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DRUG:

onvansertib (PCM-075)

i
Other names: PCM-075, NMS-1286937, NMS-P937, PCM075, PCM 075
Company:
Cardiff Oncology, Nerviano Medical Sciences
Drug class:
PLK1 inhibitor
5d
New P1/2 trial • Combination therapy • Metastases
|
5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • onvansertib (PCM-075) • Onivyde (nanoliposomal irinotecan)
1m
Onvansertib in Combination with Nanoliposomal Irinotecan, Leucovorin, and Fluorouracil for Second-Line Treatment of Participants with Metastatic Pancreatic Ductal Adenocarcinoma (clinicaltrials.gov)
P2, N=43, Active, not recruiting, Cardiff Oncology | Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Dec 2024
Trial completion date • Trial primary completion date • Combination therapy • Metastases
|
5-fluorouracil • leucovorin calcium • onvansertib (PCM-075) • Onivyde (nanoliposomal irinotecan)
1m
P2 data • Journal • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
Avastin (bevacizumab) • onvansertib (PCM-075)
2ms
Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial. (PubMed, J Clin Oncol)
Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).
P2 data • Journal • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
Avastin (bevacizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • onvansertib (PCM-075)
2ms
PLK1 Inhibitor Onvansertib Enhances the Efficacy of Alpelisib in PIK3CA-Mutated HR-Positive Breast Cancer Resistant to Palbociclib and Endocrine Therapy: Preclinical Insights. (PubMed, Cancers (Basel))
Our findings support that targeting PLK1 and PI3Kα with onvansertib and alpelisib, respectively, may be a promising strategy for patients with PIK3CA-mutant HR+ breast cancer failing ET + CDK4/6i therapies and warrant clinical evaluation.
Preclinical • Journal
|
HER-2 (Human epidermal growth factor receptor 2) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PLK1 (Polo Like Kinase 1)
|
HR positive • HER-2 negative • PIK3CA mutation • CDK4 mutation
|
Ibrance (palbociclib) • Piqray (alpelisib) • onvansertib (PCM-075)
5ms
Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas. (PubMed, Cell Death Dis)
We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.
Journal • BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • RAD51 (RAD51 Homolog A)
|
Lynparza (olaparib) • onvansertib (PCM-075)
5ms
Enrollment change • Trial withdrawal • Combination therapy • Metastases
|
gemcitabine • albumin-bound paclitaxel • onvansertib (PCM-075)
6ms
AKT Inhibition Sensitizes to Polo-Like Kinase 1 Inhibitor Onvansertib in Prostate Cancer. (PubMed, Mol Cancer Ther)
We initially confirmed that the PLK1 specific inhibitor onvansertib (ONV) could enhance responses to a PARP inhibitor (olaparib) in prostate cancer xenografts...We confirmed in vitro synergy between ONV and the AKT inhibitor ipatasertib (IPA) and found that the combination increased apoptosis...Studies in three PTEN deficient prostate cancer xenograft models showed that co-treatment with IPA and ONV led to significant tumor growth inhibition compared to monotherapies. Together these in vitro and in vivo studies demonstrate that the efficacy of PLK1 antagonists can be enhanced by PARP or AKT inhibition, and support further development of these combination therapies.
Journal • PARP Biomarker
|
PTEN (Phosphatase and tensin homolog) • BIRC5 (Baculoviral IAP repeat containing 5) • PLK1 (Polo Like Kinase 1)
|
Lynparza (olaparib) • ipatasertib (RG7440) • onvansertib (PCM-075)
8ms
New P2 trial • Combination therapy • Metastases
|
gemcitabine • albumin-bound paclitaxel • onvansertib (PCM-075)
8ms
Study of PLK1 Inhibitor, Onvansertib, in Relapsed Small Cell Lung Cancer (clinicaltrials.gov)
P2, N=37, Active, not recruiting, Taofeek Owonikoko | Not yet recruiting --> Active, not recruiting
Enrollment closed
|
onvansertib (PCM-075)
10ms
Polo-like kinase 1 inhibition in KRAS-mutated metastatic colorectal cancer. (PubMed, Clin Cancer Res)
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.
Journal • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • PLK1 (Polo Like Kinase 1)
|
KRAS mutation
|
onvansertib (PCM-075)
10ms
Enrollment open • Trial initiation date • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
KRAS mutation • NRAS mutation
|
Avastin (bevacizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • onvansertib (PCM-075)
10ms
Onvansertib for the Treatment of Recurrent or Refractory Chronic Myelomonocytic Leukemia (clinicaltrials.gov)
P1, N=25, Recruiting, Mayo Clinic | Trial primary completion date: Dec 2025 --> Dec 2026
Trial primary completion date
|
onvansertib (PCM-075)
10ms
Trial completion
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene)
|
KRAS mutation • BRAF mutation • KRAS exon 2 mutation
|
Avastin (bevacizumab) • 5-fluorouracil • irinotecan • leucovorin calcium • onvansertib (PCM-075)
11ms
Onvansertib in Combination with FOLFIRI and Bevacizumab in Second-line Treatment of KRAS-mutant Metastatic Colorectal Cancer: A Phase 1b Clinical Study. (PubMed, Clin Cancer Res)
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.
P1 data • Journal • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • PLK1 (Polo Like Kinase 1)
|
KRAS mutation • KRAS wild-type • RAS wild-type
|
Avastin (bevacizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • onvansertib (PCM-075)
1year
Polo-like kinase 1 inhibitor NMS-P937 represses nasopharyngeal carcinoma progression via induction of mitotic abnormalities. (PubMed, J Biochem Mol Toxicol)
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.
Journal • PARP Biomarker
|
CCNE1 (Cyclin E1) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • CCNB1 (Cyclin B1)
|
CCNE1 expression
|
onvansertib (PCM-075)
1year
Phase classification
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene)
|
KRAS mutation • BRAF mutation • KRAS exon 2 mutation
|
Avastin (bevacizumab) • 5-fluorouracil • irinotecan • leucovorin calcium • onvansertib (PCM-075)
1year
Enrollment closed
|
5-fluorouracil • leucovorin calcium • onvansertib (PCM-075) • Onivyde (nanoliposomal irinotecan)
1year
Targeted PARP or MEK/ERK Inhibition in Patients With Pancreatic Cancer (clinicaltrials.gov)
P1, N=80, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Feb 2026 --> Feb 2028 | Trial primary completion date: Jun 2024 --> Jun 2026
Trial completion date • Trial primary completion date
|
UGT1A1 (UDP glucuronosyltransferase family 1 member A1) • CD4 (CD4 Molecule)
|
UGT1A1*1*1
|
Lynparza (olaparib) • Cotellic (cobimetinib) • onvansertib (PCM-075) • temuterkib (LY3214996)
1year
Onvansertib + Paclitaxel In TNBC (clinicaltrials.gov)
P1/2, N=50, Recruiting, Antonio Giordano, MD | Phase classification: P1b/2 --> P1/2
Phase classification • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
|
paclitaxel • onvansertib (PCM-075)
1year
PLK1 Inhibitor Onvansertib Extends the Response and Overcomes Resistance to Paclitaxel in Palbociclib-resistant HR+ Breast Cancer Patient-derived Xenografts. (SABCS 2023)
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.
Clinical
|
PLK1 (Polo Like Kinase 1)
|
HR positive
|
Ibrance (palbociclib) • paclitaxel • onvansertib (PCM-075)
1year
Trial completion • Combination therapy • Metastases
|
abiraterone acetate • prednisone • onvansertib (PCM-075)
1year
New P2 trial • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
KRAS mutation • NRAS mutation
|
Avastin (bevacizumab) • 5-fluorouracil • oxaliplatin • irinotecan • leucovorin calcium • onvansertib (PCM-075)
over1year
PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer. (PubMed, Eur J Pharmacol)
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.
Journal
|
CASP3 (Caspase 3) • CDK1 (Cyclin-dependent kinase 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
onvansertib (PCM-075) • VS-5584
over1year
Enrollment closed • Enrollment change • Trial primary completion date • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
NRAS mutation • RAS mutation
|
Avastin (bevacizumab) • 5-fluorouracil • irinotecan • leucovorin calcium • onvansertib (PCM-075)
over1year
Spliceosome mutations are associated with clinical response in a phase 1b/2 study of the PLK1 inhibitor onvansertib in combination with decitabine in relapsed or refractory acute myeloid leukemia. (PubMed, Ann Hematol)
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.
P1/2 data • Journal • Combination therapy
|
SF3B1 (Splicing Factor 3b Subunit 1) • SRSF2 (Serine and arginine rich splicing factor 2)
|
SF3B1 mutation • SRSF2 mutation
|
decitabine • onvansertib (PCM-075)
over1year
Pentafuhalol-B, a Phlorotannin from Brown Algae, Strongly Inhibits the PLK-1 Overexpression in Cancer Cells as Revealed by Computational Analysis. (PubMed, Molecules)
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.
Journal
|
PLK1 (Polo Like Kinase 1)
|
volasertib (NBL-001) • onvansertib (PCM-075)
over1year
Trial primary completion date • Combination therapy • Metastases
|
CA 19-9 (Cancer antigen 19-9)
|
5-fluorouracil • leucovorin calcium • onvansertib (PCM-075) • Onivyde (nanoliposomal irinotecan)
almost2years
Plk1 signaling as a therapeutic target for HPV- head and neck cancer (AACR 2023)
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.
PARP Biomarker
|
PLK1 (Polo Like Kinase 1)
|
onvansertib (PCM-075)
almost2years
Concurrent inactivation of PI3K and PLK1 is synergistic and overcomes acquired resistance to PI3K inhibitors in NOTCH1MUT HNSCC (AACR 2023)
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.
Preclinical • PARP Biomarker
|
NOTCH1 (Notch 1) • PLK1 (Polo Like Kinase 1) • CASP3 (Caspase 3) • AURKB (Aurora Kinase B) • ANXA5 (Annexin A5)
|
NOTCH1 mutation
|
Aliqopa (copanlisib) • onvansertib (PCM-075) • bimiralisib (PQR309)
almost2years
Onvansertib inhibits the proliferation and improves the cisplatin-resistance of lung adenocarcinoma via β-catenin/c-Myc signaling pathway. (PubMed, Am J Cancer Res)
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.
Journal
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
|
cisplatin • onvansertib (PCM-075)
2years
Enrollment open • Preclinical • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
NRAS mutation • RAS mutation
|
Avastin (bevacizumab) • 5-fluorouracil • irinotecan • leucovorin calcium • onvansertib (PCM-075)
2years
Plk1 Inhibitors and Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling. (PubMed, Cancer Res)
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.
Journal
|
PLK1 (Polo Like Kinase 1)
|
abiraterone acetate • onvansertib (PCM-075)
2years
Onvansertib in Combination With FOLFIRI and Bevacizumab for Second Line Treatment of Metastatic Colorectal Cancer Patients With a Kras Mutation (clinicaltrials.gov)
P1b/2, N=68, Active, not recruiting, Cardiff Oncology | Recruiting --> Active, not recruiting | N=100 --> 68
Enrollment closed • Enrollment change • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene)
|
KRAS mutation • BRAF mutation • KRAS exon 2 mutation
|
Avastin (bevacizumab) • 5-fluorouracil • irinotecan • leucovorin calcium • onvansertib (PCM-075)
2years
Targeting PLK1 As a Novel Strategy for Acute Myeloid Leukemias with Fanconi Anemia Pathway Mutations (ASH 2022)
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.
BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • FANCA (FA Complementation Group A) • PLK1 (Polo Like Kinase 1) • CHEK1 (Checkpoint kinase 1) • FANCD2 (FA Complementation Group D2) • FANCG (FA Complementation Group G) • BUB1 (BUB1 Mitotic Checkpoint Serine/Threonine Kinase)
|
FANCA mutation
|
volasertib (NBL-001) • onvansertib (PCM-075)
2years
Onvansertib + Paclitaxel In TNBC (clinicaltrials.gov)
P1b/2, N=50, Recruiting, Antonio Giordano, MD | Phase classification: P1/2 --> P1b/2
Phase classification • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
|
paclitaxel • onvansertib (PCM-075)
2years
Onvansertib + Paclitaxel In TNBC (clinicaltrials.gov)
P1/2, N=50, Recruiting, Antonio Giordano, MD
New P1/2 trial • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
|
paclitaxel • onvansertib (PCM-075)
2years
Onvansertib + Paclitaxel In TNBC (clinicaltrials.gov)
P1/2, N=50, Recruiting, Antonio Giordano, MD | Not yet recruiting --> Recruiting | Phase classification: P1b/2 --> P1/2
Enrollment open • Phase classification • Combination therapy • Metastases
|
HER-2 (Human epidermal growth factor receptor 2)
|
HER-2 negative
|
paclitaxel • onvansertib (PCM-075)
2years
New P2 trial • Preclinical • Combination therapy • Metastases
|
KRAS (KRAS proto-oncogene GTPase) • NRAS (Neuroblastoma RAS viral oncogene homolog)
|
NRAS mutation • RAS mutation
|
Avastin (bevacizumab) • 5-fluorouracil • irinotecan • leucovorin calcium • onvansertib (PCM-075)
over2years
Early decreases in KRAS mutant allele frequency (MAF) predicts clinical benefit to the PLK1 inhibitor onvansertib in combination with FOLFIRI/bev in 2L treatment of metastatic colorectal carcinoma (mCRC) (ESMO 2022)
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.
Clinical • Combination therapy
|
KRAS (KRAS proto-oncogene GTPase)
|
KRAS mutation
|
5-fluorouracil • irinotecan • leucovorin calcium • onvansertib (PCM-075)