Trabectedin

Trabectedin is an antineoplastic agent that acts directly on DNA. It showed antiproliferative activity in vitro and in vivo against a range of human tumour cell lines and experimental tumours, including sarcoma, breast, non-small cell lung, ovarian and melanoma.

Mechanism of Action

• DNA binding: binds to the minor groove of DNA and bends the helix toward the major groove; it alkylates guanine at the N2 position. One ring of the molecule protrudes from the groove and can interact with nearby nuclear proteins.
• Downstream effects: the binding triggers a cascade affecting several transcription factors, DNA-binding proteins and DNA repair pathways (notably transcription-coupled nucleotide excision repair), which perturbs the cell cycle. Cells are blocked in the G2 phase, and cells in G1 are the most sensitive.
• Drug resistance: it is also reported to inhibit overexpression of the multidrug resistance-1 gene, which codes for P-glycoprotein.
• Cardiac electrophysiology: in a placebo-controlled QT/QTc study in patients with advanced solid malignancies, trabectedin did not prolong the QTc interval.

Pharmacokinetics

• Distribution: exposure after intravenous constant-rate infusion is proportional to dose up to and including 1.8 mg/m², with a multiple-compartment profile. The volume of distribution at steady state exceeds 5,000 L, consistent with extensive tissue and plasma protein binding; 94–98% is bound to plasma proteins.
• Metabolism: CYP3A4 is the major isozyme responsible for oxidative metabolism at clinically relevant concentrations, and other P450 enzymes may contribute. Trabectedin does not induce or inhibit the major P450 enzymes.
• Elimination: renal excretion of unchanged drug is low (under 1%). The terminal half-life is long (population value 180 hours). After a radiolabelled dose, mean recovery of radioactivity was 58% in the faeces and 5.8% in the urine. Plasma clearance is about 30.9 L/h (whole-blood clearance about 35 L/h, roughly half of human hepatic blood flow, a moderate extraction ratio), with inter-patient variability of 49% and intra-patient variability of 28%.
• With pegylated liposomal doxorubicin (PLD): trabectedin plasma clearance is 31% lower in combination, while PLD pharmacokinetics are unchanged.
• Special populations: clearance is not affected by age (19–83 years), sex, body weight (36–148 kg) or body surface area (0.9–2.8 m²). Hepatic impairment roughly doubles systemic exposure on average (see Special Instructions).

• Soft tissue sarcoma: treatment of adults with advanced soft tissue sarcoma, after failure of anthracyclines and ifosfamide, or who are unsuited to receive these agents. Efficacy data are based mainly on liposarcoma and leiomyosarcoma patients.
• Ovarian cancer: in combination with pegylated liposomal doxorubicin (PLD), treatment of patients with relapsed platinum-sensitive ovarian cancer.

• Hypersensitivity to trabectedin or to any of the excipients.
• Concurrent serious or uncontrolled infection.
• Breastfeeding (during treatment and for 3 months afterwards).
• Combination with yellow fever vaccine.

Most patients have adverse reactions of some grade (91% with monotherapy, 99.4% with the combination), and fewer than a third have serious grade 3 or 4 reactions (10% and 25%). The most common reactions are neutropenia, nausea, vomiting, increased AST/ALT, anaemia, fatigue, thrombocytopenia, anorexia and diarrhoea. Fatal reactions occurred in 1.9% of patients on monotherapy and 0.6% on the combination, often from several events together, including pancytopenia, febrile neutropenia (some with sepsis), hepatic involvement, renal or multiorgan failure and rhabdomyolysis. Reactions marked below “ovarian cancer only” were reported only in ovarian cancer patients.

Very common (≥1/10): neutropenic infection; neutropenia, thrombocytopenia, anaemia, leukopenia; decreased appetite; headache; dyspnoea, cough; abdominal pain, nausea, vomiting, constipation, diarrhoea, stomatitis; increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and bilirubin; palmar-plantar erythrodysaesthesia syndrome (ovarian cancer only); back pain, increased blood creatine phosphokinase; fatigue, pyrexia, oedema, mucosal inflammation (ovarian cancer only); increased blood creatinine, decreased blood albumin.

Common (≥1/100 to <1/10): sepsis; febrile neutropenia; hypersensitivity; dehydration, hypokalaemia; insomnia; dizziness, dysgeusia, peripheral sensory neuropathy, syncope (ovarian cancer only); palpitations and left ventricular dysfunction (ovarian cancer only); hypotension, flushing; pulmonary embolism (ovarian cancer only); dyspepsia; increased gamma-glutamyltransferase; rash, alopecia, skin hyperpigmentation (ovarian cancer only); arthralgia, myalgia; injection site reaction; weight decreased.

Uncommon (≥1/1,000 to <1/100): septic shock; capillary leak syndrome; pulmonary oedema; rhabdomyolysis; extravasation, soft tissue necrosis.

Rare (≥1/10,000 to <1/1,000): hepatic failure.

Important serious reactions are severe neutropenia and thrombocytopenia, hepatotoxicity, rhabdomyolysis, cardiac dysfunction, capillary leak syndrome, hypersensitivity reactions (very rarely fatal) and tissue necrosis after extravasation.

Interaction studies have been performed only in adults.

• Strong CYP3A4 inhibitors (for example oral ketoconazole, fluconazole, ritonavir, clarithromycin, aprepitant): trabectedin is metabolised mainly by CYP3A4. Ketoconazole raised trabectedin exposure by about 21% (Cmax) and 66% (AUC) without new safety concerns. Close monitoring of toxicities is required, and the combination should be avoided if possible; if it is needed, adjust the dose if toxicity occurs.
• Strong CYP3A4 inducers (for example rifampicin, phenobarbital, St John’s wort): rifampicin lowered exposure by about 22% (Cmax) and 31% (AUC). Avoid if possible.
• P-glycoprotein inhibitors (for example ciclosporin, verapamil): trabectedin is a P-glycoprotein substrate in preclinical data, so they may alter its distribution or elimination. The relevance (for example CNS toxicity) has not been established, so take care.
• Alcohol: avoid during treatment because of the hepatotoxicity of trabectedin.
• Hepatotoxic medicines: use caution, as the risk of liver toxicity may increase.
• Medicines associated with rhabdomyolysis (for example statins): use caution, as the risk of rhabdomyolysis may increase.
• Phenytoin: may reduce phenytoin absorption and worsen convulsions. The combination is not recommended.
• Vaccines: live attenuated vaccines are not recommended, and the yellow fever vaccine is specifically contraindicated.
• Food: avoid St John’s wort, and take care with grapefruit products, which inhibit CYP3A4 and may raise trabectedin levels.

Yondelis must be given under the supervision of a physician experienced in the use of chemotherapy, and its use is confined to qualified oncologists or other health professionals specialised in administering cytotoxic agents. Intravenous administration through a central venous line is strongly recommended. For reconstitution and dilution, see section 6.6 of the SmPC.

Premedication

All patients must receive corticosteroids, for example 20 mg of dexamethasone intravenously 30 minutes before PLD (in combination therapy) or before Yondelis (in monotherapy). This is not only anti-emetic prophylaxis but also appears to provide hepatoprotective effects. Additional anti-emetics may be given as needed.

Recommended Dose

• Soft tissue sarcoma: 1.5 mg/m² body surface area as an intravenous infusion over 24 hours, with a three-week interval between cycles.
• Ovarian cancer: 1.1 mg/m² as a 3-hour infusion every three weeks, given immediately after PLD 30 mg/m². To minimise PLD infusion reactions, the first PLD dose is given at a rate no greater than 1 mg/minute; if there is no reaction, later PLD infusions may run over 1 hour (see the PLD SmPC).
• The same dose is given in every cycle as long as no grade 3–4 toxicity occurs and the patient meets the re-treatment criteria.
• Duration: no pre-defined limit in clinical trials; treatment continued while clinical benefit was seen. No cumulative toxicity was observed with repeated cycles.

Criteria for Treatment and Monitoring

• Required before treatment and before each re-treatment: neutrophils at least 1,500/mm³; platelets at least 100,000/mm³; bilirubin at or below the upper limit of normal (ULN); alkaline phosphatase up to 2.5 times ULN (consider 5-nucleotidase or gamma-glutamyl transpeptidase if the rise could be of bone origin); albumin at least 25 g/L; ALT and AST up to 2.5 times ULN; creatine phosphokinase (CPK) up to 2.5 times ULN; haemoglobin at least 9 g/dL.
• Kidney function: creatinine clearance at least 30 mL/min for monotherapy; for the combination, serum creatinine up to 1.5 mg/dL (132.6 µmol/L) or creatinine clearance at least 60 mL/min.
• If the criteria are not met, delay treatment by up to 3 weeks until they are.
• Monitor blood counts, bilirubin, alkaline phosphatase, aminotransferases and CPK weekly during the first two cycles and at least once between treatments in later cycles.

Dose Adjustments

• Reduce the dose by one level for later cycles if, between cycles: neutrophils fall below 500/mm³ for more than 5 days or with fever or infection; platelets fall below 25,000/mm³; bilirubin rises above ULN or alkaline phosphatase above 2.5 times ULN; AST or ALT stays above 2.5 times ULN (monotherapy) or 5 times ULN (combination) beyond day 21; or any other grade 3 or 4 reaction occurs (such as nausea, vomiting or fatigue).
• Soft tissue sarcoma: 1.5 mg/m² (start), 1.2 mg/m² (first reduction), 1 mg/m² (second reduction).
• Ovarian cancer: Yondelis 1.1, 0.9 and 0.75 mg/m²; PLD 30, 25 and 20 mg/m².
• If further reductions are needed, consider stopping treatment. After a reduction for toxicity, dose escalation in later cycles is not recommended. Colony stimulating factors can be used for haematological toxicity according to local practice.

Special Populations

• Elderly: no specific studies. About 20% of the 1,164 patients in the monotherapy safety analysis were over 65, and 24% of the 333 ovarian cancer patients on the combination were 65 or older (6% over 75), with no relevant safety differences. Dose adjustment based on age alone is not routinely recommended.
• Hepatic impairment: special caution is advised and dose adjustment may be needed, because exposure and the risk of hepatotoxicity increase. Patients with raised serum bilirubin at baseline must not be treated.
• Renal impairment: no studies in creatinine clearance below 30 mL/min (monotherapy) or below 60 mL/min (combination), so Yondelis must not be used in these patients. No adjustment is needed for mild or moderate impairment.
• Children: Yondelis should not be used under 18 years in paediatric sarcomas because of efficacy concerns.

Liver and Kidney Function

Patients must meet specific liver function criteria to start treatment. Exposure to trabectedin is on average about doubled in hepatic impairment, so patients with clinically relevant liver disease such as active chronic hepatitis need close monitoring and dose adjustment if required. Reversible acute rises in AST and ALT occur in most patients; rises between cycles may require dose adjustment. Creatinine clearance must be monitored before and during treatment.

Neutropenia and Thrombocytopenia

Grade 3 or 4 neutropenia and thrombocytopenia are very common. A full blood count with differential and platelets is required at baseline, weekly for the first two cycles and then once between cycles. Patients who develop fever should seek medical attention promptly, and active supportive therapy should start immediately.

Nausea and Vomiting

Anti-emetic prophylaxis with a corticosteroid such as dexamethasone must be given to all patients.

Rhabdomyolysis and Raised CPK

Trabectedin must not be used if CPK is above 2.5 times ULN. Rhabdomyolysis is uncommon and usually accompanies myelotoxicity, severe liver test abnormalities or renal or multiorgan failure. Monitor CPK closely in these situations and in patients with muscle weakness or pain. If rhabdomyolysis occurs, start supportive measures promptly (parenteral hydration, urine alkalinisation, dialysis as indicated) and stop Yondelis until the patient has fully recovered. Take care with other medicines associated with rhabdomyolysis, such as statins.

Injection Site Reactions and Extravasation

Central venous access is strongly recommended. Through a peripheral line, patients may develop a potentially severe injection site reaction. Extravasation may cause tissue necrosis requiring debridement; there is no specific antidote, and it is managed by local standard practice.

Hypersensitivity

After marketing, hypersensitivity reactions with very rare fatal outcomes have been reported with trabectedin alone or with PLD.

Cardiac Dysfunction

Monitor for cardiac adverse events and myocardial dysfunction. A thorough cardiac assessment, including left ventricular ejection fraction (LVEF) by echocardiogram or MUGA scan, is required before starting and at 2- to 3-month intervals until treatment ends. The risk may be higher with LVEF below the lower limit of normal, a prior cumulative anthracycline dose above 300 mg/m², age over 65 or cardiovascular disease. Stop trabectedin for grade 3 or 4 cardiac events indicating cardiomyopathy, or if LVEF falls below the lower limit of normal (an absolute decrease of 15% or more, or below the lower limit with an absolute decrease of 5% or more).

Capillary Leak Syndrome

Cases, some fatal, have been reported. If unexplained oedema with or without hypotension develops, reassess serum albumin; a rapid fall may indicate capillary leak syndrome. If confirmed after other causes are excluded, stop trabectedin and treat according to institutional guidelines.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: clinical data are insufficient, but given its mechanism trabectedin may cause serious birth defects, and it crossed the placenta in rats. It should not be used in pregnancy. If pregnancy occurs during treatment, the patient must be informed of the risk to the foetus and monitored carefully; genetic counselling may be considered, and newborns should be monitored if it is used late in pregnancy.
• Contraception: women of childbearing potential must use highly effective contraception during treatment and for 8 months afterwards, and tell their doctor immediately if pregnancy occurs. Men of fertile age must use highly effective contraception during treatment and for 5 months afterwards.
• Breastfeeding: it is not known whether trabectedin passes into milk. Breastfeeding is contraindicated during treatment and for 3 months afterwards.
• Fertility: trabectedin can have genotoxic effects and may cause irreversible infertility, so advice on conserving eggs or sperm should be sought before treatment. Genetic counselling is recommended for patients who want children after therapy.

Excipients

Each vial contains potassium (2 mg or 8 mg) and sucrose (0.1 g or 0.4 g). The SmPC states that the medicine contains less than 1 mmol (39 mg) potassium per vial, that is to say it is essentially ‘potassium-free’.

Effect on Driving

No studies on driving have been performed, but fatigue and asthenia have been reported. Patients who experience either must not drive or use machines.

Store in a refrigerator (2–8 °C). Keep the cold chain unbroken during transport and storage. For storage after reconstitution and dilution, see Shelf Life. Each carton holds one type I colourless glass vial (0.25 mg or 1 mg) with a butyl rubber stopper and an aluminium flip-off seal.

• Unopened vials: 60 months.
• After reconstitution: chemical and physical stability has been shown for 30 hours up to 25 °C. From a microbiological point of view, the reconstituted solution should be diluted and used immediately. Otherwise in-use storage times and conditions are the responsibility of the user and would normally not exceed 24 hours at 2–8 °C, unless reconstitution took place under controlled and validated aseptic conditions.
• After dilution: chemical and physical stability has been shown for 30 hours up to 25 °C.

Prescription only (Rx), on restricted medical prescription. Yondelis must be given under the supervision of a physician experienced in the use of chemotherapy, and its use is confined to qualified oncologists or other health professionals specialised in administering cytotoxic agents. It is given as an intravenous infusion, so it is supplied to the hospital or clinic that administers it, under refrigerated cold-chain handling (2–8 °C).