Tasonermin

Tasonermin is recombinant human tumour necrosis factor alfa-1a (TNFα-1a), produced in E. coli. In isolated limb perfusion (ILP) it reaches high and fairly stable concentrations in the tumour-bearing limb. Its antitumour activity is thought to rest on direct and indirect effects on tumour cells, on the tumour blood vessels and on the immune system.

Mechanism of Action

• Direct effect on tumour cells: tasonermin is cytotoxic or cytostatic in vitro to a variety of tumour cell lines. Its direct cytotoxic effect is mediated through TNF receptor 1 and the death-receptor pathway, which ends in apoptosis.
• Effect on tumour blood vessels: it changes the shape of endothelial cells and reduces their proliferation, and alters the expression of adhesion molecules, proteins that modulate coagulation, interleukins and haematopoietic growth factors. This produces a procoagulant state with microvascular thrombosis, and leukocytes adhere and move into the tumour, which becomes infiltrated by lymphocytes, monocytes and granulocytes. Tumour vessels are much more sensitive than normal vessels; the reason is not known.
• Immunomodulation: it enhances the proliferation of activated B and T lymphocytes and the development of cytotoxic T cells and immunoglobulin-secreting cells, activates monocytes and macrophages to kill tumour cells, and makes granulocytes more phagocytic, with respiratory burst, degranulation and adherence to endothelium. It also induces cytokines and low-molecular-weight mediators (prostaglandins, platelet-activating factor). Its antitumour activity is much weaker in immunodeficient animals, which suggests that these immune effects matter.
• Result: the combined changes lead to haemorrhagic necrosis of the tumour.

Pharmacokinetics

• Systemic pharmacokinetics: information is sparse. Clearance falls and half-life rises as the dose increases. The terminal half-life at the maximum tolerated intravenous dose (150 µg/m²) was 15–30 minutes. DrugBank gives a volume of distribution of 55 L and 17 L, and clearance of 2 L/min and 0.5 L/min, after intravenous doses of 35 and 150 µg/m².
• During isolated limb perfusion: in 51 patients, maximum concentrations in the perfusion circuit were reached 30 minutes after the start of ILP and ranged between 3,000 and 4,000 ng/mL. With systemic leakage below 2% (38 of 51 patients), the maximum systemic concentration was reached 5 minutes after the start and was about 200 times lower than in the circuit. With leakage above 2% (13 of 51 patients), the maximum systemic concentration was still at least ten times lower than in the circuit.
• Absorption, metabolism and elimination: there is no oral form, and no absorption, metabolism, protein-binding or elimination-route data are available. Tasonermin is assumed to be broken down like other circulating proteins.
• Special populations: the SmPC gives no pharmacokinetic data for special populations.

• Soft tissue sarcoma of the limbs: in adults, in combination with melphalan via mild hyperthermic isolated limb perfusion (ILP), as an adjunct to surgery for subsequent removal of the tumour so as to prevent or delay amputation, or in the palliative situation, for irresectable soft tissue sarcoma of the limbs.

The SmPC lists contraindications for each component of the procedure.

• Contraindications to Beromun:
  • hypersensitivity to tasonermin or any of the excipients;
  • significant cardiovascular disease, for example congestive heart failure (NYHA class II, III or IV), severe angina pectoris, cardiac arrhythmias, myocardial infarction within the previous 3 months, venous thrombosis, occlusive peripheral arterial disease or recent pulmonary embolism;
  • severe pulmonary dysfunction;
  • a recent history of, or active, peptic ulcer;
  • severe ascites;
  • significant haematological dysfunction, for example leucocytes below 2.5 × 10⁹/L, haemoglobin below 9 g/dL, platelets below 60 × 10⁹/L, haemorrhagic diathesis or an active bleeding disorder;
  • significant renal dysfunction, for example nephrotic syndrome, serum creatinine above 150 µmol/L or creatinine clearance below 50 mL/min;
  • significant hepatic dysfunction, for example AST, ALT or alkaline phosphatase above 2 times the upper limit of normal, or bilirubin above 1.25 times the upper limit of normal;
  • hypercalcaemia above 12 mg/dL (2.99 mmol/L);
  • contraindications to vasopressor substances or to anticoagulants;
  • simultaneous treatment with cardiotoxic substances (for example anthracyclines);
  • pregnancy and lactation.
• Contraindications to melphalan: see the SmPC of melphalan.
• Contraindications to the ILP procedure: severe ascites; severe lymphoedema of the limb; contraindications to vasopressor agents, to anticoagulants, to radioactive tracer monitoring or to limb hyperthermia; blood supply to the extremity beyond the tumour suspected to depend highly on tumour-associated vessels (this can be clarified by an arteriogram); pregnancy and lactation.

Undesirable effects may be related to Beromun, to melphalan, to the ILP procedure and associated measures, or to a combination of these. The most frequent reactions in clinical trials were fever, nausea, vomiting, fatigue, arrhythmia, chills, pain, wound infection and skin reaction. Reactions are either local, affecting the limb treated with ILP, or systemic; systemic reactions include mild constitutional reactions and toxic effects on different organ systems.

Very common (≥1/10): arrhythmia; nausea, vomiting; hepatotoxicity; skin reaction; fever, chills, pain, fatigue.

Common (≥1/100 to <1/10): infection, wound infection; leukopenia, thrombocytopenia; hypersensitivity reaction; nerve injury, peripheral neurotoxicity, altered state of consciousness, headache; cardiac failure; venous thrombosis, arterial thrombosis, shock, hypotension; adult respiratory distress syndrome; diarrhoea, constipation; skin necrosis, peripheral oedema; compartment syndrome, myalgia; proteinuria; night sweats; extremity necrosis severe enough to warrant amputation.

Uncommon (≥1/1,000 to <1/100): sepsis; peripheral arterial occlusive disease; pulmonary oedema; upper abdominal pain, erosive gastritis; onychomadesis (loss of nails); acute renal failure; increased blood creatinine.

Extremity necrosis and compartment syndrome may be severe enough to warrant amputation. Late-onset peripheral arterial occlusive disease of the lower limbs has been reported several years after ILP, mostly in patients with established cardiovascular risk factors or who had additional irradiation of the treated limb.

No interaction studies have been performed.

• Interferon-gamma: it has been given together with tasonermin in ILP without demonstrated added value, and clinical data indicate that the overall incidence of adverse events is higher when patients are exposed to both.
• Cardiotoxic substances (for example anthracyclines): avoid, because tasonermin could enhance cardiotoxicity, as seen in preclinical 13-week toxicity studies. Simultaneous treatment is a contraindication.
• Medicines likely to cause significant hypotension: concurrent use is not recommended.
• Routine perioperative medicines: standard anaesthetic agents, analgesics, antipyretics, intravenous fluids, anticoagulants and vasopressor agents are used routinely during ILP. There is no evidence that they counteract the effects of tasonermin and no significant interactions have been noted so far, but caution is advised.
• Melphalan: see its SmPC for its interactions.

Beromun is given only as part of a mild hyperthermic isolated limb perfusion (ILP), in specialised centres by surgical teams experienced in the management of limb sarcomas and the ILP procedure, with an intensive care unit readily available and facilities for continuous monitoring of leakage of the medicinal product into the systemic circulation. It must not be administered systemically. The SmPC of melphalan should be consulted before an ILP is begun.

Recommended Dose

• Beromun: 3 mg total dose by ILP for an upper limb; 4 mg total dose by ILP for a lower limb.
• Melphalan: dose calculated by the litre-volume method of Wieberdink, to a maximum of 150 mg: 13 mg per litre of perfused upper limb volume and 10 mg per litre of perfused lower limb volume.

Perfusion Procedure

• Handling: gloves are recommended when preparing and handling Beromun solutions; if the powder or reconstituted solution touches skin or mucous membranes, wash thoroughly with water. Reconstitution instructions are in section 6.6 of the SmPC.
• Circuit: the perfusion circuit (roller pump, oxygenator with integrated reservoir, heat exchanger, connecting tubing) is prepared before surgery and primed with 700 to 800 mL of perfusate with a haematocrit of 0.25 to 0.30. The perfusion level is chosen to cover the affected tissue (external iliac, common femoral, femoro-popliteal, popliteal, axillary and brachial routes are accepted) and catheters are introduced. Heat loss is prevented with thermal blankets, limb temperature is monitored continuously by thermistor probes in subcutaneous tissue and muscle, an unaffected hand or foot is protected with Esmarch bandages, and a tourniquet is applied to the proximal limb.
• Leakage check: once the limb is connected to the isolated circuit, the flow rate is set to 35 to 40 mL per litre of limb volume per minute and leakage into the systemic circulation is checked with a radioactive tracer. Flow rate and tourniquet are adjusted until leakage is stable and does not exceed 10%. Beromun is given only if leakage is below 10%.
• Giving Beromun: once the temperature in the distal subcutaneous tissue of the limb is above 38 °C (but not exceeding 39 °C) and the perfusate pH is between 7.2 and 7.35, Beromun is injected as a bolus into the arterial line of the circuit.
• Melphalan: after 30 minutes of perfusion with Beromun alone, melphalan is added as a bolus into the reservoir or slowly into the arterial line. The temperature is then raised to above 39 °C (but not exceeding 40 °C) at two measuring sites in the tumour area. Perfusion including melphalan lasts 60 minutes, so the total perfusion lasts 90 minutes.
• Washout: at the end, the perfusate is collected in the reservoir while washout fluid is added to the circuit at the same flow rate, until the perfusate is clear, pink and transparent. A standard washout with dextran 70 intravenous infusion or similar fluid is always used: 3 to 6 litres after lower limb perfusion and 1 to 2 litres after upper limb perfusion; popliteal and brachial perfusions may need no more than 1 litre. Periods of interrupted oxygen supply to the limb should be as brief as possible (20 minutes at most).

Leakage Limits

• The perfusion flow rate should not exceed 40 mL per litre of limb volume per minute. Leakage is measured with radioactively labelled albumin or erythrocytes injected into the circuit, with continuous monitoring of radioactivity in the systemic circulation.
• The perfusion is terminated if cumulative leakage into the systemic circulation exceeds 10%; a standard washout then follows, using at least 2 litres of dextran 70 intravenous infusion or similar fluid.

Repeat Perfusion

Surgical resection of the tumour remnant should be undertaken whenever possible. When necessary, a second ILP can be considered 6 to 8 weeks after the first, taking the leakage rate of the first ILP into account.

Special Populations

• Children and adolescents: safety and efficacy below 18 years have not been established; no data are available.
• Renal and hepatic function: significant renal or hepatic dysfunction is a contraindication (see Contraindications).

Specialised Centre and Systemic Leakage

ILP must be undertaken in specialised centres by surgical teams experienced in limb sarcoma and the ILP procedure, with an intensive care unit readily available and continuous monitoring for leakage. Beromun must not be administered systemically. The maximum tolerated dose of tasonermin for ILP is 4 mg, which is 10 times the systemic maximum tolerated dose, so serious undesirable effects are to be expected whenever there is significant systemic leakage.

Anaesthesia, Monitoring and Shock Prophylaxis

• General anaesthesia and mechanical ventilation follow standard methods. A constant level of anaesthesia is important to avoid large swings in systemic blood pressure, which can affect leakage between the systemic circulation and the perfusion circuit.
• Central venous and arterial pressure monitoring during ILP is strongly recommended. Blood pressure, urine output and electrocardiogram are monitored routinely in the first 24 to 48 hours afterwards, or longer if indicated; a Swan-Ganz catheter may be considered.
• Fever, chills and other influenza-like symptoms can be prevented and treated by giving paracetamol (oral or suppository) or another analgesic or antipyretic before the ILP.
• To prevent shock, patients are maximally hydrated before, during and after the perfusion, which also ensures a high urine output to clear residual tasonermin. Resuscitation fluids (crystalloid and colloid solutions) are kept ready; colloids and hydroxyethyl starch are preferred because they are less likely to leave the vascular system. A vasopressor such as dopamine can be considered during and after the ILP. In severe shock before the end of the ILP, the perfusion is discontinued and appropriate treatment given.

Systemic Toxicity

If signs of systemic toxicity appear, for example fever, cardiac arrhythmias, shock or hypotension, or adult respiratory distress syndrome, general supportive measures are used and the patient is transferred immediately to an intensive care unit. Volume expanders and vasopressors are recommended, and artificial respiration may be needed. Renal and hepatic function are monitored closely, and haematological disorders, in particular leukopenia, thrombocytopenia and clotting dysfunction, may be expected.

Compartment Syndrome

Compartment syndrome (pain, swelling and neurological symptoms) and muscle damage in the perfused limb have been seen in isolated patients, so patients are monitored during the first three days after the ILP. If it is diagnosed, treatment to consider is fasciotomy of all muscle compartments of the affected limb and, if muscle damage raises myoglobin in plasma and urine, forced diuresis with alkalinisation of the urine.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: there are no adequate data from use in pregnant women, animal studies are insufficient, and the potential risk to humans is unknown. Beromun is contraindicated in pregnancy.
• Breastfeeding: it is not known whether tasonermin passes into human milk. Breast-feeding is contraindicated within 7 days of the ILP.
• Fertility: there are no data on effects on male or female fertility.

Sodium and Latex

A vial contains 20.12 mg (0.87 mmol) of sodium, and 37.82 mg (1.64 mmol) after reconstitution in 0.9% sodium chloride solution. The reconstituted product contains up to 151.27 mg (6.58 mmol) of sodium per recommended dose, which patients on a controlled sodium diet should take into account. The container contains latex rubber, which may cause severe allergic reactions.

Effect on Driving

The SmPC states that the effect on the ability to drive and use machines is not relevant.

Store in a refrigerator at 2–8 °C. Beromun is supplied as a pack of 4 vials of powder (type I glass vial with chlorobutyl rubber stopper and aluminium flip-off cap) and is held under cold-chain handling until reconstitution. Storage after reconstitution is described under Shelf Life.

Unopened vials: 4 years. Reconstituted solution: chemical and physical in-use stability has been shown for up to 48 hours at 25 °C. From a microbiological point of view the reconstituted product should be used immediately; otherwise in-use storage times and conditions are the responsibility of the user and would normally not be longer than 24 hours at 2–8 °C, unless reconstitution took place in controlled and validated aseptic conditions.

Prescription only (Rx), on restricted medical prescription. Beromun is used only for isolated limb perfusion in specialised centres, by surgical teams experienced in limb sarcoma and the ILP procedure, with an intensive care unit available. It is therefore supplied to the hospital or clinic that administers it, under refrigerated (2–8 °C) cold-chain handling.