Anticancer agent - VNP-40101M
One of the most commonly used classes of anticancer drugs is the DNA alkylating agents, which attack the DNA in tumour cells and deactivate it by crosslinking. However, as they generate reactive species they have serious toxicity problems, so effective alternatives with better toxicity profiles would be extremely useful.
One of the most commonly used classes of anticancer drugs is the DNA alkylating agents, which attack the DNA in tumour cells and deactivate it by crosslinking. However, as they generate reactive species they have serious toxicity problems, so effective alternatives with better toxicity profiles would be extremely useful.
US company Vion Pharmaceuticals is developing VNP-41010M, a bifunctional 1,2-bis(sulfinyl)hydrazine drug that generates more of the beneficial reactive species on activation, and fewer of those that simply give toxic effects: it chloroethylates and carbamoylates, but does not hydroxyethylate or vinylate, as the currently available drugs do.1
Several clinical trials have been carried out. In a Phase I trial, 38 patients with refractory or relapsed leukaemia of various types were given the drug by intravenous infusion every four weeks, starting with a dose of 220mg/m2 and escalating by about a third for subsequent doses.2 In total, 52 courses were given, and the most common adverse events related to the infusion process. The trial indicated that a dose of 600mg/m2 was the best place to start, as one of the seven patients escalated to 708mg/m2 experienced prolonged myelosuppression. One patient with myelodysplastic syndrome achieved complete remission at 300mg/m2, and one with acute myeloid leukaemia at 600mg/m2.
However, in a Phase II trial in 53 patients with relapsed AML with an initial complete response of less than 12 months was less successful.3 They were given 600mg/m2 as a single intravenous infusion, and only one achieved a second complete response, lasting more than 20 months, and in another leukaemic blasts were cleared from the bone marrow, but with incomplete platelet recovery. The mean overall survival rate of 2.3 months was on a par with 233 matched patients receiving other monotherapy regimes.
Its efficacy and safety at 600mg/m2 as a single intravenous infusion was looked at in another Phase II study, with a second induction for those exhibiting a partial response or haematological improvement, and a consolidation course of 400mg/m2 given to those achieving complete response, with or without complete platelet recovery.4 A total of 105 elderly patients with newly diagnosed AML or high risk MDS were treated, and it was well tolerated. Nineteen of the patients died within 30 days of the start of treatment, but 28 achieved complete response, and a further five without complete platelet recovery.
It has also been looked at in a variety of recurrent gliomas and astrocytomas. A total of 38 patients were given intravenous doses of 300mg/m2 every six weeks.5 Four developed grade 4 thrombocytopoenia, and three grade 3 nutropenia. No objective radiographic responses were observed, but 15 patients had a best response of stable disease. Various other trials are under way in a number of different cancers.