onvansertib (PCM-075)

P2, N=35, Not yet recruiting, OHSU Knight Cancer Institute

P2, N=37, Active, not recruiting, Taofeek Owonikoko | Not yet recruiting --> Active, not recruiting

Inhibition of Polo-like kinase 1 (Plk1) is a promising new target and therapeutic strategy in metastatic colorectal cancer, especially those with KRAS mutations. New data support further development of onvansertib, and highlights the role of circulating tumor DNA in phase 1 clinical trials.

P2, N=90, Recruiting, Cardiff Oncology | Not yet recruiting --> Recruiting | Initiation date: Nov 2023 --> Feb 2024

P1, N=25, Recruiting, Mayo Clinic | Trial primary completion date: Dec 2025 --> Dec 2026

P1/2, N=68, Completed, Cardiff Oncology | Active, not recruiting --> Completed

Onvansertib combined with FOLIFRI/bevacizumab exhibited manageable safety and promising efficacy in second-line treatment of KRAS-mutant metastatic CRC patients. Further exploration of this combination therapy is ongoing.

ROS scavenger N-acetylcysteine partially reversed ROS levels induced by NMS-P937. Overall, NMS-P937 suppressed NPC cell proliferation and increased ROS levels, causing cell cycle abnormalities and apoptosis. NMS-P937 holds great promise as a therapeutic agent for treating nasopharyngeal carcinoma.

P1/2, N=68, Active, not recruiting, Cardiff Oncology | Phase classification: P1b/2 --> P1/2

P2, N=43, Active, not recruiting, Cardiff Oncology | Recruiting --> Active, not recruiting

P1, N=80, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Feb 2026 --> Feb 2028 | Trial primary completion date: Jun 2024 --> Jun 2026

P1/2, N=50, Recruiting, Antonio Giordano, MD | Phase classification: P1b/2 --> P1/2

Notably, the antitumor activity of the onvansertib and paclitaxel combination was very durable, showing a robust delay in tumor relapse after stopping therapy. Together, our data strongly support that combining paclitaxel with the PLK1 inhibitor onvansertib extends its benefit and overcomes paclitaxel resistance, and represents a promising therapeutic strategy for HR+ breast cancer patients after progression on a combination of endocrine and CDK4/6 inhibitor therapy.

P2, N=72, Completed, Cardiff Oncology | Active, not recruiting --> Completed

P2, N=90, Not yet recruiting, Cardiff Oncology

The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells. VS-5584 combined with NMS-P937 exhibited a synergistic effect in inhibiting NSCLC cell growth. These findings suggest that VS-5584 has potential as a therapeutic strategy for treating NSCLC.

P2, N=23, Active, not recruiting, Cardiff Oncology | Recruiting --> Active, not recruiting | N=150 --> 23 | Trial primary completion date: Nov 2024 --> Nov 2025

In the phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations.

Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer.

P2, N=40, Recruiting, Cardiff Oncology | Trial primary completion date: Feb 2023 --> Mar 2024

Therefore, in this study we sought to establish if Plk1 inhibition with onvansertib (currently in Phase I/II clinical trials) alone and in combination with radiation would inhibit HPV- and HPV+ HNSCC growth...Our findings that HPV+ HNSCC cells are more resistant to Plk1 inhibition than HPV- HNSCC cells provides novel mechanistic insight into these disease subtypes. As HPV- HNSCC is typically more resistant to standard therapies, these results support a novel combinatorial approach using an already approved Plk1 inhibitor with radiation to improve HPV- HNSCC patient outcomes.

We further tested the PLK1-specific inhibitor onvansertib (0-100nM) combined with pan-PI3K inhibitor copanlisib (0-200nM) or dual inhibitor bimiralisib (0-1μM). We will further validate this combination in vivo to determine the effect of combined PI3K and PLK1 inhibition on tumor growth and survival. These novel findings may lead to the development of a better therapeutic approach for NOTCH1MUT HNSCC and for patients who develop acquired resistance to targeted therapies.

Notably, the protein levels of β-catenin and c-Myc were affected by onvansertib. Taken together, our findings provide insight into the function of onvansertib and shed light on the potential clinical application of onvansertib for the treatment of patients with LUAD.

P2, N=150, Recruiting, Cardiff Oncology | Not yet recruiting --> Recruiting

In a murine patient-derived xenograft model of abiraterone-resistant metastatic castration resistant prostate cancer (mCRPC), combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared to either agent alone. Overall, this work establishes a mechanistic basis for the phase 2 clinical trial (NCT03414034) testing combined onvansertib and abiraterone in mCRPC patients and indicates this combination may have broad utility for cancer treatment.

P1b/2, N=68, Active, not recruiting, Cardiff Oncology | Recruiting --> Active, not recruiting | N=100 --> 68

The clinical success of PLK1 inhibitors, such as volasertib and onvansertib, has been limited by the absence of predictive biomarkers of response and adverse side effects. Together, these findings indicate that PLK1 inhibition causes damage to mitotic chromosomes and subsequent activation of the FA pathway. Our work identifies a mitosis-specific vulnerability of FA-deficient cells and suggests that genetic disruptions of the FA pathway may be predictive of sensitivity to PLK1 inhibition, providing a preclinical rationale for the development of precision therapies.

P1b/2, N=50, Recruiting, Antonio Giordano, MD | Phase classification: P1/2 --> P1b/2

P1/2, N=50, Recruiting, Antonio Giordano, MD

P1/2, N=50, Recruiting, Antonio Giordano, MD | Not yet recruiting --> Recruiting | Phase classification: P1b/2 --> P1/2

P2, N=150, Not yet recruiting, Cardiff Oncology

Stratification of pts based on KRAS MAF changes in ctDNA after 1 treatment cycle identified a subset of pts (∼50%) with increased clinical benefit (ORR and PFS). This data supports the use of KRAS MAF changes in liquid biopsies as a response biomarker to Onv+FOLFIRI/bev in future clinical studies.

P1b/2, N=100, Recruiting, Cardiff Oncology | Trial completion date: May 2022 --> Dec 2023 | Trial primary completion date: May 2022 --> Dec 2023

We used patient-derived xenografts (PDXs) of ovarian carcinoma resistant to cisplatin (DDP) to test in vivo the combination of paclitaxel (15 mg/kg i.v. once a week for 3 weeks) and onvansertib, a plk1 inhibitor, (50 mg/kg orally 4 days a week for 3 weeks). Ex vivo tumors treated with the combination showed greater induction of γH2AX, marker of apoptosis and DNA damage, and pSer10H3, a marker of mitotic block. The efficacy of onvansertib and paclitaxel combination in these preclinical ovarian cancer models supports the clinical translatability of this combination as an effective therapeutic approach for platinum-resistant high-grade ovarian carcinoma.

P1, N=80, Recruiting, OHSU Knight Cancer Institute | N=40 --> 80 | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Jun 2022 --> Jun 2024

The combination of the PLK1 inhibitor onvansertib and the PARPi olaparib showed potent anti-tumor activity in olaparib-resistant BRAC1 mutant HGSOC PDX models. Additional studies are ongoing to further assess the potential of the combination in BRCA wild-type and mutant ovarian, prostate, pancreatic and breast cancer preclinical models.

We found that inhibition of BARD1 (both by siRNA/shRNA and CRISPR-KO) not only sensitized the cells to olaparib or oxaliplatin but enhanced DNA damage in cells, as analyzed by comet assays and γ-H2AX immunofluorescence staining. Our ongoing and future studies are aimed at understanding the interaction of BARD1 and PLK1 in PDAC cells and analyze the effects of onvansertib and olaparib on tumor growth in vivo. Accomplishment of these studies will establish novel therapeutic targets and synthetic lethal combinations that have not been explored yet for deadly pancreatic cancers, ultimately benefiting patient survival in the long run.

Taken together, these data suggest that alterations in PTEN and MTOR, two key genes of the PI3K signaling pathway, are potential biomarkers for sensitivity to onvansertib/abi combination in mCRPC patients with early abi-resistance. Preclinical studies are underway to assess the activity of onvansertib/abi in combination with PI3K-pathway inhibitors.

P1b/2, N=100, Recruiting, Cardiff Oncology | N=44 --> 100

Onvansertib is a highly selective, ATP-competitive, orally bioavailable PLK1 inhibitor that is synergistic with irinotecan and with 5FU in xenograft models of mKRAS CRC. We present preliminary safety, efficacy, and biomarker data from an ongoing Ph1b/2 trial of onvansertib + FOLFIRI-bev in pts with mKRAS mCRC progressing after 1L treatment with fluoropyrimidine + oxaliplatin, +/- bev... The combination of onvansertib with FOLFIRI-bev was well tolerated: observed TEAEs have been generally low-grade and manageable. The combination has demonstrated a promising ORR in 2L treatment of mCRC pts harboring various KRAS mutations, and efficacy was correlated with early changes in plasma mKRAS. Updated safety, efficacy, and biomarker analyses will be presented.