Anticancer agent - lonafarnib

Nearly a third of all human cancers possess a mutation in the Ras protein, and Ras oncogenes are involved in signal transduction pathways that regulate both growth and differentiation in cancers.

The proteins, localised on the inner surface of the plasma membrane, are initially synthesised as inactive cytosolic precursors, and then undergo a series of modifications at the C terminus to give the mature protein.

Several compounds that inhibit the enzyme FTase, which is involved in the membrane localisation of Ras, are being investigated. These include lonafarnib, which is being developed by Schering Plough.¹

Its efficacy and tolerability were investigated in a Phase I/II trial in 16 patients with myelodysplastic syndrome or secondary acute myeloid leukaemia.² Subjects were given 200mg twice a day for three courses of four weeks, with one to four weeks off in between. Most patients required dose reductions. The main side effects seen were fatigue, infections, elevation in the levels of liver enzymes, skin rash and arrhythmias.

In a multicentre randomised Phase II trial, 15 patients with unresectable or metastatic transitional cell carcinoma of the urothelial tract, and who had failed previous chemotherapy, were given 200mg lonafarnib twice a day, with allowance for dose escalation.³ Three patients were hospitalised for toxic effects, four discontinued, one achieved stable disease, and six progressed.

Its safety and efficacy were investigated in a trial with gemcitabine in patients with advanced pancreatic cancer.⁴ A total of 63 patients were randomised to receive 200mg lonafarnib twice a day, or 1000mg/m² gemcitabine weekly for seven weeks, followed by a week off. The incidence of neutropoenia and thrombocytopenia was lower in the group given lonafarnib, and 23% of patients given it had a three month progression-free survival rate, two patients had a partial response and six achieved stable disease.