INCB57643

P1, N=216, Recruiting, Incyte Corporation | N=138 --> 216

INCB057643 monotherapy (4 and 8 mg qd) and combined (4 and 6 mg qd) with ruxolitinib was generally well tolerated, whereas the 12 mg qd monotherapy dose caused 2 DLTs. There were no treatment-related fatal events. Improvements in spleen size and symptom burden were observed in patients receiving ≥8 mg in the monotherapy group and 4 mg in the combination therapy group.

This study demonstrated that the BET antagonist INCB057643 synergized with the XPO1 inhibitors (selinexor and eltanexor) to decrease cell viability and increase cell apoptosis in HGBCL-DH cells with or without TP53 mutations. Collectively, we might provide a potential promising combination therapy regimen for the management of HGBCL-DH. Clinical evaluations are warranted to confirm this conclusion.

INCB057643 is a small-molecule BET inhibitor evaluated as monotherapy and in combination with ruxolitinib (RUX) in pts with advanced malignancies in 2 previous phase 1/2 clinical trials. Treatment with INCB057643 monotherapy (4 and 8 mg qd) and in combination (4 mg qd) with RUX was generally well tolerated in this pt population. The 12-mg qd monotherapy dose was not tolerated and caused 2 DLTs. There were no treatment-related fatal events.

Treatment with a 4-mg qd dose of INCB057643 monotherapy in this patient population was generally well tolerated, with no treatment-related SAEs, no DLTs, and no TEAEs leading to treatment discontinuation. INCB057643 will be further evaluated at higher doses in dose-escalation and dose-expansion phases as monotherapy and in combination with ruxolitinib in patients with MF (preliminary combination data to be available for presentation).

P1/2, N=70, Terminated, Incyte Corporation | Completed --> Terminated; Study terminated by Sponsor

The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer.

Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced cytotoxicity in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. In summary, these findings support sub-classification of DLBCL/HGBCL with dual MYC/TP53 alterations which demonstrates distinct pathobiological features and dismal survival with standard therapy therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice.

Expression of Mut-p53 confers resistance to selinexor treatment, which can be overcome by combined INCB057643 treatment in HGBCL-DH cells. This study provides insight into the XPO1 significance and selinexor efficacy in DLBCL, important for developing combination therapy for relapsed/refractory DLBCL and HGBCL-DH.