Phase II Study of the Oral MEK Inhibitor AZD6244 in Advanced Acute Myeloid Leukemia (AML).

47 pts were enrolled on a Phase II multicenter study of AZD6244 in relapsed/refractory AML. Median age was 69 years (range, 26-83 yrs) with 57% males. ECOG performance status at baseline was 0, 1 and 2, respectively, in 12, 27 and 8 pts. 14 pts (30%) were previously untreated for AML and >60 yrs; 11 of these pts had received prior therapy for an antecedent hematologic disorder (AHD); 1 had therapy-related AML (t-AML) and only 2 pts (4%) had previously untreated de novo AML. 6 pts (13%) had AML in first relapse, 14 (30%) had AML beyond first relapse, and 13 (27%) had primary refractory disease. 4% had good risk cytogenetics, 28% intermediate risk, 49% poor risk, and 19% had other or unknown cytogenetics. Overall, 53% had AML that had evolved from an AHD and/or t-AML. Ten pts had a FLT3 ITD or TKD, 36 had no FLT3 mutation detected, and FLT3 mutational status was unknown in 1. Median number of prior therapies for AML and/or MDS was 2 (range, 0-6).

AZD6244 was given at 100mg twice daily without interruption; cycles were repeated every 28 days. Dose modifications and/or delays occurred for grade 3&4 non-hematologic toxicities, or prolonged grade1&2 toxicities. Peripheral blood and/or marrow samples were obtained at baseline for mutational analysis (RAS/c-KIT/FLT3), and at serial time points to measure p-ERK. Results: Daily AZD6244 was tolerable. 42 pts are evaluable for efficacy and safety. Median number of cycles administered was 1 (range, 1-9). 19 pts (40%) received ≥2 cycles. 4 pts required dose reduction. The most common drug-related toxicities were grade 1&2 diarrhea, nausea, fatigue and vomiting, occurring in 43%, 36%, 31% and 24%, respectively. Grade 3&4 adverse events possibly related to AZD6244 included fatigue, nausea and dehydration, occurring in 7%, 5% and 5%, respectively. 4 pts had a minor response (defined as >50% decline in peripheral blood and/or marrow blasts lasting 4 weeks). 2 additional patients also had >50% decline in marrow blasts but did not have a follow up confirmatory biopsy. In 1 of these pts, the decline in blasts was associated with sustained improvement in platelets (>100K/uL) lasting 4 months. 6 additional pts had evidence of disease stabilization, lasting a median of 34 days (range, 21-222+ days). Analysis of p-ERK by flow cytometry has just been intiated, and in the first 3 pts analyzed, baseline p-ERK levels were low, and none of these pts responded. In contrast, p-mTOR levels (downstream of the PI3 Kinase pathway) were significantly elevated in these same pts. Conclusions: Administration of the oral MEK inhibitor AZD6244 is feasible in AML. Modest evidence of antileukemic activity has been observed, consistent with the predicted cytostatic activity of this class of drugs. Analysis of the effect of AZD6244 on p-ERK and signaling intermediates of the PI3 Kinase pathway such as p-mTOR is ongoing. Given its modest toxicity profile, AZD6244 should be investigated further in combination with drugs that target other critical signaling pathways and/or dysregulated transcriptional pathways in AML. Sponsored by NCI grant NO1-CM-62201

No relevant conflicts of interest to declare.