Phase I results of decitabine in combination with midostaurin (PKC412) for elderly (age ≥ 60) newly diagnosed or relapsed/refractory adult patients with AML

Purpose: To determine the maximum-tolerated dose (MTD) and recommended Phase II dose of midostaurin, a multi-targeted tyrosine kinase inhibitor with demonstrated activity in patients with AML with FLT3 mutations, combined either sequentially (days 8-21) or concurrently (days 1-28) with intravenous decitabine 20 mg/m2 days 1-5 in elderly newly diagnosed or relapsed/refractory adult patients with AML. 

Methods: Sixteen patients (median age, 68 years) were enrolled; 8 were untreated and 8 had relapsed AML.  Only 2 of 16 patients (13%) had FLT3 ITD mutations and no patient had KITmutations. 

Results: The MTD and schedule of the combination that was identified in this trial was decitabine followed by sequential midostaurin (cohort 2).   Three patients (from cohorts 2 and 3) developed dose limiting toxicities:   2 patients developed pulmonary edema requiring mechanical ventilation and 1 patient developed a prolonged QTc > 500 msec.  Of the eleven patients evaluable for response, 82% achieved stable disease or better while on trial.  Four of the 11 patients (36%) had a complete hematologic response (2 patients had a complete cytogenetic response).  Pharmacokinetic analysis revealed results that were similar to what has been previously reported for midostaurin.

Conclusion:  The combination of decitabine with sequential midostaurin is possible without significant unexpected toxicity, but the concurrent administration of the combination led to pulmonary toxicity after only a few doses.  On the basis of these results, additional studies exploring the combination in untreated AML in elderly patients are warranted to further evaluate this combination at the MTD.