Dinutuximab Beta

Dinutuximab beta is a mouse-human chimeric monoclonal IgG1 antibody produced in a mammalian (CHO) cell line by recombinant DNA technology. It is directed specifically against the carbohydrate part of the disialoganglioside GD2, which is overexpressed on neuroblastoma cells.

Mechanism of Action

• Target binding: in vitro, the antibody binds to neuroblastoma cell lines known to express GD2.
• Cell killing: it induces complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. With human effector cells (peripheral blood mononuclear cells and granulocytes from normal donors), it caused dose-dependent lysis of human neuroblastoma and melanoma cell lines. In a mouse model it suppressed liver metastasis.
• Neurotoxicity: the nerve toxicity of the antibody is probably due to mechanical allodynia, which may be mediated by its reaction with GD2 on the surface of peripheral nerve fibres and myelin. Eye disorders may occur because it binds to optic nerve cells.
• Clinical evidence: efficacy was evaluated in a randomised controlled trial of dinutuximab beta with or without interleukin-2 (IL-2) in first-line treatment of high-risk neuroblastoma, and in two single-arm studies in relapsed or refractory disease (54 patients in a compassionate use programme and 44 in a phase II study) that gave a 10-day continuous infusion with subcutaneous IL-2, followed by oral 13-cis-retinoic acid.

Pharmacokinetics

• Studied regimens: short-term infusions (5 days of 8-hour infusions at 20 mg/m² per day) and long-term infusions (10 days of continuous infusion, 100 mg/m² per course).
• Exposure: the antibody is given intravenously only. The mean peak concentration at the end of the long-term infusion was 11.2 mg/L. Exposure rose in proportion to dose up to 100 mg/m² per course, and the peak accumulation ratio was about 1.13 after five long-term courses.
• Distribution: the population mean central volume of distribution was about 2.04 L and the peripheral volume about 2.65 L.
• Metabolism: not investigated. As a protein, it is expected to be broken down by ubiquitous proteolytic enzymes into small peptides and amino acids.
• Elimination: clearance after the long-term infusion was about 0.72 L/day/m², and the apparent terminal half-life about 8.7 days. Clearance rises when anti-drug antibody titres are high, whether or not the antibodies are neutralising.
• Special populations: the analysis covered patients aged 1 to 27 years (median 6). Volume and clearance increase with body size, exposure is comparable across ages at 100 mg/m², and gender has no clinically meaningful effect. There are no data in renal or hepatic impairment.

• High-risk neuroblastoma: patients aged 12 months and above who have previously received induction chemotherapy and achieved at least a partial response, followed by myeloablative therapy and stem cell transplantation.
• Relapsed or refractory neuroblastoma: patients with a history of relapsed or refractory neuroblastoma, with or without residual disease. Before treating relapsed neuroblastoma, any actively progressing disease should be stabilised by other suitable measures.
• Combination with interleukin-2: in patients with a history of relapsed or refractory disease and in patients who have not achieved a complete response after first-line therapy, Qarziba should be combined with IL-2.

• Hypersensitivity to dinutuximab beta or to any of the excipients.
• Acute grade 3 or 4 graft-versus-host disease, or extensive chronic graft-versus-host disease.

The safety of dinutuximab beta was evaluated in 791 patients with high-risk and relapsed or refractory neuroblastoma, of whom 212 had a continuous infusion and 416 repeated daily infusions. Most also received 13-cis-retinoic acid and 307 received IL-2. The most common reactions were pyrexia (86%) and pain (57%), which occurred despite analgesic treatment. Other frequent reactions were hypersensitivity (74.1%), vomiting (55%), diarrhoea (52%), capillary leak syndrome (36%), anaemia (49%), neutropenia (46%), thrombocytopenia (42%) and hypotension (41%).

Very common (≥1/10): Infections: infection (including pneumonia, skin infection, herpes virus infection, myelitis and encephalomyelitis), device-related infection; Blood and lymphatic: anaemia, leukopenia, neutropenia, thrombocytopenia; Immune system: hypersensitivity, cytokine release syndrome; Metabolism: fluid retention; Nervous system: headache; Eye: mydriasis, pupillotonia, eye oedema (eyelid, periorbital); Cardiac: tachycardia; Vascular: hypotension, capillary leak syndrome; Respiratory: hypoxia, cough; Gastrointestinal: vomiting, diarrhoea, constipation, stomatitis; Skin: pruritus, rash, urticaria; General: pyrexia, chills, pain, peripheral oedema, face oedema; Investigations: increased weight, transaminases, gamma-glutamyltransferase, blood bilirubin and blood creatinine.

Common (≥1/100 to <1/10): Infections: sepsis; Blood and lymphatic: lymphopenia; Immune system: anaphylactic reaction; Metabolism: decreased appetite, hypoalbuminaemia, hyponatraemia, hypokalaemia, hypophosphataemia, hypomagnesaemia, hypocalcaemia, dehydration; Psychiatric: agitation, anxiety; Nervous system: peripheral neuropathy, seizure, paraesthesia, dizziness, tremor; Eye: ophthalmoplegia, papilloedema, accommodation disorder, blurred vision, photophobia; Cardiac: cardiac failure, left ventricular dysfunction, pericardial effusion; Vascular: hypertension; Respiratory: bronchospasm, dyspnoea, respiratory failure, lung infiltration, pulmonary oedema, pleural effusion, tachypnoea, laryngospasm; Gastrointestinal: nausea, lip oedema, ascites, abdominal distension, ileus, dry lips; Skin: dermatitis (including exfoliative), erythema, dry skin, hyperhidrosis, petechiae, photosensitivity reaction; Musculoskeletal: muscle spasms; Renal and urinary: oliguria, urinary retention, hyperphosphaturia, haematuria, proteinuria; General: injection site reaction; Investigations: decreased weight, decreased glomerular filtration rate, hypertriglyceridaemia, prolonged activated partial thromboplastin time, prolonged prothrombin time, prolonged thrombin time.

Uncommon (≥1/1,000 to <1/100): Blood and lymphatic: disseminated intravascular coagulation, eosinophilia; Immune system: serum sickness; Nervous system: increased intracranial pressure, posterior reversible encephalopathy syndrome; Vascular: hypovolaemic shock, veno-occlusive disease; Gastrointestinal: enterocolitis; Hepatobiliary: hepatocellular injury; Renal and urinary: renal failure.

Not known: Blood and lymphatic: atypical haemolytic uraemic syndrome.

Among the hypersensitivity reactions, hypotension occurred in 42.2%, urticaria in 7% and bronchospasm in 1%; cytokine release syndrome was reported in 32% and serious anaphylactic reactions in 3.5%. Pain typically occurs during the first infusion and lessens over the courses. About 10% of capillary leak syndrome cases were severe (grade 3–4), and they became less frequent over the courses. Eye problems (impaired accommodation correctable with glasses, mydriasis 2%, periorbital or eyelid oedema 3%, blurred vision 3%, photophobia 3%) were usually reversible after stopping treatment, but ophthalmoplegia (2%) and optic atrophy were also reported. Motor and sensory peripheral neuropathy occurred in 9% of patients, mostly grade 1–2 and resolving. Posterior reversible encephalopathy syndrome (0.7%) and seizures (1.7%) were reported. Combining Qarziba with IL-2 raises the risk, especially pyrexia (94% versus 80% without IL-2), capillary leak syndrome (45% versus 20%), pain (70% versus 62%), hypotension (44% versus 27%) and peripheral neuropathy (9% versus 5%).

No interaction studies have been performed. Higher TNF-α and IL-6 levels could indirectly reduce CYP activity, so interactions with other medicines cannot be excluded.

• Corticosteroids: concomitant treatment is not recommended from 2 weeks before the first course until 1 week after the last course, because of their immunosuppressive activity, except in life-threatening conditions.
• Vaccinations: should be avoided during treatment and until 10 weeks after the last course, because of immune stimulation by dinutuximab beta and a possible risk of rare neurological toxicities.
• Intravenous immunoglobulins: concomitant use is not recommended, as they may interfere with the antibody-dependent cellular cytotoxicity on which dinutuximab beta depends.
• Interleukin-2: used with Qarziba in relapsed or refractory disease, it increases the risk of adverse reactions (see Side Effects).

Qarziba is restricted to hospital use and must be given under the supervision of a physician experienced in oncological therapies. It must be administered by a healthcare professional prepared to manage severe allergic reactions, including anaphylaxis, in an environment where full resuscitation services are immediately available. It is given as an intravenous infusion through a peripheral or central line; other intravenous medicines are given through a separate infusion line. Premedication should always be considered before each infusion (see Special Instructions). For dilution see section 6.6 of the SmPC.

Recommended Dose

• Treatment is 5 consecutive courses of 35 days each. The dose is based on body surface area, to a total of 100 mg/m² per course.
• Continuous infusion: 10 mg/m² per day over the first 10 days of each course (240 hours in total), at 2 mL per hour (48 mL per day) using an infusion pump.
• Daily infusions: 20 mg/m² over 8 hours on each of the first 5 days of each course, at about 13 mL per hour.
• With IL-2: subcutaneous injections of 6×10⁶ IU/m² per day for two periods of 5 consecutive days, an overall 60×10⁶ IU/m² per course. The first 5-day period starts 7 days before the first dinutuximab beta infusion, and the second starts together with the infusion (days 1 to 5 of each course).

Before Each Course

The following are checked, and treatment is delayed until they are met: pulse oximetry above 94% on room air; absolute neutrophil count of at least 500/µL, platelets of at least 20,000/µL and haemoglobin above 8.0 g/dL; ALT/AST below 5 times the upper limit of normal; and creatinine clearance or glomerular filtration rate above 60 mL/min/1.73 m².

Dose Adjustments

• Depending on the physician’s assessment of severity, the dose can be reduced by 50% or the infusion interrupted temporarily. The infusion period is then extended or, if the patient tolerates it, the rate is increased up to 3 mL per hour (continuous infusion) so that the full dose is still given.
• According to the SmPC table, for grade 1–2 reactions the infusion rate is decreased to 50% and returned to the original rate once the reaction resolves. For grade 3 or higher reactions, the infusion is interrupted with supportive measures, resumed at 50% of the rate when the reaction resolves or improves to grade 1–2, then returned to the original rate. If a reaction recurs, the infusion is discontinued and resumed the next day if it resolves.
• The table also gives specific instructions for hypersensitivity reactions, dilated pupils with a sluggish light reflex (with or without photophobia), capillary leak syndrome and central neurotoxicity, which should be followed.
• Permanent discontinuation is required for: grade 3 or 4 anaphylaxis; prolonged grade 2 peripheral motor neuropathy; grade 3 peripheral neuropathy; grade 3 vision toxicity of the eye; grade 4 hyponatraemia (below 120 mEq/L) despite appropriate fluid management; recurrent or grade 4 capillary leak syndrome (requiring ventilator support); severe central neurotoxicity (grade 3 or 4 with substantial prolonged neurological deficit without a detectable reason, recurrent grade 1–3 neurotoxicity, or permanent neurological deficit); and any grade of posterior reversible encephalopathy syndrome or transverse myelitis.

Special Populations

• Renal and hepatic impairment: there are no data.
• Children: the safety and efficacy of Qarziba in children under 12 months have not been established, and no data are available.

Traceability

To improve the traceability of biological medicines, the name and batch number of the product given should be clearly recorded.

Pain Management

Neuropathic pain usually occurs at the start of treatment, and premedication with analgesics, including intravenous opioids, before each infusion is required. The SmPC recommends triple therapy with non-opioid analgesics (following WHO guidelines), gabapentin and opioids; the individual dose may vary widely.

• Non-opioid analgesics, for example paracetamol or ibuprofen, are used throughout treatment.
• Gabapentin: start at 10 mg/kg/day, 3 days before the dinutuximab beta infusion. Increase to 2×10 mg/kg/day orally the next day, and to 3×10 mg/kg/day orally the day before the infusion starts and thereafter. The maximum single dose is 300 mg. The schedule is kept as long as the patient needs it. Oral gabapentin is tapered off after intravenous morphine has been weaned, and at the latest after the infusions have stopped.
• Opioids are standard, and the first infusion day and course usually need a higher dose than later ones. Before a continuous intravenous morphine infusion, a morphine bolus of 0.02 to 0.05 mg/kg/hour is started 2 hours before the dinutuximab beta infusion; the rate is then 0.03 mg/kg/hour alongside the infusion. With daily infusions, morphine continues at a lower rate (for example 0.01 mg/kg/hour) for 4 hours after the infusion ends. With continuous infusion, morphine may be weaned over 5 days by stepping the rate down (for example to 0.02, 0.01 and 0.005 mg/kg/hour). If continuous morphine is needed for more than 5 days, it is reduced by 20% per day after the last day of the antibody infusion.
• After intravenous morphine has been weaned, severe neuropathic pain can be treated with oral morphine sulphate on demand (0.2 to 0.4 mg/kg every 4 to 6 hours), and moderate neuropathic pain with oral tramadol.

Hypersensitivity Reactions and Cytokine Release Syndrome

Severe infusion-related reactions, including cytokine release syndrome, anaphylactic and hypersensitivity reactions, may occur despite premedication. A severe reaction (including cytokine release syndrome) requires immediate discontinuation of treatment and may need emergency treatment. Cytokine release syndrome often starts within minutes to hours of the first infusion, with fever, low blood pressure and urticaria. Anaphylaxis can occur within a few minutes of the first infusion, commonly with bronchospasm and urticaria.

• Premedication: an intravenous antihistamine (for example diphenhydramine) about 20 minutes before each infusion, repeated every 4 to 6 hours as required during the infusion.
• Monitoring: patients are closely monitored for anaphylaxis and allergic reactions, particularly in the first and second courses.
• Treatment: an intravenous antihistamine, adrenaline and intravenous prednisolone must be immediately available at the bedside. Recommended treatment is an intravenous prednisolone bolus and intravenous adrenaline boluses every 3 to 5 minutes as needed. For a bronchial or pulmonary reaction, inhaled adrenaline is recommended, repeated every 2 hours according to response.

Capillary Leak Syndrome

Capillary leak syndrome is a loss of vascular tone with leakage of plasma proteins and fluid into the extravascular space. It usually develops within hours of starting treatment, with symptoms such as hypotension and tachycardia appearing after 2 to 12 hours. Circulatory and respiratory function must be monitored carefully.

Eye Disorders

Eye disorders may occur because the antibody binds to optic nerve cells. No dose change is needed for impaired accommodation that glasses correct, if it is tolerable. Treatment must be interrupted for grade 3 vision toxicity (subtotal vision loss), and section 4.2 of the SmPC lists grade 3 vision toxicity among the reasons for permanent discontinuation. Any eye problem calls for prompt referral to an ophthalmology specialist.

Peripheral Neuropathy

Motor or sensory neuropathy lasting more than 4 days must be evaluated, and non-inflammatory causes such as disease progression, infection, metabolic syndromes and concomitant medicines excluded. Treatment is stopped permanently for any objective prolonged weakness attributable to the antibody. For moderate (grade 2) neuropathy, treatment is interrupted and may be resumed once the neurological symptoms resolve.

Central Neurotoxicity

If central neurotoxicity occurs, the infusion is interrupted immediately and the patient treated symptomatically, after ruling out other factors such as active infection, spread of neuroblastoma to the central nervous system and neurotoxic concomitant medicines. Criteria for permanent discontinuation are listed under Dose Adjustments.

Infections and Blood Counts

Patients are likely to be immunocompromised after earlier therapy, and usually have a central venous catheter, so they are at risk of systemic infection. There should be no evidence of systemic infection, and any infection should be controlled, before treatment starts. Erythropenia, thrombocytopenia and neutropenia have been reported; grade 4 haematological toxicity that improves to at least grade 2 or baseline by the start of the next course does not need a dose change. Liver function and electrolytes should be monitored regularly.

Atypical Haemolytic Uraemic Syndrome

Atypical haemolytic uraemic syndrome has been reported, in some cases fatal. Signs and symptoms should be watched for. If it is diagnosed, prompt treatment is required and dinutuximab beta must be permanently discontinued.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no data in pregnant women and no animal data on teratogenicity or embryotoxicity. GD2 is expressed on neuronal tissues, especially during embryofoetal development, and the antibody may cross the placenta, so Qarziba may cause foetal harm. It should not be used during pregnancy.
• Contraception: Qarziba should not be used in women of childbearing potential who are not using contraception, and contraception is recommended for 6 months after treatment stops.
• Breastfeeding: there are no data, and it is unknown whether dinutuximab beta passes into breast milk. Breast-feeding should be stopped during treatment and for 6 months after the last dose.
• Fertility: effects in humans are unknown. No dedicated fertility studies were done, but toxicity studies in guinea pigs and cynomolgus monkeys showed no adverse effects on reproductive organs.

Effect on Driving

Dinutuximab beta has a major influence on the ability to drive and use machines. Patients should not drive or use machines during treatment.

Store in a refrigerator at 2–8 °C, with the vial kept in the outer carton to protect it from light. Qarziba is a cold-chain product: the 2–8 °C temperature is maintained from supply until the vial is prepared for infusion. It is supplied as a 6 mL clear Type I glass vial with a halobutyl rubber stopper and aluminium flip-off cap, containing a minimum extractable volume of 4.5 mL; each carton holds one vial. For storage after dilution, see Shelf Life.

Unopened vial: 4 years. Diluted solution: chemical and physical in-use stability has been shown for up to 48 hours at 25 °C (50 mL syringe) and for up to 7 days at 37 °C (250 mL infusion bag), after cumulative storage in a refrigerator (2–8 °C) for 72 hours. From a microbiological point of view, the product should be used immediately. If it is not, the in-use storage time is the responsibility of the user and would not normally be longer than 24 hours at 2–8 °C, unless dilution took place under controlled and validated aseptic conditions.

Prescription only (Rx). Qarziba is subject to restricted medical prescription and is restricted to hospital use only, under the supervision of a physician experienced in oncological therapies. It is supplied to the hospital that administers it, in the cold chain at 2–8 °C.