Unituxin Drug Information

Unituxin (dinutuximab) is indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy . Unituxin is a GD2-binding monoclonal antibody indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.

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 Unituxin 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 Unituxin 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 Unituxin in combination with GM-CSF, IL-2, and RA (Unituxin/RA group), including 109 randomized patients and 25 patients with biopsy-proven residual disease who were non-randomly assigned to receive Unituxin.

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 Unituxin/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 Unituxin/RA group (19%) and progressive disease (17%) in the RA group.

The most common adverse drug reactions (≥25%) in the Unituxin/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 Unituxin/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 Unituxin/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 Unituxin/RA Group in Study 1 Adverse Reaction Includes adverse reactions that occurred in at least 10% of patients in the Unituxin/RA group with at least a 5% (All Grades) or 2% (Grades 3 to 5) absolute higher incidence in the Unituxin/RA group compared to the RA group., Adverse drug reactions were graded using CTCAE version 3.0. Unituxin/RA (N=134) RA (N=106) All Grades (%) Grades 3 to 4 (%) All Grades (%) Grades 3 to 4 (%) General Disorders and Administration Site Conditions Pain 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. 85 51 16 6 Pyrexia 72 40 27 6 Edema 17 0 0 0 Blood and Lymphatic System Disorders Based on investigator reported adverse reactions.

Thrombocytopenia 66 39 43 25 Lymphopenia 62 51 36 20 Anemia 51 34 22 16 Neutropenia 39 34 16 13 Immune System Disorders Infusion reactions 60 25 9 1 Vascular Disorders Hypotension 60 16 3 0 Capillary leak syndrome One Grade 5 adverse reaction. 40 23 1 0 Hemorrhage 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. 17 6 6 3 Hypertension 14 2 7 1 Metabolism and Nutrition Disorders Hyponatremia 58 23 12 4 Hypokalemia 43 37 4 2 Hypoalbuminemia 33 7 3 0 Hypocalcemia 27 7 0 0 Hypophosphatemia 20 8 3 0 Hyperglycemia 18 6 4 1 Hypertriglyceridemia 16 1 11 1 Decreased appetite 15 10 5 4 Hypomagnesemia 12 2 1 0 Investigations Increased alanine aminotransferase 56 23 31 3 Increased aspartate aminotransferase 28 10 7 0 Increased serum creatinine 15 2 6 0 Increased weight 10 0 0 0 Gastrointestinal Disorders Vomiting 46 6 19 3 Diarrhea 43 13 15 1 Nausea 10 2 3 1 Skin and Subcutaneous Tissue Disorders Urticaria 37 13 3 0 Respiratory, Thoracic and Mediastinal Disorders Hypoxia 24 12 2 1 Cardiac Disorders Tachycardia Includes preferred terms tachycardia and sinus tachycardia. 19 2 1 0 Infections and Infestations Sepsis 18 16 9 9 Device related infection 16 16 11 11 Renal and Urinary Disorders Proteinuria 16 0 3 1 Nervous System Disorders Peripheral neuropathy 13 3 6 0 Table 6 compares the per-patient incidence of selected adverse reactions occurring during cycles containing Unituxin in combination with GM-CSF (Cycles 1, 3, and 5) with cycles containing Unituxin in combination with IL-2 (Cycles 2 and 4). Table 6: Comparison of Adverse Events by Treatment Cycle in the Unituxin/RA Group in Study 1 Preferred Term Includes preferred terms with a per-patient incidence of at least 20% in the Unituxin and RA group for either IL-2 or GM-CSF containing cycles., Adverse drug reactions were graded using CTCAE version 3.0. All Grades Severe GM-CSF N=134 (%) IL-2 Seven patients who received GM-CSF in Cycle 1 discontinued prior to starting Cycle 2. N=127 (%) GM-CSF N=134 (%) IL-2 N=127 (%) GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-2, interleukin-2; RA, 13-cis-retinoic acid General Disorders and administration site conditions Pyrexia 55 65 10 37 Pain 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. 77 61 43 35 Blood and Lymphatic System Disorders Based on investigator-reported adverse reactions. Thrombocytopenia 62 61 31 33 Lymphopenia 54 61 33 50 Anemia 42 42 21 24 Neutropenia 25 32 19 28 Immune System Disorders Infusion reactions 47 54 10 20 Vascular Disorders Hypotension 43 54 5 16 Capillary leak syndrome 22 36 11 20 Metabolism and Nutrition Disorders Hyponatremia 36 55 5 21 Hypokalemia 26 39 13 33 Hypoalbuminemia 29 29 3 5 Hypocalcemia 20 21 2 6 Investigations Increased alanine aminotransferase 43 48 15 13 Aspartate aminotransferase increased 16 21 4 7 Gastrointestinal Disorders Diarrhea 31 37 6 13 Vomiting 33 35 3 2 Skin and Subcutaneous Tissue Disorders Urticaria 25 29 7 7 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 Unituxin in Study 2 was similar to that observed in Study 1. Study 3 was a multicenter, single-arm safety study of Unituxin 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 Unituxin 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 Laboratory Test Laboratory abnormalities with a per-patient incidence of at least 20% (all grades) and at least a 5% per-patient incidence of severe (Grade 3 or 4) laboratory abnormalities. Grade Based on CTCAE version 4.0. All Grades % Grades 3 to 4 % ND, not determined Hematology Anemia 100 46 Neutropenia 99 63 Thrombocytopenia 98 49 Chemistry Hypoalbuminemia 100 8 Hypocalcemia 97 7 Hyponatremia 93 36 Hyperglycemia 87 6 Aspartate Aminotransferase Increased 84 8 Alanine Aminotransferase Increased 83 13 Hypokalemia 82 41 Hypophosphatemia 78 6 Urinalysis Urinalysis results were reported as positive or negative without assessment of grade. Urine protein 66 ND Red blood cell casts 38 ND

Postmarketing Experience

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

No drug-drug interaction studies have been conducted with dinutuximab.

Pregnancy Risk Summary Based on its mechanism of action, Unituxin 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.

Pediatric Use The safety and effectiveness of Unituxin as part of multi-agent, multimodality therapy have been established in pediatric patients with high-risk neuroblastoma based on results of an open-label, randomized (1:1) trial conducted in 226 patients aged 11 months to 15 years (median age 3.8 years) (Study 1). Prior to enrollment, patients achieved at least a partial response to prior first-line therapy for high-risk neuroblastoma consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and received radiation therapy to residual soft tissue disease. Patients randomized to the Unituxin/13-cis-retinoic acid (RA) arm (Unituxin/RA) received up to 5 cycles of Unituxin in combination with alternating cycles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) plus RA, followed by 1 cycle of RA alone. Patients randomized to the RA arm received up to 6 cycles of RA monotherapy.

Study 1 demonstrated an improvement in event-free survival (EFS) and overall survival (OS) in patients in the Unituxin/RA arm compared to those in the RA arm . Juvenile Animal Toxicity Data Juvenile monkeys (13 to 18 months of age at study start) received dinutuximab daily via intravenous infusion for 4 consecutive days over five 28-day cycles at doses of 1, 3, or 10 mg/kg. Monkeys also received morphine during infusion for pain management. At the high dose of 10 mg/kg (approximately equal to the 17.5 mg/m 2 clinical dose), mild degeneration of nerve fibers in the brain (medulla oblongata) and moderate degeneration of nerve fibers in the spinal cord (cervical, thoracic, and lumbar) were present.

Mild neuronal and nerve fiber degeneration were also present in the dorsal root ganglia (cervical, thoracic, and lumbar). Nerve fiber degeneration in the spinal cord and neuronal degeneration in dorsal root ganglia persisted 6 months after the end of dosing, though at lower severity. At the 10 mg/kg dose level, nerve conduction velocity (NCV) analysis showed motor and sensory NCV decreases of less than 10% compared to vehicle controls, starting on Day 27 and continuing to Day 83. Sensory NCV decreases were still present at the end of the dosing period but were on a trend towards recovery 6 months after the end of dosing.

Unituxin is contraindicated in patients with a history of anaphylaxis to dinutuximab. History of anaphylaxis to dinutuximab.