LY3295668

P1, N=71, Active, not recruiting, Eli Lilly and Company | Trial completion date: Aug 2024 --> Aug 2025

It also evaluated the efficacy of the ABL TKI asciminib and the aurora kinase inhibitor LY3295668. Combining asciminib and aurora kinase inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with CML. These findings have clinical implications for a potential novel therapeutic strategy for CML patients.

P1, N=10, Active, not recruiting, Melbourne Health | Recruiting --> Active, not recruiting

P1/2, N=32, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting

P2, N=95, Recruiting, AnHeart Therapeutics Inc. | Not yet recruiting --> Recruiting | Trial completion date: Feb 2027 --> Jul 2027 | Trial primary completion date: Jan 2026 --> Mar 2027

JHH6 cells, an undifferentiated HCC-derived in vitro model, were treated for 72 hours with two inhibitors of the kinase activity of AURKA (Alisertib and AK-01) and short interfering RNA (siRNA) targeting AURKA. AURKA is positively correlated with PD-L1 in both HCC and non-tumor tissues. The inhibition of kinase activity of AURKA enhances the number of polynucleated cells due to defects in chromosome separation and incorrect mitosis. The reduced expression of PD-L1 following AURKA inhibition highlights the potentiality of AURKA inhibitors in cancer therapy, possibly in combination with new immune checkpoint inhibitors.

P1a/1b, N=400, Recruiting, Eli Lilly and Company | Trial completion date: Nov 2023 --> Sep 2025 | Trial primary completion date: Nov 2023 --> Sep 2025

This study aims to evaluate the effects of two different AURKA inhibitors (Alisertib and AK-01) in liver cancer, focusing on the role of AURKA in the regulation of Programmed deathligand 1 (PD-L1) expression. This study underlines the relevance of AURKA as a key player in liver cancer thus suggesting possible future applications of AURKA inhibitors as therapy for liver cancer. In this regard, the link with PD-L1 may suggest a feasible strategy consisting of the use of AURKA inhibitors in combination with PD-1/PD-L1 inhibitors.

Key objectives of Phase 1b are to determine the safety and tolerability of LY3537982 monotherapy, and in combination with various agents: abemaciclib, erlotinib, cetuximab, an investigational ERK inhibitor (LY3214996), an investigational Aurora A kinase inhibitor (LY3295668), and an anti-PD1 antibody. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, symptomatic CNS malignancy, symptomatic CNS metastasis, or carcinomatous meningitis. The trial is currently enrolling patients (NCT04956640).

While direct therapeutic targeting of MYCN protein remains challenging, we previously demonstrated synergistic activity of dual targeting of BCL-2 (venetoclax) and AURKA (MLN8237) in MYCN-amplified NB (Ham Cancer Cell, 2016). Dual targeting of AURKA and BCL2 with LY3295668 and venetoclax is tolerable and demonstrates compelling anti-tumor activity in MYCN-amplified NB PDX models, validating our earlier findings (Ham et al). These preclinical results provisionally support clinical development of this combination for NB patients with MYCN amplification. Assessment of additional PDX models is currently ongoing and will be reported.

LY3295668 is well tolerated, achieves pharmacologically-relevant unbound concentrations in GBM PDX models, and is associated with significant target modulation. Preclinical combination of LY3295668 with radiation therapy leads to synergistic effects and supports future clinical study of this multimodal strategy in glioblastoma patients.

BCL2+ lymphoma cells, WSU-NHL (single hit; BCL2 only), DoHH2 (DHL; BCL2 and MYC), and VAL (THL; BCL2, MYC, and BCL6) were evaluated for cell viability (ATP quantification) and apoptosis (Annexin V/7AAD staining), after treatment with various concentrations of VEN with or without MLN8237 (AURK-A inhibitor), LY3295668 (AURK-A inhibitor), or AZD2811 (AURK-B inhibitor). p53 knockdown in DoHH2 cells resulted in similar resistance to VEN and combination treatment. Taken together these data suggest AURK inhibition overcomes downregulation of p53/p21/BAX axis by BCL2+ lymphomas in response to BCL2 inhibition, hence lay the groundwork for further evaluation of this combination in clinical settings.

P1a/1b, N=260, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

We found that AK-01 potently suppresses MCC survival through apoptosis and cell cycle arrest, particularly in MCPyV-negative MCC cells without RB expression. Despite the challenge posed by its short in vivo durability upon discontinuation, the swift and substantial tumor suppression with low toxicity makes AK-01 a strong potential candidate for MCC management, particularly in combination with existing regimens.

P1a/1b, N=260, Not yet recruiting, Eli Lilly and Company

LY3537982 inhibited KRAS-GTP loading with an IC50 value of 3.35 nM in the KRAS-G12C mutant H358 lung cancer cell line, while AMG510 and MRTX849 had IC50 values of 47.9 nM and 89.9 nM, respectively...Mechanism-based combinational screens have also identified certain targeted therapies that can synergize with LY3537982 to achieve better anti-tumor activity in vitro and in vivo, including abemaciclib, the selective AurA inhibitor LY3295668, and cetuximab. Together these data suggest that in certain biologic contexts, broader and more durable anti-tumor activity could be achieved with combination regimens. A first-in-human Phase 1 clinical trial is planned for 2021.

Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934 .

P1/2, N=13, Completed, Eli Lilly and Company | Active, not recruiting --> Completed | Trial completion date: Dec 2019 --> Apr 2020 | Trial primary completion date: Dec 2019 --> Apr 2020

P1b, N=5, Completed, Eli Lilly and Company | Active, not recruiting --> Completed | N=100 --> 5

P1b, N=100, Active, not recruiting, Eli Lilly and Company | Trial completion date: Mar 2021 --> May 2020 | Trial primary completion date: Mar 2021 --> May 2020

A rolling 6 design will be followed for dose escalation in both a monotherapy cohort and a combination cohort testing LY3295668 together with cyclophosphamide and topotecan...Enrollment began 16 Dec 2019 and is ongoing. Research Funding: Eli Lilly & Co.

P1b, N=100, Active, not recruiting, Eli Lilly and Company | Recruiting --> Active, not recruiting

LY3295668, an AurA inhibitor with over 1000-fold selectivity versus AurB, is distinguished by minimal toxicity to bone marrow cells at concentrations active against RB1mut cancer cells and leads to durable regression of RB1mut tumor xenografts at exposures that are well tolerated in rodents. Genetic suppression screens identified enforcers of the spindle assembly checkpoint (SAC) as essential for LY3295668 cytotoxicity in Rb-deficient cancers and suggest a model in which a primed SAC creates a unique dependency on AurA kinase for mitotic exit and survival.

Derivative resistant cell lines with RB1 loss or AURKA gain demonstrated enhanced sensitivity to a novel AURKA inhibitor (LY3295668), while cells with RAS activation were highly sensitive to ERK inhibition (via LY3214996). CCNE2-overexpressing cells were highly sensitive to prexasertib, a CHEK1 inhibitor. The genomic landscape of resistance to CDK4/6i is heterogeneous with multiple potential mediators that play well-established roles in cell division and oncogenic signal transduction... The genomic landscape of resistance to CDK4/6i is heterogeneous with multiple potential mediators that play well-established roles in cell division and oncogenic signal transduction. We present novel mechanisms of clinical resistance including activation of AKT1 and RAS family oncogenes as well as amplification of AURKA and CCNE2. These drivers were able to provoke resistance to CDK4/6i in vitro.

P2, N=12, Completed, British Columbia Cancer Agency | Active, not recruiting --> Completed | Trial completion date: Aug 2018 --> Nov 2018