NEW YORK – Syros Pharmaceuticals said on Thursday it has dosed the first RARA-positive newly diagnosed, unfit acute myeloid leukemia patient in a Phase II trial of its RARa agonist tamibarotene in combination with the Bcl-2 inhibitor venetoclax (AbbVie/Genentech's Venclexta) and the chemotherapy azacitidine.
The SELECT-AML-1 trial will randomize 80 patients with AML to receive either the tamibarotene-venetoclax-azacitidine regimen or venetoclax-azacitidine. The trial will begin as a single-arm study to evaluate the safety of the triplet regimen before randomizing patients into two arms. The primary endpoint is composite complete response rate.
Last year, Syros presented Phase II data showing that RARA-positive newly diagnosed AML patients who cannot receive standard chemo had a 67 percent overall response rate and a 61 percent composite complete response rate on tamibarotene. In that same study, researchers found that RARA-positive newly diagnosed, unfit AML patients had a monocytic disease phenotype associated with resistance to venetoclax, which is the standard-of-care treatment with azacitidine.
According to Syros, together these data suggest that the RARA biomarker may be identifying AML patients who benefit from tamibarotene but not venetoclax. The company hopes that the tamibarotene-venetoclax-azacitidine triplet combination could help overcome patients' resistance to venetoclax, David Roth, chief medical officer at Syros, said in a statement.
"AML is a complex, heterogenous disease, and many patients may present upfront with both monocytic and non-monocytic leukemia cells," Roth said. "By employing a triplet strategy that combines tamibarotene with venetoclax and azacitidine, we believe we can simultaneously target both cell types, reducing the emergence of resistant disease and increasing the likelihood of deeper and more durable responses."
The Cambridge, Massachusetts-based company is also studying tamibarotene in a Phase III trial in patients with newly diagnosed RARA-positive myelodysplastic syndrome.