In a phase 1/2 study presented at the 2014 ASCO meeting, researchers determined a dosing level of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor combined with Yervoy® (ipilimumab) that was well tolerated in metastatic melanoma patients and showed promising tumor response and duration of response. Adverse events previously observed with Yervoy were found to be reversible with proper management.
IDO1 is an enzyme that is over-expressed in cancers and suppresses T-cell response in patients, which leads to immune tolerance. The drug studied in this work, INCB024360, selectively inhibits IDO1.
In this dose-escalation study, INCB024360 was combined with Yervoy. A cohort of 7 patients was given 300 mg of INCB024360 twice per day. The second cohort was given 25 mg, twice per day. Both cohorts were treated with the same dose of Yervoy.
Five of the seven patients developed elevated levels of the liver enzyme ALT after 30 – 76 days of treatment. These patients were subsequently taken off treatment and given corticosteroids. After 90 days, all patients were re-enrolled at a lower dose of INCB024360 (25 mg, twice per day), in which the immune related adverse events were considered manageable. One patient had a dose limiting toxicity. A second patient discontinued the study due to development of colitis; a third discontinued due to salivary amylase elevation.
Six of 8 patients showed tumor reduction; 3 patients had confirmed immune related partial response. The duration of response was 179, 148, and greater than 127 (ongoing) days.
Given the tumor response and duration results, researchers suggested that inclusion of INCB024360 with ipilimumab therapy could potentially improve melanoma patient outcomes. A new cohort to receive 50 mg, twice per day, of INCB024360 with Yervoy is currently enrolling.
Reference: Gibney, Geoffrey Thomas et al. Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab in patients with melanoma. J Clin Oncol 32:5s, 2014 (suppl; abstr 3010).
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