Preliminary results from a phase 1/2 study of INCB024360 combined with ipilimumab (ipi) in patients (pts) with melanoma.

GT Gibney, O Hamid, TC Gangadhar, J Lutzky… - 2014 - ascopubs.org
GT Gibney, O Hamid, TC Gangadhar, J Lutzky, AJ Olszanski, T Gajewski, B Chmielowski…
2014ascopubs.org
3010 Background: Indoleamine 2, 3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing
enzyme that is overexpressed in cancers and induces immune tolerance by suppressing T-
cell responses. INCB024360, a potent, selective IDO1 inhibitor, was generally well tolerated
as monotherapy up to 700 mg BID. Preclinical data support anti-tumor synergy for
INCB024360 when administered with antibody antagonists to checkpoint receptors.
Methods: This is an ongoing dose-escalation study of INCB024360 combined with ipi (3 …
3010
Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is a tryptophan-catabolizing enzyme that is overexpressed in cancers and induces immune tolerance by suppressing T-cell responses. INCB024360, a potent, selective IDO1 inhibitor, was generally well tolerated as monotherapy up to 700 mg BID. Preclinical data support anti-tumor synergy for INCB024360 when administered with antibody antagonists to checkpoint receptors. Methods: This is an ongoing dose-escalation study of INCB024360 combined with ipi (3 mg/kg IV q 3 wks x 4) in pts with metastatic melanoma. Enrollment in 2 cohorts (300 mg BID, 25 mg BID) is complete. Toxicity, ORR (irRC), Duration of Response (DoR), and OS were evaluated. The DLT evaluation period was 8 wks andassessments for response were every 9 wks. Results: Seven pts were enrolled at 300 mg BID. When 5 pts developed clinically significant ALT elevations after 30–76 days on treatment, enrollment was stopped. ALT elevations were reversible with corticosteroids and treatment discontinuation. Six of 7 pts had evaluable on-study scans prior to discontinuation and all showed irSD. Time to subsequent therapy was >90 days in all 7 pts and >180 days in 4 of 7 pts. Enrollment was restarted at 25 mg BID (n=8), where 1 pt with progression of prior extensive liver metastases had a DLT (G3 AST elevation). Immune-related AEs (irAEs) were generally G1/2 and manageable with continued dosing or temporary dose interruption; 1 pt each discontinued for G3 colitis and G3 salivary amylase elevation. Six of 8 pts had tumor reduction by the 1st evaluation. Confirmed disease control rate was 75% (6/8). Three pts had confirmed irPR (2 occurred by the 1st or 2nd scan); DoR was 179, 148, and >127 (ongoing) days. Three pts had irSD for 116, >173 (ongoing), and >187 (ongoing) days. Pharmacodynamic effects at 25 mg BID were similar to those that were sufficient in preclinical models to achieve maximal therapeutic effect. A 50 mg BID cohort is enrolling. Conclusions: INCB024360 25 mg BID with ipi was generally well tolerated and irAEs previously observed with ipi were reversible with appropriate management. Tumor response and duration data suggest the potential for enhanced melanoma patient outcomes compared to ipi monotherapy. Clinical trial information: NCT01604889.
ASCO Publications