A Phase I Trial of Escalating Dose of the Rapamycin Analog Everolimus in Combination with the Kinase Inhibitor Midostaurin in Patients (pts) with Relapsed, Refractory or Poor Prognosis Acute Myeloid Leukemia (AML)

In pts with mutant FLT3 AML single agent studies with inhibitors of FLT3, such as midostaurin, yielded a high rate of peripheral blast reduction but complete and partial remissions were uncommon. One approach to overcome resistance is to combine a FLT3 inhibitor with an agent that down-regulates another leukemogenic pathway including those downstream to activated FLT3. Preclinical work has suggested that mTOR inhibitors, such as rapamycin or its analogs including everolimus, and the FLT3 inhibitor midostaurin synergistically kill mutant FLT3 dependent cell lines.

To identify the maximum tolerated dose (MTD) of everolimus that can be given in combination with 50 mg orally twice daily midostaurin (established as well tolerated and capable of decreasing peripheral blast count [Fischer JCO 2010]), to determine toxicities, to observe anti-leukemic effects, to measure pharmacokinetics of each agent when administered in combination, and to observe pharmacodynamic effects including decrease in the phospho-FLT3 to total FLT3 ratio in blasts as evidence of enzyme inhibition.

In this phase I study pts were treated with a combination of midostaurin at 50 mg po BID continuously beginning on day 2 and everolimus po administered on day 1 and continuously from day 8 onward. Dose escalation of everolimus was conducted according to standard 3 + 3 schema; the doses of everolimus explored were 5 mg QOD (dose level 1) and 5 mg QD (dose level 2). An additional 15 pts were enrolled at the MTD.

A total of 29 pts were enrolled (24 with relapsed and/or refractory AML, 4 with newly diagnosed AML considered inappropriate candidates for standard therapy, and 1 with relapsed CMML; 11 FLT^wt, 14 FLT3-ITD positive, 3 FLT3 D835Y positive, 1 FLT3 D835H positive). The mean age was 66 (range 40–85) and ECOG performance statuses were 0 in 6 pts, 1 in 16 pts, and 2 in 7 pts. After 1 of 3 pts treated at the everolimus starting dose of 5 mg QOD experienced a DLT (grade 5 infection) the cohort was expanded to 6 pts; of the latter 3 pts enrolled 1 experienced a DLT of grade 3 hypoxia. The eligibility criteria were subsequently amended so as to be more stringent, including a DLCO requirement of 50% predicted. After an additional 3 evaluable pts tolerated the 5 mg QOD dose, we escalated to 5 mg QD; 3 of 4 pts treated at this dose level experienced DLT (grade 3 hypoxia, grade 3 mucositis, grade 5 soft-tissue infection), and subsequent pts were treated at the MTD, everolimus 5 mg QOD (25 pts in total received this dose). The most common drug-related toxicities at the MTD (any grade) were fatigue (40%), nausea (32%), hypertriglyceridemia (24%), vomiting (24%), hyperglycemia (20%), and elevated AST (20%). In addition to the pt who died in the first everolimus cohort, 5/25 pts discontinued due to drug-related grade 3 toxicity, including pneumonia (1), hypoxia (2), allergic reaction (1), and nausea (1). Grade 3 events that did not result in treatment discontinuation included thrombocytopenia (1), dyspnea (2), hyponatremia (1), hypokalemia (1), gum pain (1), abdominal pain (1), pneumonitis (1), and febrile neutropenia (2).

One mutant FLT3 D835Y pt achieved CR and went on to allogeneic SCT. 3 pts (2 FLT3-ITD positive, 1 FLT^wt) experienced a blast response (a ≥50% peripheral or bone marrow blast reduction) with 2 of these pts ultimately progressing and 1 discontinuing due to toxicity. Overall blast response or better was achieved in 4/29 pts (14%), 8 pts had stable disease, and 17 pts had progressive disease and/or received less than 15 days of therapy (6). In the 6 pts who received less than 15 days of therapy reasons for treatment termination included grade 3 (1) and grade 5 toxicity (2), progressive disease (2), and physician decision (1). The incidence of blast response or better in FLT3^mut pts (4/18, 22%) was not clearly higher than that observed in other studies involving midostaurin administered at 50 mg po BID as a single agent. Pharmacokinetic and pharmacodynamic data are being analyzed, though at least one patient's blasts revealed a treatment-related decrease in the phospho FLT3/FLT3 ratio, suggesting enzyme inhibition.

The combination of midostaurin (50 mg BID) and everolimus (5 mg QOD) is tolerable and has efficacy in AML, but it is unclear whether the addition of the rapamycin analog results in superior outcomes compared with midostaurin alone.

Stone:Novartis: Consultancy, Research Funding. Off Label Use: evorlimus in AML. Griffin:Novartis: Consultancy, Research Funding. DeAngelo:Novartis: Consultancy.