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Plexxikon Launching Phase I/II Trial for PLX3397 in AML Patients with Flt3 Mutations


Originally published Dec. 12.

Plexxikon said this week that it is launching a Phase I/II trial to study the safety and efficacy of its drug candidate PLX3397 in AML patients whose tumors harbor cancer-driving Flt3 mutations, which occur in 20 percent to 30 percent of AML patients.

In a preclinical AML model, researchers from Plexxikon and Johns Hopkins University reported that PLX3397, an inhibitor of Fms, Kit, and oncogenic Flt3 activity, was able to significantly regress tumors. "This preclinical work also showed that PLX3397 retained activity against certain drug-resistant forms of mutated Flt3 that can occur with other treatments," the company said in a statement announcing the early study data.

The researchers presented their data at American Society of Hematology conference in San Diego, Calif., this week.

"Given PLX3397's selectivity for relevant mutations, we are exploring this potential personalized medicine for AML patients with Flt3 mutations," said Plexxikon CEO Peter Hirth in a statement.

Based on leads from early studies, the company has initiated a Phase I/II study in a Flt3-mutated AML patient population. According to, this study will measure the safety of the drug and assess the extent to which one year of treatment impacts patients' remission rate.

Plexxikon is currently recruiting AML patients for this study. In order to participate, patients must test positive for a Flt3-ITD activating mutation.

Phase I dose escalation testing in patients with solid tumors showed that PLX3397 was "well tolerated" at therapeutic drug levels. "Plasma from Phase I patients contained sufficient levels of PLX3397 to block signaling in Flt3-mutant AML cells ex vivo," Plexxikon said. "Additionally, PLX3397 has been tested in primary AML patient blood samples, which showed a clear dose response to drug at clinically achievable drug levels."

In addition to advancing PLX3397 to Phase II studies in patients with Flt3-mutated AML, Plexxikon is also investigating the drug in Hodgkin lymphoma patients.

PLX3397 is an oral agent that is being evaluated in several clinical trials for the treatment of different cancers, including AML. PLX3397 selectively co-inhibits three key targets, allowing down-modulation of a number of cell types, including macrophages, microglia, osteoclasts and mast cells, as well as the inhibition of Flt3 mutations that are key oncogenic drivers in AML.

Patients with a D835 mutation at screening will be excluded from the study. Although D835 mutations are prevalent in AML patients, the prognostic impact of these markers is not well established, according to various published reports.

The ongoing pharmacogenomic research involving PLX3397 suggests that Plexxikon is growing its investment in personalized drug development. Recently Plexxikon and collaborator Roche gained FDA approval for the personalized melanoma drug Zelboraf. The drug is intended to treat advanced melanoma patients whose tumors harbor BRAF mutations. At the same time FDA approved Zelboraf, the agency also green-lighted Roche's BRAF mutation test kit as a companion test to pick out best responders to the drug (PGx Reporter 8/17/2011).

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