Soft tissue sarcoma

For the treatment of soft tissue sarcoma, the recommended dose is 1.5 mg/m² body surface area, administered as an intravenous infusion over 24 hours with a three-week interval between cycles.

All patients must receive corticosteroids e.g. 20 mg of dexamethasone intravenously 30 minutes prior to PLD (in combination therapy) or trabectedin (in monotherapy); not only as anti-emetic prophylaxis, but also because it appears to provide hepatoprotective effects. Additional anti-emetics may be administered as needed.

The following criteria are required to allow treatment with trabectedin:

• Absolute neutrophil count (ANC) ≥1,500/mm³
• Platelet count ≥100,000/mm³
• Bilirubin ≤ upper limit of normal (ULN)
• Alkaline phosphatase ≤2.5 x ULN (consider hepatic isoenzymes 5-nucleotidase or gamma glutamyl transpeptidase (GGT), if the elevation could be osseous in origin).
• Albumin ≥25 g/l
• Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 x ULN
• Creatinine clearance ≥30 ml/min (monotherapy), serum creatinine ≤1.5 mg/dl (≤132.6 μmol/l) or creatinine clearance ≥60 ml/min (combination therapy)
• Creatine phosphokinase (CPK) ≤2.5 x ULN
• Haemoglobin ≥9 g/dl

The same criteria as above must be met prior to re-treatment. Otherwise treatment must be delayed for up to 3 weeks until the criteria are met.

Additional monitoring of haematological parameters bilirubin, alkaline phosphatase, aminotransferases and CPK should occur weekly during the first two cycles of therapy, and at least once between treatments in subsequent cycles.

The same dose should be given for all cycles provided that no grade 3-4 toxicities are seen and that the patient fulfils the re-treatment criteria.

Dose adjustments during treatment

Prior to re-treatment, patients must fulfil the baseline criteria defined above. If any of the following events occur at any time between cycles, the dose must be reduced one level, according to table below, for subsequent cycles:

• Neutropenia <500/mm³ lasting for more than 5 days or associated with fever or infection
• Thrombocytopenia <25,000/mm³
• Increase of bilirubin > ULN and/or alkaline phosphatase >2.5 x ULN

Increase of aminotransferases (AST or ALT) >2.5 x ULN (monotherapy) or >5 x ULN (combination therapy), which has not recovered by day 21

Any other grade 3 or 4 adverse reactions (such as nausea, vomiting, fatigue)

Once a dose has been reduced because of toxicity, dose escalation in the subsequent cycles is not recommended. If any of these toxicities reappear in subsequent cycles in a patient exhibiting clinical benefit, the dose may be further reduced (see below). Colony stimulating factors can be administered for haematologic toxicity according to local standard practice.

Dose modification table for trabectedin (as single agent for soft tissue sarcoma (STS) or in combination for ovarian cancer) and PLD:

In the event that further dose reductions are necessary, treatment discontinuation should be considered.

Duration of treatment

In clinical trials, there were no pre-defined limits to the number of cycles administered. Treatment continued whilst clinical benefit was noted. trabectedin has been administered for 6 or more cycles in 29.5% and 52% of patients treated with the monotherapy and combination dose and schedule respectively. The monotherapy and combination regimens have been used for up to 38 and 21 cycles respectively. No cumulative toxicities have been observed in patients treated with multiple cycles.

Intravenous administration over 24 hours through a central venous line is strongly recommended.