Anticancer agent - brostallicin
Sarcomas are cancers of soft and connective tissues. They are rare, accounting for less than 1% of all solid cancers.
Sarcomas are cancers of soft and connective tissues. They are rare, accounting for less than 1% of all solid cancers.
There are many forms of sarcoma, with a variety of pathological and clinical characteristics; the most common, fibrosarcoma, accounts for almost a fifth of all cases. Metastatic sarcoma is commonly treated with doxorubicin, with ifosfamide often coadministered. Second line treatment options are limited, and many drugs have been investigated in trials but with little effect.
A new class of cytotoxic agent is showing promise in treating sarcomas - DNA minor groove binders. The DNA sequence specificity of these agents means they have a selective mechanism of action; they fit between the two phosphate-sugar backbones in the double helix and are selective for thymine-adenine-rich sequences.
One drug that acts in this way - PharmaMar's Yondelis (trabectedin) - is already on the market. Another, the synthetic second generation minor groove binder brostallicin, was discovered by Pharmacia and transferred to Cell Therapeutics after the merger with Pfizer.1
A Phase I study was carried out to determine the maximum tolerated dose, dose limiting toxicities and pharmacokinetics of brostallicin in patients with advanced solid tumour malignancies.2 A 10-minute intravenous infusion was given on days 1, 8 and 15 of a 28 day cycle, with a starting dose of 0.3mg/m2 a week. A total of 14 patients were given 32 complete cycles. Febrile neutropoenia was the dose limiting toxicity, and was seen in three of five patients given 4.8mg/m2 a week. The maximum tolerated dose was established at 2.4mg/m2 a week.
In a Phase II trial, 21 patients with gastrointestinal stromal tumours (GIST) and 43 with advanced or inoperable non-GIST soft tissue sarcomas who had failed first line therapy, were given the drug in intravenous doses of 10mg/m2 every three weeks.3 It was generally well tolerated, and major side-effects included granulocytopoenia and febrile neutropoenia, with fatigue also common. None of the GIST group had a confirmed response and this group was discontinued after the first interim analysis, but there were two confirmed partial responses in the non-GIST group.
As a result, trials are continuing in patients with non-GIST sarcomas, and a comparative trial against doxorubicin as a first line therapy is being carried out.