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Clinical Trial Data

The Children's Oncology Group's (COG) ANBL0032 was a landmark phase 3, randomized, multi-institutional, clinical trial1

Unituxin® has been studied in many clinical trials conducted by COG, the world's largest organization devoted exclusively to pediatric cancer research. The pivotal trial that led to FDA approval of Unituxin was COG's ANBL0032 study, which showed that antibody therapy with Unituxin (known as ch14.18 during the study), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) , and retinoic acid (RA) was associated with a significantly improved outcome compared with standard therapy in patients with high-risk neuroblastoma.1,2

Explore the robust ANBL0032 clinical trial data:

Learn how the study was conducted

Review the results and efficacy of Unituxin

See the long-term survival data

ANBL0032 study overview

Study design: ANBL0032 was a randomized, open-label, multi-institutional trial to determine whether adding Unituxin, GM-CSF, and IL-2 to standard retinoic acid (RA) therapy after induction chemotherapy, surgery, autologous stem cell transplant, and radiation therapy improved outcomes in patients with high-risk neuroblastoma.1

Patients with high-risk neuroblastoma who had a response to induction therapy and stem-cell transplantation were randomly assigned, in a 1:1 ratio, to receive 6 cycles of standard therapy (RA alone) or 6 cycles of the Unituxin antibody therapy regimen with alternating GM-CSF and IL-2.1,3

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ANBL0032 study overview

*Randomization occurred between day 50 and day 77 after autologous stem cell transplantation.3

Efficacy end points: Event-free survival (EFS) and overall survival (OS) were compared between the Unituxin group and the standard-therapy group on an intention-to-treat basis.1,3

Results

Improved EFS compared with RA alone

Unituxin compared with standard treatment showed 2-year EFS rates of 66±5% vs 46±5% (P=0.01), respectively. EFS was defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death.1

2-year EFS rate in children with treatment-responsive high-risk neuroblastoma1

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2-year EFS rate in children with treatment-responsive high-risk neuroblastoma

Significantly improved outcomes with the antibody therapy regimen vs RA alone led to an early termination of the randomized portion of the clinical trial, and all eligible patients were then nonrandomized to receive the Unituxin regimen. 1

Long-term survival benefit at 5 years

The antibody therapy regimen demonstrated a significant long-term survival benefit in 226 eligible randomized patients as part of the extended follow-up of COG's ANBL0032 randomized phase 3 trial, according to results published in Clinical Cancer Research.4

5-year EFS

5-year EFS was 57±4.7% for patients randomized to the Unituxin group (n=114) vs 46±5.1% for those randomized to the RA-only group (n=112; P=0.042).4

5-year EFS rate in children with treatment-responsive high-risk neuroblastoma4

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5-year EFS rate in children with treatment-responsive high-risk neuroblastoma chart

5-year OS

5-year OS was 73% for patients randomized to the Unituxin group (n=114) vs 57% for those randomized to the RA-only group (n=112; P=0.045).4

MOA

Watch the video to see how Unituxin works.

Safety Profile
Safety Profile

Review the well-established safety profile.

References: 1. Yu AL, Gilman AL, Ozkaynak MF, et al; the Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363(14):1324-1334. 2. Children's Oncology Group website. About us. https://childrensoncologygroup.org/index.php/62-about-us/about-us. Accessed June 11, 2021. 3. Unituxin [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2020. 4. Yu AL, Gilman AL, Ozkaynak MF, et al. Long-term follow-up of a phase III study of ch14.18 (dinutuximab) + cytokine immunotherapy in children with high-risk neuroblastoma: Children's Oncology Group study ANBL0032. Clin Cancer Res. 2021;27(8):2179-2189.

Indication

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.

Important Safety Information for Unituxin
  • Boxed WARNING
  • Serious Infusion Reactions
    • Serious and potentially life-threatening infusion reactions (facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension) occurred in 26% of patients treated with Unituxin.
    • Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion.
    • Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion.
    • Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis.
  •  
  • Neurotoxicity
    • Unituxin causes serious neurologic adverse reactions including severe neuropathic pain and peripheral neuropathy.
    • Severe neuropathic pain occurs in the majority of patients.
    • Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion.
    • In clinical studies of patients with high-risk neuroblastoma, severe (Grade 3) peripheral sensory neuropathy ranged from 2% to 9%.
    • In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases.
    • Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Serious Infusion Reactions

  • Serious infusion reactions requiring urgent intervention including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of Unituxin included facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension. Infusion reactions generally occurred during or within 24 hours of completing the Unituxin infusion. Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity reactions in some cases.
  • Severe (Grade 3 or 4) infusion reactions occurred in 35 (26%) patients in the Unituxin/13-cis-retinoic acid (RA) group compared to 1 (1%) patient receiving RA alone. Severe urticaria occurred in 17 (13%) patients in the Unituxin/RA group but did not occur in the RA group. Serious adverse reactions consistent with anaphylaxis and resulting in permanent discontinuation of Unituxin occurred in 2 (1%) patients in the Unituxin/RA group. Additionally, 1 (0.1%) patient had multiple cardiac arrests and died within 24 hours after having received Unituxin in Study 2.

Neurotoxicity

  • Pain: 114 (85%) patients treated in the Unituxin/RA group experienced pain despite pre-treatment with analgesics including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the Unituxin/RA group compared to 5 (5%) patients in the RA group. For severe pain, decrease the Unituxin infusion rate to 0.875 mg/m2/hour. Discontinue Unituxin if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures.
  • Peripheral Neuropathy: Severe (Grade 3) peripheral sensory neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy occurred in 2 (1%) patients in the Unituxin/RA group. Permanently discontinue Unituxin in patients with peripheral motor neuropathy of Grade 2 or greater severity, Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, or Grade 4 sensory neuropathy.
  • Neurological Disorders of the Eye:
    • Neurological disorders of the eye experienced by two or more patients treated with Unituxin included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema. In Study 1, 3 (2%) patients in the Unituxin/RA group experienced blurred vision, compared to no patients in the RA group. Diplopia, mydriasis, and unequal pupillary size occurred in 1 patient each in the Unituxin/RA group, compared to no patients in the RA group. The duration of eye disorders occurring in Study 1 was not documented. In Study 3, eye disorders occurred in 16 (15%) patients, and in 3 (3%) patients resolution of the eye disorder was not documented. Among the cases with documented resolution, the median duration of eye disorders was 4 days (range: 0, 221 days).
    • Interrupt Unituxin in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss.
    • Upon resolution and if continued treatment with Unituxin is warranted, decrease the Unituxin dose by 50%.
    • Permanently discontinue Unituxin in patients who experience loss of vision and in patients with recurrent eye disorder following dose reduction.
  • Prolonged Urinary Retention: Urinary retention that persists for weeks to months following discontinuation of opioids has occurred in patients treated with Unituxin. Permanently discontinue Unituxin in patients with prolonged urinary retention that does not resolve with discontinuation of opioids.
  • Transverse Myelitis: Transverse myelitis has occurred in patients treated with Unituxin. Promptly evaluate any patient with signs or symptoms such as weakness, paresthesia, sensory loss, or incontinence. Permanently discontinue Unituxin in patients who develop transverse myelitis.
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has occurred in patients treated with Unituxin. Institute appropriate medical treatment and permanently discontinue Unituxin in patients with signs and symptoms of RPLS (e.g., severe headache, hypertension, visual changes, lethargy, or seizures).

Capillary Leak Syndrome

  • Severe (Grade 3 to 5) capillary leak syndrome occurred in 31 (23%) patients in the Unituxin/RA group and in no patients treated with RA alone.
  • Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin and institute supportive management in patients with symptomatic or severe capillary leak syndrome.

Hypotension

  • Severe (Grade 3 or 4) hypotension occurred in 22 (16%) patients in the Unituxin/RA group compared to no patients in the RA group.
  • Prior to each Unituxin infusion, administer required intravenous hydration.
  • Closely monitor blood pressure during Unituxin treatment.
  • Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin and institute supportive management in patients with symptomatic hypotension.

Infection

  • Severe (Grade 3 or 4) bacteremia requiring intravenous antibiotics or other urgent intervention occurred in 17 (13%) patients in the Unituxin/RA group compared to 5 (5%) patients treated with RA alone. Sepsis occurred in 24 (18%) of patients in the Unituxin/RA group and in 10 (9%) patients in the RA group.
  • Monitor patients closely for signs and symptoms of systemic infection and temporarily discontinue Unituxin in patients who develop systemic infection until resolution of the infection.

Bone Marrow Suppression

  • Severe (Grade 3 or 4) thrombocytopenia (39% vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%), and febrile neutropenia (4% vs. 0 patients) occurred more commonly in patients in the Unituxin/RA group compared to patients treated with RA alone.
  • Monitor peripheral blood counts closely during Unituxin therapy.

Electrolyte Abnormalities

  • Electrolyte abnormalities occurring in at least 25% of patients who received Unituxin/RA in Study 1 included hyponatremia, hypokalemia, and hypocalcemia. Severe (Grade 3 or 4) hypokalemia and hyponatremia occurred in 37% and 23% of patients in the Unituxin/RA group, respectively, compared to 2% and 4% of patients in the RA group.
  • Monitor serum electrolytes daily during therapy with Unituxin.

Atypical Hemolytic Uremic Syndrome

  • Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in two patients following receipt of the first cycle of Unituxin.
  • Permanently discontinue Unituxin and institute supportive management.

Embryo-Fetal Toxicity

  • Unituxin may cause fetal harm.
  • Advise pregnant women of the potential risk to a fetus.
  • Advise females of reproductive potential to use effective contraception during treatment, and for two months after the last dose of Unituxin.

ADVERSE REACTIONS

The most common serious adverse reactions (≥ 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

The most common adverse drug reactions (≥ 25%) in Unituxin/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%), infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%). In post-approval use of Unituxin, the adverse reactions of prolonged urinary retention, transverse myelitis, and reversible posterior leukoencephalopathy syndrome were observed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

UTXISIhcpJAN18

Please see Full Prescribing Information , including Boxed WARNING, for Unituxin.

UNITUXIN® (dinutuximab) INJECTION, FOR INTRAVENOUS USE
Indication

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.

Important Safety Information for Unituxin
  • Boxed WARNING
  • Serious Infusion Reactions
    • Serious and potentially life-threatening infusion reactions (facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension) occurred in 26% of patients treated with Unituxin.
    • Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion.
    • Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion.
    • Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis.
  •  
  • Neurotoxicity
    • Unituxin causes serious neurologic adverse reactions including severe neuropathic pain and peripheral neuropathy.
    • Severe neuropathic pain occurs in the majority of patients.
    • Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion.
    • In clinical studies of patients with high-risk neuroblastoma, severe (Grade 3) peripheral sensory neuropathy ranged from 2% to 9%.
    • In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy has occurred. Resolution of motor neuropathy did not occur in all cases.
    • Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, and moderate to severe peripheral motor neuropathy.

CONTRAINDICATIONS

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

WARNINGS AND PRECAUTIONS

Serious Infusion Reactions

  • Serious infusion reactions requiring urgent intervention including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of Unituxin included facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension. Infusion reactions generally occurred during or within 24 hours of completing the Unituxin infusion. Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity reactions in some cases.
  • Severe (Grade 3 or 4) infusion reactions occurred in 35 (26%) patients in the Unituxin/13-cis-retinoic acid (RA) group compared to 1 (1%) patient receiving RA alone. Severe urticaria occurred in 17 (13%) patients in the Unituxin/RA group but did not occur in the RA group. Serious adverse reactions consistent with anaphylaxis and resulting in permanent discontinuation of Unituxin occurred in 2 (1%) patients in the Unituxin/RA group. Additionally, 1 (0.1%) patient had multiple cardiac arrests and died within 24 hours after having received Unituxin in Study 2.

Neurotoxicity

  • Pain: 114 (85%) patients treated in the Unituxin/RA group experienced pain despite pre-treatment with analgesics including morphine sulfate infusion. Severe (Grade 3) pain occurred in 68 (51%) patients in the Unituxin/RA group compared to 5 (5%) patients in the RA group. For severe pain, decrease the Unituxin infusion rate to 0.875 mg/m2/hour. Discontinue Unituxin if pain is not adequately controlled despite infusion rate reduction and institution of maximum supportive measures.
  • Peripheral Neuropathy: Severe (Grade 3) peripheral sensory neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy occurred in 2 (1%) patients in the Unituxin/RA group. Permanently discontinue Unituxin in patients with peripheral motor neuropathy of Grade 2 or greater severity, Grade 3 sensory neuropathy that interferes with daily activities for more than 2 weeks, or Grade 4 sensory neuropathy.
  • Neurological Disorders of the Eye:
    • Neurological disorders of the eye experienced by two or more patients treated with Unituxin included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema. In Study 1, 3 (2%) patients in the Unituxin/RA group experienced blurred vision, compared to no patients in the RA group. Diplopia, mydriasis, and unequal pupillary size occurred in 1 patient each in the Unituxin/RA group, compared to no patients in the RA group. The duration of eye disorders occurring in Study 1 was not documented. In Study 3, eye disorders occurred in 16 (15%) patients, and in 3 (3%) patients resolution of the eye disorder was not documented. Among the cases with documented resolution, the median duration of eye disorders was 4 days (range: 0, 221 days).
    • Interrupt Unituxin in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss.
    • Upon resolution and if continued treatment with Unituxin is warranted, decrease the Unituxin dose by 50%.
    • Permanently discontinue Unituxin in patients who experience loss of vision and in patients with recurrent eye disorder following dose reduction.
  • Prolonged Urinary Retention: Urinary retention that persists for weeks to months following discontinuation of opioids has occurred in patients treated with Unituxin. Permanently discontinue Unituxin in patients with prolonged urinary retention that does not resolve with discontinuation of opioids.
  • Transverse Myelitis: Transverse myelitis has occurred in patients treated with Unituxin. Promptly evaluate any patient with signs or symptoms such as weakness, paresthesia, sensory loss, or incontinence. Permanently discontinue Unituxin in patients who develop transverse myelitis.
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has occurred in patients treated with Unituxin. Institute appropriate medical treatment and permanently discontinue Unituxin in patients with signs and symptoms of RPLS (e.g., severe headache, hypertension, visual changes, lethargy, or seizures).

Capillary Leak Syndrome

  • Severe (Grade 3 to 5) capillary leak syndrome occurred in 31 (23%) patients in the Unituxin/RA group and in no patients treated with RA alone.
  • Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin and institute supportive management in patients with symptomatic or severe capillary leak syndrome.

Hypotension

  • Severe (Grade 3 or 4) hypotension occurred in 22 (16%) patients in the Unituxin/RA group compared to no patients in the RA group.
  • Prior to each Unituxin infusion, administer required intravenous hydration.
  • Closely monitor blood pressure during Unituxin treatment.
  • Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin and institute supportive management in patients with symptomatic hypotension.

Infection

  • Severe (Grade 3 or 4) bacteremia requiring intravenous antibiotics or other urgent intervention occurred in 17 (13%) patients in the Unituxin/RA group compared to 5 (5%) patients treated with RA alone. Sepsis occurred in 24 (18%) of patients in the Unituxin/RA group and in 10 (9%) patients in the RA group.
  • Monitor patients closely for signs and symptoms of systemic infection and temporarily discontinue Unituxin in patients who develop systemic infection until resolution of the infection.

Bone Marrow Suppression

  • Severe (Grade 3 or 4) thrombocytopenia (39% vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%), and febrile neutropenia (4% vs. 0 patients) occurred more commonly in patients in the Unituxin/RA group compared to patients treated with RA alone.
  • Monitor peripheral blood counts closely during Unituxin therapy.

Electrolyte Abnormalities

  • Electrolyte abnormalities occurring in at least 25% of patients who received Unituxin/RA in Study 1 included hyponatremia, hypokalemia, and hypocalcemia. Severe (Grade 3 or 4) hypokalemia and hyponatremia occurred in 37% and 23% of patients in the Unituxin/RA group, respectively, compared to 2% and 4% of patients in the RA group.
  • Monitor serum electrolytes daily during therapy with Unituxin.

Atypical Hemolytic Uremic Syndrome

  • Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in two patients following receipt of the first cycle of Unituxin.
  • Permanently discontinue Unituxin and institute supportive management.

Embryo-Fetal Toxicity

  • Unituxin may cause fetal harm.
  • Advise pregnant women of the potential risk to a fetus.
  • Advise females of reproductive potential to use effective contraception during treatment, and for two months after the last dose of Unituxin.

ADVERSE REACTIONS

The most common serious adverse reactions (≥ 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

The most common adverse drug reactions (≥ 25%) in Unituxin/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%), infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%). In post-approval use of Unituxin, the adverse reactions of prolonged urinary retention, transverse myelitis, and reversible posterior leukoencephalopathy syndrome were observed. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

UTXISIhcpJAN18

Please see Full Prescribing Information , including Boxed WARNING, for Unituxin.

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