, hypotension, hyponatremia, increased alanine aminotransferase, anemia, vomiting, diarrhea, hypokalemia, capillary leak syndrome, neutropenia, urticaria, hypoalbuminemia, increased aspartate aminotransferase, and hypocalcemia. The most common serious adverse reactions (≥5%) in the dinutuximab/RA group were infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

Table 5 lists the adverse reactions reported in at least 10% of patients in the dinutuximab/RA group for which there was a between group difference of at least 5% (all grades) or 2% (Grade 3 or greater severity).

Table 5. Selected Adverse Reactions Occurring in at Least 10% of Patients in the Dinutuximab/RA Group in Study 1:

* Includes adverse reactions that occurred in at least 10% of patients in the dinutuximab/RA group with at least a 5% (All Grades) or 2% (Grades 3 to 5) absolute higher incidence in the dinutuximab/RA group compared to the RA group.
^† Adverse drug reactions were graded using CTCAE version 3.0.
^‡ Includes preferred terms abdominal pain, abdominal pain upper, arthralgia, back pain, bladder pain, bone pain, chest pain, facial pain, gingival pain, infusion related reaction, musculoskeletal chest pain, myalgia, neck pain, neuralgia, oropharyngeal pain, pain, pain in extremity, and proctalgia.
^§ Based on investigator reported adverse reactions.
^¶ One Grade 5 adverse reaction.
^# Includes preferred terms gastrointestinal hemorrhage, hematochezia, rectal hemorrhage, hematemesis, upper gastrointestinal hemorrhage, hematuria, hemorrhage urinary tract, renal hemorrhage, epistaxis, respiratory tract hemorrhage, disseminated intravascular coagulation, catheter site hemorrhage, hemorrhage, and hematoma.
^Þ Includes preferred terms tachycardia and sinus tachycardia

Table 6 compares the per-patient incidence of selected adverse reactions occurring during cycles containing dinutuximab in combination with GM-CSF (Cycles 1, 3, and 5) with cycles containing dinutuximab in combination with IL-2 (Cycles 2 and 4).

Table 6. Comparison of Adverse Events by Treatment Cycle in the Dinutuximab/RA Group in Study 1:

GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-2, interleukin-2; RA, 13-cis-retinoic acid
* Includes preferred terms with a per-patient incidence of at least 20% in the dinutuximab and RA group for either IL-2 or GM-CSF containing cycles.
^† Adverse drug reactions were graded using CTCAE version 3.0.
^‡ Seven patients who received GM-CSF in Cycle 1 discontinued prior to starting Cycle 2.
^§ Includes preferred terms abdominal pain, abdominal pain upper, arthralgia, back pain, bladder pain, bone pain, chest pain, facial pain, gingival pain, infusion related reaction, musculoskeletal chest pain, myalgia, neck pain, neuralgia, oropharyngeal pain, pain, pain in extremity, and proctalgia.
^¶ Based on investigator-reported adverse reactions.

Study 2 and Study 3

Study 2 was a single-arm, multicenter, expanded access trial that enrolled patients with high-risk neuroblastoma (N=783). The reported adverse event profile of dinutuximab in Study 2 was similar to that observed in Study 1.

Study 3 was a multicenter, single-arm safety study of dinutuximab in combination with GM-CSF, IL-2, and RA. In Study 3, adverse events of all CTCAE grades and laboratory data were systematically and comprehensively collected. Of 104 patients enrolled and treated in Study 3, 77% of patients completed study therapy. In general, the adverse reaction profile of dinutuximab observed in Study 3 was similar to that observed in Study 1 and Study 2. The following adverse reactions not previously reported in Study 1 were reported in at least 10% of patients in Study 3: nasal congestion (20%) and wheezing (15%). Table 7 provides the per-patient incidence of laboratory abnormalities in Study 3.

Table 7. Per-patient Incidence of Selected (≥5% Grade 3 to 4) Laboratory Abnormalities in Study 3:

ND, not determined

Immunogenicity

As with all therapeutic proteins, there is a 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 in other studies or to other products may be misleading.

Among the 418 patients who were treated with dinutuximab in combination with GM-CSF, IL-2, and RA in Study 2, Study 3 and Study DIV-NB-201, 86 patients (20.6%) tested positive for anti-dinutuximab antibodies (ADA). Of the 86 ADA positive patients, 45 (52.3%) tested positive for neutralizing antibodies.

Among the 27 patients who were treated with dinutuximab in combination with lenalidomide and isotretinoin in Study NANT 2011-04, 13 patients (48.1%) tested positive for ADA. Of the 13 ADA positive patients, 2 (15.4%) also tested positive for neutralizing antibodies.

The clearance of dinutuximab was 60% higher for the ADA positive patients than the ADA negative patients. The presence of ADA did not have a clinically significant effect on the incidence or severity of adverse reactions. There were insufficient number of patients with ADA to determine whether ADA alters the efficacy of dinutuximab.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of dinutuximab. 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.

Neurotoxicity: prolonged urinary retention, transverse myelitis, and reversible posterior leukoencephalopathy syndrome (RPLS).