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Oncology Xagena

Epacadostat, an oral inhibitor of indoleamine 2,3-dioxygenase-1, in patients with advanced solid malignancies


Indoleamine 2,3-dioxygenase-1 ( IDO1 ) catalyzes the degradation of tryptophan to N-formyl-kynurenine. Overexpressed in many solid malignancies, IDO1 can promote tumor escape from host immunosurveillance.
This first-in-human phase 1 study investigated the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of Epacadostat, a potent and selective inhibitor of IDO1.

Fifty-two patients with advanced solid malignancies were treated with Epacadostat ( 50 mg once daily or 50, 100, 300, 400, 500, 600, or 700 mg twice daily [ BID ] ) in a dose-escalation 3 + 3 design and evaluated in 28-day cycles.
Treatment was continued until disease progression or unacceptable toxicity.

One dose-limiting toxicity ( DLT ) occurred at the dose of 300 mg BID ( grade 3, radiation pneumonitis ); another DLT occurred at 400 mg BID ( grade 3, fatigue ).

The most common adverse events in more than 20% of patients overall were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough.

Treatment produced significant dose-dependent reductions in plasma kynurenine levels and in the plasma kynurenine / tryptophan ratio at all doses and in all patients.

Near maximal changes were observed at doses of greater than or equal to 100 mg BID with more than 80% to 90% inhibition of IDO1 achieved throughout the dosing period.

Although no objective responses were detected, stable disease lasting greater than or equal to 16 weeks was observed in 7 of 52 patients.

In conclusion, Epacadostat was generally well tolerated, effectively normalized kynurenine levels, and produced maximal inhibition of IDO1 activity at doses of more than 100 mg BID. ( Xagena )

Beatty GL et al, Clin Cancer Res 2017; Epub ahead of print

XagenaMedicine_2017



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