VIC-1911

The success of post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has driven efforts to optimize partner therapies that balance GVHD and relapse prevention. We report phase I dose-finding results of PTCy, sirolimus (SIR), and VIC-1911, a selective oral Aurora kinase A (AURKA) inhibitor, following myeloablative allogeneic hematopoietic cell transplantation (alloHCT)...Clinical outcomes included no grade III-IV acute GVHD through day 180 (0%) and low rates of moderate/severe chronic GVHD (6%) and relapse (0%) through 1 year (5/16 received maintenance). The 1-year overall survival for this cohort was 94%.VIC-1911 at 75 mg BID, combined with PTCy and SIR, effectively suppresses AURKA activity, offering promising GVHD and relapse prevention with a favorable safety profile and promising early clinical outcomes.

We developed NN-01-195 as a novel chimeric small molecule that combines an AURKA inhibitor related to TAS-119/VIC-1911 with an HSP90-binding moiety related to SNX2112, and evaluated its function. Further, in combination with an inhibitor of the G2/M checkpoint protein WEE1, NN-01-195 is more potent than VIC-1911 in limiting growth of xenograft tumors. These data support the exploration of NN-01-195 and improved analogs as promising new candidates for therapeutic evaluation.

P1, N=9, Not yet recruiting, Shanghai Jiao Tong University School of Medicine

P1/2, N=16, Completed, Masonic Cancer Center, University of Minnesota | Active, not recruiting --> Completed | Trial completion date: Mar 2028 --> Jun 2025

P1, N=3, Terminated, Vitrac Therapeutics, LLC | Phase classification: P1a/1b --> P1

Our studies indicate a synergistic benefit from combined PARPi and AURKAi in mutant and wild-type BRCA EOC tumors.

P1/2, N=16, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=75 --> 16 | Trial primary completion date: Mar 2025 --> Sep 2024

P=N/A, N=15, Recruiting, RenJi Hospital

P=N/A, N=30, Recruiting, RenJi Hospital | Not yet recruiting --> Recruiting | Initiation date: Feb 2023 --> Jul 2023

Introduction: With the wider use of post-transplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis, there is interest in replacing tacrolimus (TAC) with sirolimus (SIR, mTOR inhibitor) to avoid calcineurin inhibitor toxicity, maintain excellent GVHD control, and potentially allow for a greater graft-versus-tumor effect...Patients undergoing myeloablative TBI-based alloHCT with PTCy/SIR plus mycophenolate mofetil (MMF), without VIC on a separate protocol, served as a control...Unlike alisertib, VIC-1911 is not myelosuppressive, providing rationale for this trial... A VIC-1911 dose of 75 mg BID from day +5 to day +45 effectively suppresses AURKA activity as determined by a low frequency of pH3ser10+ CD4+ T cells, ablating CD28 T cell costimulation when combined with sirolimus, resulting in no dose-limiting toxicities. VIC 75 mg BID will be studied further in an expanded phase I cohort to obtain estimates of efficacy in preventing both GVHD and relapse in PTCy-based myeloablative alloHCT.

In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p ≤ 0.01), SB-743921 (p ≤ 0.01) and VIC-1911 (p ≤ 0.05). Kaplan-Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p ≤ 0.0001).

P1a/1b, N=4, Terminated, Vitrac Therapeutics, LLC | N=140 --> 4 | Trial completion date: Nov 2026 --> Aug 2023 | Recruiting --> Terminated | Trial primary completion date: Mar 2026 --> Aug 2023; Sponsor decision