Acute myeloid leukaemia - cloretazine
DNA alkylating agents derive their anticancer activity from their ability to cross-link DNA. Drugs such as carmustine and lomustine have been used to treat numerous types of tumour for many years, but they generate reactive species and thus pose serious toxicity problems.
DNA alkylating agents derive their anticancer activity from their ability to cross-link DNA. Drugs such as carmustine and lomustine have been used to treat numerous types of tumour for many years, but they generate reactive species and thus pose serious toxicity problems.
Novel DNA alkylating agents with better toxicity profiles would be of great benefit, and cloretazine is one such drug that is being developed by Vion Pharmaceuticals in the US.1
In a Phase II trial, 53 patients with relapsed acute myeloid leukaemia (AML) were given 600mg/m2 cloretazine as a single intravenous infusion, but the conclusion was that there was very little activity in this population.2 It was subsequently given to 105 elderly patients with newly diagnosed AML or high-risk myelodysplastic syndromes, initially as a 600mg/m2 intravenous infusion, with a second induction for those patients who experienced a partial response or a haematological improvement. A consolidation course of 400mg/m2 was given to patients achieving complete remission or remission with incomplete platelet recovery.3 The drug was well tolerated, and 28 patients achieved complete remission and a further five remission with incomplete platelet recovery, giving an overall response rate of 31%.
The drug is being investigated in several other cancers, too. Doses of 300 mg/m2 were given intravenously every six weeks to 38 patients with recurrent malignant glioma, recurrent anaplastic astrocytoma or anaplastic oligodendroglioma.4 No objective radiographic responses were seen in the 36 evaluable patients but 15 had a best response of stable disease, and the conclusion was that this dosing schedule had little efficacy in these patients.
Several other clinical trials are under way in different cancers, including using it as monotherapy in young patients with recurrent, refractory or progressive primary brain tumours, in relapsed chronic lymphocytic leukaemia and in Richter's syndrome. It is also being tested in combination with temozolomide in patients with refractory or relapsed leukaemias.