Anticancer agent - mapatumumab
One of the main reasons why cancer cells proliferate is the deregulation of programmed cell death, or apoptosis.
One of the main reasons why cancer cells proliferate is the deregulation of programmed cell death, or apoptosis.
Tumour necrosis factor related apoptosis inducing ligand, or TRAIL, receptors are a good target for inducing apoptosis, and one drug that is being developed by Human Genome Sciences to act at it is the monoclonal antibody mapatumumab.1
In one Phase I trial, 49 patients with refractory advanced solid tumours were given doses of 0.3 to 10 mg/kg of the antibody every 14 days for a median of two cycles.2 At the lowest doses, side effects were insignificant, and those given the highest dose experienced liver toxicities. No antibodies to mapatumumab were seen, and it did not induce any hypersensitivity reactions. No patients achieved an objective response, but two had persistent stable disease for at least eight months, one of which had sarcoma and the other appendix carcinoma.
Another Phase I trial was carried out in 24 patients, who received doses of 0.01 to 3.0 mg/kg every 28 days.3 There were no objective responses, but eight patients experienced stable disease for two to 14 months.
It has also been investigated in combination with carboplatin and paclitaxel.4 Patients were given 3, 10 or 20 mg/kg of the antibody along with carboplatin and paclitaxel every 21 days. Four patients achieved a partial response, and no drug-drug interactions were seen between the antibody and the cytotoxic drugs.
Another combination being looked at is with gemcitabine and cisplatin.5 In a 21 day cycle, a total of 32 patients with solid tumours were given gemcitabine on days 1 and 8, cisplatin on day 1, and mapatumumab every 21 days at doses of 1, 3, 10 and 20mg. Side effects experienced by the patients included nausea, vomiting and liver function problems. Nine of the patients achieved a partial response, seven of which were confirmed; three of these had pancreatic cancer, two biliary tract cancer, two adenocarcinoma, one head and neck and the ninth with an unknown primary. Fourteen further patients had stable disease. Trials are continuing, both as monotherapy in tumours where apoptosis is signalled through TRAIL, and in combination with cytotoxic drugs.