Many different kinase growth factors implicated in tumour development have provided targets for cancer drugs
Many different kinase growth factors implicated in tumour development have provided targets for cancer drugs; numerous kinase inhibitors are already available and many are in clinical trials.
Cephalon’s lestaurtinib, licensed from Kyoka Hakko Kogyo of Japan,1 acts at several different receptor tyrosine kinases, notably the tropomyosin receptor kinases TrkA, TrkB and TrkC, as well as Fms-like tyrosine kinase 3, or FLT-3. The last of these is particularly common in acute myeloid leukaemia, and it is also being investigated as a possible therapy for other cancers.
In an open label Phase I/II trial, 14 patients with relapsed or refractory AML and FLT3-activating mutations were given 60mg of the drug twice a day.2 Five achieved a measurable clinical response such as reductions of blasts in the bone marrow and peripheral blood, albeit only lasting from two weeks to three months.
A Phase II trial looked at 29 patients aged over 60 with previously untreated AML who were unsuitable for intensive chemotherapy.3 Subjects were given 60mg, escalating to 80mg, twice a day for eight weeks. It was generally well tolerated, with the most common adverse events including nausea, vomiting, diarrhoea and constipation. Three out of five patients with a mutated FLT-3 gene had a haematological response, compared with just five of the 22 with a normal FLT-3 gene.
In another Phase II trial, 34 relapsed AML patients with FLT-3 mutations were randomised, half to receive mitoxantrone, etoposide and cytarabine chemotherapy alone, and the remainder chemotherapy plus the new drugs.4 A total of 10 of the lestaurtinib group achieved complete remission or partial response within six weeks of the study starting, compared with four of the chemotherapy-only group.
However, a recent study was less promising. In a randomised study in 224 patients with FLT-3 mutant AML in their first relapse, subjects were given chemotherapy alone or chemotherapy plus lestaurtinib.5 FLT-3 inhibition correlated with the remission rate in the lestaurtinib group, but the target inhibition after two weeks was achieved by only 58% of the patients, and the clinicians were unable to make any conclusions about the efficacy of the combination.
It is also being investigated as a potential therapy for children with refractory neuro-blastoma.6 A total of 47 patients were given the drug twice a day for five days out of seven in 28 day cycles, with the dose starting at 70% of the recommended Phase II dose for adults. All but one were evaluable for response, and 42 for dose escalation. Three experienced reversible pancreatitis, but other side-effects were mild. Two achieved a partial response and a further nine had prolonged stable disease. Trials continue.
1. D.E Gingrich and R.L. Hudkins et al. Bioorg. Med. Chem. Lett. 2002, 12, 2829
2. B.D. Smith et al. Blood 2004, 103, 3669
3. S. Knapper et al. Blood 2006, 108, 3262
4. M. Levis et al. Blood 2005, 106 (11), Abst 403
5. M. Levis et al. Blood 2011, Jan 26 (epub ahead of print)
6. J.E. Mintum et al. Cancer. Chemother. Pharmacol. 2001, Feb 22 (epub ahead of print)