Leukaemia – midostaurin

Published: 8-Feb-2016

Midostaurin, is under development at Novartis for the treatment of acute myeloid leukaemia and other blood cancers

Natural products are a rich source material for investigational drugs, both in native form and as a starting point for medicinal chemistry programmes. One such drug, midostaurin, is under development at Novartis for the treatment of acute myeloid leukaemia and other blood cancers.

The semisynthetic molecule is a benzoyl derivative of the alkaloid staurosporin, isolated from the bacterium Streptomyces staurosporeus.1 The multi-kinase inhibitor has activity against cells with a mutation that activates the FMS-like tyrosine kinase 3 receptor, or FLT3, a mutation that occurs in blasts of about a third of patients with AML and is associated with a poorer prognosis.

In a Phase IIb trial, 95 patients with AML or myelodisplastic syndrome, 60 of whom had wild-type and the remainder mutated FLT3, were randomised to receive 50 or 100mg of midostaurin orally twice a day.2 If there was no response, the disease progressed or unacceptable toxicity was experienced, treatment was stopped after two months. Of the 92 patients who could be assessed for response, 71% of those with mutant FLT3 achieved a reduction in peripheral blood or bone marrow blasts of at least 50%, compared with 42% of those without the mutation.

One FLT3 mutant patient receiving the higher dose achieved a partial response. The drug was well tolerated at both dosage levels, with no differences in toxicity or response rate between the two.

It has also been investigated in a Phase I/II trial in combination with the cytotoxic agent 5-azacytidine.3 A total of 14 patients with AML or MDS were dosed in the Phase I part of the trial, and 40 in the Phase II.

Patients were given 75mg/m2 of 5-azacytidine daily on the first seven days, plus 25mg midostaurin twice a day in the first cohort of Phase I, or 50mg twice a day in the second cohort plus all those in the Phase II part. The overall response rate was 26%, and the median remission duration 20 weeks. This was significantly longer in those patients who had FLT3 mutations and who had not previously been treated with an FLT3 inhibitor or who had had a transplant.

Positive results from a global Phase III trial were recently reported. Adult patients under the age of 60 with newly diagnosed FLT3-mutated AML were given midostaurin plus standard induction and consolidation chemotherapy.4 More than 3,000 patients were screened for eligibility, and 717 selected to take part in the study, which compared oral doses of midostaurin or placebo with up to two cycles of standard induction chemotherapy with infused daunorubicin and cytarabine, and up to four cycles of consolidation high-dose chemotherapy, followed by midostaurin or placebo as a single agent for up to a year in those who continued in complete remission after the consolidation chemotherapy.

The primary endpoint was overall survival, and the secondary endpoint event free survival. Those patients given midostaurin had a 23% improvement in overall survival over those given placebo, with the median overall survival for the midostaurin group 75 months, and 26 months for placebo. Event free survival was also significantly greater for the treated group.

It has also been investigated, unsuccessfully, in a Phase IIa trial in patients with melanoma.5 Novartis now plans to submit the drug for approval, in combination with a companion diagnostic.


1. Y. Ikegami et al. Arzneimittelforschung 1995, 45, 1225

2. T. Fischer et al. J. Clin. Oncol. 2010, 28, 4339

3. P. Strati et al. Am. J. Hematol. 2015, 90, 276

4. R.M. Stone et al. Blood 2015, 126, 6

5. M.J. Millward et al. Br. J. Cancer 2006, 95, 829

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