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A randomized phase II trial of the tyrosine kinase inhibitor PKC412 in patients with acute myeloid leukemia /high-risk myelodysplastic syndromes characterized by wild-type or mutated FLT3

A randomized phase II trial of the tyrosine kinase inhibitor PKC412 in patients with acute myeloid leukemia /high-risk myelodysplastic syndromes characterized by wild-type or mutated FLT3

Blood 102(11): 614a-615a

The Fms-like tyrosine kinase 3 (FLT3) is a receptor expressed on leukemic blasts in 80% of AML patients, and is constitutively activated due to mutations in 30% (either an internal tandem duplication, juxtamembrane region, or an activating loop mutation). PKC412 is a multi-targeted tyrosine kinase inhibitor, which at an oral dose of 75 mg tid demonstrated activity in 20 relapsed/refractory AML/MDS pts with FLT-3 mutations (Stone et al, ASCO.2003). Subsequently, 28 pts (16 untreated and 9 relapsed AML, 2 MDS, 1 CMML) with either WT (n=21) or mutated (n=7) FLT-3 were randomized to oral PKC412 at 50 mg bid or 100 mg bid daily. Patients were discontinued if they did not respond by two months, or for disease progression or unacceptable toxicity. The median age was 72 (range 35 to 81). Response was defined as complete, partial or hematologic improvement (HI), the former two using standard criteria and HI if there was either a) improvement in RBC, ANC or PLT counts, as defined by Cheson et al, Blood. 2000; 96:3671-3674, or b) at least a gtoreq50% decrease in blood and/or bone marrow blasts. CR/PR did not occur. Two out of three WT patients with MDS/CMML had HI. HI rates in AML pts are given. Ten of 21 (48%) WT patients responded with 6/10 (60%) at the 50 mg and 4/11 (36%) at the 100 mg bid dose(p=.39). All FLT3 mutated pts demonstrated HI. Overall, HI rates appeared unaffected by prior treatment. In all cases HI was brief (median 7 days, range 2-62). Nine pts completed at least two months of treatment and remain on study (up to 116 days) and five patients continue but have not reached two months. Fourteen patients discontinued prior to two months of treatment (eight adverse events, of which seven were considered due to complications likely related to AML and one due to pulmonary edema possibly related to PKC412), six pts had disease progression/no response. Of the 25 patients with adverse event data available 15/25 (60%) experienced Grade 1/2 nausea, and 10/25 (40%) experienced Grade 1/2 vomiting or diarrhea possibly drug-related. Survival time in 20 patients enrolled at MDACC age 65 or older with untreated AML/high-risk MDS was similar to that seen in 77 pts age 65 or older given AML chemotherapy at MDACC in 2002 (p=.76); the PKC412 pts were slightly older (p=.04) and more often had abnormal cytogenetics. These preliminary results suggest that PKC412 has hematologic activity in both mutated and wild-type pts and appears associated with a similar survival time to chemotherapy alone. This activity warrants further studies, including combination with chemotherapy, in WT and FLT3 mutated sub-types. The pharmacokinetic, pharmacodynamic, and covariate adjusted survival data will be updated.

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Accession: 034319201

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