onvansertib (PCM-075) / Nerviano Medical Sciences, Cardiff Oncology - LARVOL DELTA

Efficacy of novel agents in the treatment of acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis (ASH 2025) - "Newer agents included for AML were Guadectiabine, Magrolimab, Alvocidib, Enasidenib, Flotetuzumab, Vadastuximab, Mitoxantrone, Pevonedistat, Entospletinib, Eprenetapopt, Belinostat, Onvansertib, Panobinostat, Cediranib Maleate, Nilotinib, Emavusertib, and anti-CD45 antibody (DOTA-BC8). The newer agents investigated for MDS included Rigosertib, Imetelstat, Pembrolizumab, Enasidenib, Sabatolimab, Ivosidenib, Elitercept, Pevonedistat, Emavusertib, Atezolizumab, and Olutasidenib...All patients were treated concomitantly with either azacitidine (77%) or decitabine (23%)... This meta-analysis and systematic review demonstrate promising efficacy for novel agents in AML and MDS patients. There is a need for prospective trials with larger patient populations to investigate these agents further."

Retrospective data • Review • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Neutropenia • TP53

MC210807: Phase 1 clinical trial assessing the safety and efficacy of onvansertib, a novel, oral, PLK1 inhibitor in Relapsed/Refractory myeloproliferative chronic myelomonocytic leukemia (CMML). (ASH 2025) - P1 | "This was conclusivelydemonstrated in the phase 3 DACOTA study, where decitabine did not improve event-free survival incomparison to hydroxyurea (median 12.1 versus 10.3 months, P=0.27) in advanced myeloproliferativeCMML (MP-CMML). In MP-CMML, PLK1 inhibition with onvansertib is relatively well tolerated and showspreliminary efficacy in approximately 40% of patients, with one patient having an optimal marrowresponse at the 9 mg/m2 dose. Future directions include a dose expansion phase and studying upfrontcombination with DNA methyltransferase inhibitors."

Clinical • P1 data • Acute Kidney Injury • Atrial Fibrillation • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Dermatology • Hematological Malignancies • Infectious Disease • Leukemia • Nephrology • Septic Shock • ASXL1 • KMT2A • KRAS • NRAS • SRSF2 • TET2

Cardiff Oncology Announces Clinical Data from Investigator-Sponsored Trial with Onvansertib in Chronic Myelomonocytic Leukemia at ASH 2025 (GlobeNewswire) - "In this Phase 1 dose escalation trial (N=9), onvansertib as a monotherapy was shown to be relatively well-tolerated, and demonstrated preliminary efficacy in approximately 40% of patients, with one patient having an optimal marrow response at the 9 mg/m2 dose....Cardiff Oncology is not currently planning to develop onvansertib for CMML."

Discontinued • P1 data • Chronic Myelomonocytic Leukemia

Targeting PLK1 Reduces MMP10 to Enhance Radiosensitivity in HPV- Head and Neck Cancer. (PubMed, Clin Cancer Res) - "These findings suggest that combining PLK1 inhibition with radiation may improve therapeutic response for HPV- HNSCC via MMP10, offering a novel approach to overcome radiation resistance."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • MMP10 • PLK1

Cardiff Oncology…Provides Business Update (GlobeNewswire) - "An update from the ongoing Phase 2 CRDF-004 trial in first-line RAS-mutated mCRC is expected in 1Q 2026."

P2 data • Colorectal Cancer

PLK1 INHIBITION OFFERS A CLINICALLY RELEVANT STRATEGY FOR DIPG WITH TP53-DEPENDENT THERAPEUTIC SYNERGY (SIOP 2025) - "We evaluated the efficacy of PLK1 inhibition using BI-2536, volasertib, and onvansertib in patient-derived DIPG models, with a focus on TP53 status, pharmacokinetics, and synergy with RT...Co-treatment with vinorelbine significantly increased volasertib CNS accumulation to ~57 nM (p=0.0021), potentiating a combinatorial therapeutic strategy... PLK1 inhibition shows strong anti-tumour activity in DIPG and synergises with RT in TP53-deficient models. These findings support biomarker-guided PLK1-targeted strategies and highlight the need to optimise CNS delivery for clinical translation."

Clinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Pediatrics • Solid Tumor • PLK1 • TP53

PLK1 inhibition enhances gemcitabine-induced apoptosis through PLK1-dependent ERK1/2-Bim and AKT1/Noxa signals in pancreatic cancer cells. (PubMed, Med Oncol) - "We detected the expression of PLK1 in pancreatic cancer tissues and cell lines and study the effects of PLK1 and Gemcitabine on cell viability and apoptosis of GEM-resistant pancreatic cancer PANC-1 cells and Gemcitabine sensitive BxPC-3 cells; Using inhibitors or siRNA, we further investigate the effects of PLK1 on ERK1/2, AKT1, and pro-apoptotic genes PUMA, Bim, and Noxa; We finally investigated the effect of the combined onvansertib and Gemcitabine on the growth of PANC-1 subcutaneous transplant tumors in nude mice and explored its possible mechanism of action...BI2536 (a PLK1 kinase inhibitor) treatment recures the Gemcitabine sensitivity in the PLK -transfected BxPC-3 cells by upregulation of Bim and Noxa expression in vitro...Targeting PLK1 sensitizes PDAC cells to gemcitabine in vitro and in vivo. This indicates that combination therapy with PLK1 inhibitor may overcome gemcitabine resistance, offering a promising new therapeutic option for the treatment of..."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • Transplantation • AKT1 • PMAIP1

PLK1-mediated PDHA1 phosphorylation drives metabolic reprogramming in lung cancer. (PubMed, Oncogene) - "It is well-established that pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation of PDH leads to its inactivation and that dichloroacetic acid (DCA), a PDK inhibitor, has been investigated in preclinical and early clinical studies as a potential therapeutic agent for lung cancer. This study aims to elucidate how PLK1-associated activity drives the metabolic reprogramming from OXPHOS to glycolysis during cellular transformation, thereby contributing to lung carcinogenesis. Our results provide support for a clinical trial to evaluate the efficacy of Onvansertib plus DCA in treating lung cancer."

Journal • Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • PDHA1 • PLK1

PLK1 inhibitors for the treatment of colorectal cancer. (PubMed, Ann Med Surg (Lond)) - "A recent phase I trial reported a 44% partial response rate of onvansertib, a PLK1 inhibitor, in the treatment of patients with KRAS-mutated metastatic colorectal cancer, indicating that PLK1 inhibitor might be suitable for the treatment of this specific subtype of cancer. This review summarizes the results of preclinical experiments and clinical trials of PLK1 inhibitors, with colorectal cancer as a focus, in hope of facilitating future investigations in this research field."

Journal • Review • Colorectal Cancer • Oncology • Solid Tumor • KRAS

High-throughput virtual screening, identification and in vitro biological evaluation of novel inhibitors of PLK1 and NRP1. (PubMed, J Enzyme Inhib Med Chem) - "PLN-5 showed nanomolar inhibitory potency against PLK1 (IC50 = 2.07 ± 0.13 nM) and NRP1 (IC50 = 5.15 ± 0.24 nM), exceeding the positive controls onvansertib and EG00229 by approximately 9-fold and 124-fold, respectively...Importantly, MTT assays showed that PLN-5 had significant antiproliferative activity (IC50 = 0.27 ± 0.02 μM) against human lung cancer cells, with no significant inhibitory effect on normal lung cells. In conclusion, these results demonstrate the therapeutic potential of PLN-5 as a dual-targeting antitumor agent that warrants further development."

Journal • Preclinical • Lung Cancer • Oncology • Solid Tumor • NRP1 • PLK1

Single-cell transcriptomic and pharmacological studies of onvansertib for small cell lung cancer treatment. (PubMed, Biomed Pharmacother) - "Onvansertib impairs a normal cell cycle transition by downregulating the cell division process, leading to G2/M phase arrest. Altogether, this work demonstrates the therapeutic mechanisms and in vitro and in vivo pharmacological profiles of onvansertib in SCLC."

Journal • Hematological Disorders • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Cardiff Oncology Reports Second Quarter 2025 Results and Provides Business Update (GlobeNewswire) - "Total operating expenses were approximately $14.9 million for the three months ended, June 30, 2025, an increase of $2.2 million from $12.7 million for the same period in 2024. The increase in operating expenses was primarily due to costs associated with our CRDF-004 clinical trial, other clinical programs and outside service costs related to the development of our lead drug candidate, onvansertib, as well as salaries and wages for key hires and additional stock option grants."

Commercial • Colorectal Cancer

Cardiff Oncology Announces Positive Data from Ongoing Randomized Phase 2 First-line RAS-mutated mCRC Clinical Trial (CRDF-004) (GlobeNewswire) - P2 | N=113 | NCT06106308 | Sponsor: Cardiff Oncology | "The CRDF-004 phase 2 trial enrolled patients with mCRC who have a documented KRAS or NRAS mutation. Onvansertib is added to SoC consisting of FOLFIRI plus bevacizumab or FOLFOX plus bevacizumab....Trial demonstrates 49% confirmed ORR in the 30mg onvansertib dose arm versus 30% confirmed ORR in the control arm in intent-to-treat population (N=110)....Both the 20mg and 30mg onvansertib arms demonstrated an early separation of the PFS curves compared to the control arm at a median follow up time of 6 months. While the median PFS has not been reached, there was a dose dependent effect in favor of the 30mg onvansertib dose....The safety analysis was conducted for the 104 patients who were dosed in the trial. Onvansertib in combination with chemo/bevacizumab was well-tolerated and there were no major or unexpected toxicities observed....Update on first-line mCRC program expected by 1Q 2026."

P2 data • Colorectal Cancer

EFFICACY AND OUTCOMES OF NOVEL THERAPEUTIC AGENTS AS MONOTHERAPY OR IN COMBINATION WITH CONVENTIONAL THERAPY IN ACUTE MYELOID LEUKEMIA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2025) - "Agents included Guadectiabine 28%, Magrolimab 7% Alvocidib 3%, Enasidenib 23%,, Flotetuzumab 4%, Vadastuximab 9%, Mitoxantrone 9%, Pevonedistat 2%, Entospletinib 3%, Eprenetapopt 20%, Belinostat 0.5%, Onvansertib 3%, Panobinostat 2%, Cediranib Maleate 1%, Nilotinib 2%, Emavusertib 0.5%, and anti-CD45 antibody (DOTA-BC8) 0.5%. The conventional therapies were azacitidine 20% and cytarabine 17%... This study shows the promising efficacy of novel agents in AML and highlights the need for further prospective trials with larger patient populations to better understand the efficacy and safety outcomes of these agents in patients with AML."

Combination therapy • Monotherapy • Retrospective data • Review • Acute Myelogenous Leukemia • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Thrombocytopenia • TP53

Onvansertib-Based Second-Line Therapies in Combination with Gemcitabine and Carboplatin in Patient-Derived Platinum-Resistant Ovarian Carcinomas. (PubMed, Int J Mol Sci) - "The activity of the combinations of onvansertib, an inhibitor of polo-like kinase 1, with gemcitabine or carboplatin was tested using patient-derived xenografts of high-grade serous ovarian carcinoma resistant to cisplatin (DDP). The molecular mechanism underlying the efficacy of the combinations suggests a higher induction of DNA damage which seems plausible considering that, in both cases, gemcitabine and carboplatin, respectively, interfere with DNA metabolism and induce alkylation damage. The results suggest that the combinations of onvansertib/gemcitabine and onvansertib/carboplatin are safe and were shown to be of therapeutic value in the platinum-resistant setting of ovarian carcinoma, strongly supporting their clinical translatability."

Journal • Platinum resistant • High Grade Serous Ovarian Cancer • Oncology • Ovarian Cancer • Solid Tumor • PLK1

Cardiff Oncology…Announces Timing for the Next Update from the CRDF-004 Trial in First-Line RAS-mutated mCRC (GlobeNewswire) - "The company also announced it will share additional clinical data from its lead program in RAS-mutated mCRC on July 29, 2025....Company will hold a conference call on July 29 at 4:30 p.m. ET/1:30 p.m. PT to share additional clinical data from its randomized Phase 2 CRDF-004 trial evaluating onvansertib + standard of care for the treatment of first-line RAS-mutated metastatic colorectal cancer ('mCRC')."

P2 data • Colorectal Cancer

A phase 1b study of Plk1 inhibitor onvansertib in combination with paclitaxel in metastatic triple-negative breast cancer (mTNBC) patients. (ASCO 2025) - P1/2 | "The combination of onvansertib and P demonstrated a safe toxicity profile and promising clinical activity in pretreated mTNBC pts and warrant further exploration of the combination at the RP2D. Best response per RECIST 1.1 among different DL."

Clinical • Combination therapy • IO biomarker • Metastases • P1 data • Anemia • Breast Cancer • Fatigue • Oncology • Solid Tumor • Triple Negative Breast Cancer • PLK1

A phase 1b/2 trial of onvansertib in combination with NALIRIFOX for first line treatment of advanced pancreatic cancer (PANCONVA trial). (ASCO 2025) - P1/2 | "NALIRIFOX (Nano-liposomal Irinotecan 50 mg/m2, Oxaliplatin 60 mg/m2, Leucovorin 400 mg/m2, 5-FU 2400 mg/m2) will be administered intravenously on D1 of the 14-day cycle...Otherwise, 11 additional evaluable pts will be accrued for a total of 21 evaluable pts. The null hypothesis will be rejected if 12 or more responses are observed in 21 evaluable pts."

Clinical • Combination therapy • Metastases • P1/2 data • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CYP2C19 • CYP3A4 • KRAS

Cardiff Oncology Announces Positive Data from Investigator-Initiated Trial of Onvansertib in Combination with Paclitaxel in Metastatic Triple-Negative Breast Cancer Presented at ASCO 2025 (GlobeNewswire) - P1b/2 | N=50 | NCT05383196 | "Cardiff Oncology...announced positive data from an investigator-initiated Phase 1b clinical trial evaluating onvansertib in combination with paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC) at the American Society of Clinical Oncology (ASCO) Annual Meeting....Onvansertib in combination with paclitaxel demonstrated 40% objective response rate by RECIST 1.1 at RP2D of 18mg/m2 (n=10), with two confirmed partial responses and two unconfirmed partial responses. The combination of onvansertib and paclitaxel was well-tolerated demonstrated a safe and manageable toxicity profile with myelosuppression being the most common adverse event. Collectively, this clinical data further supports the potential exploration of the combination of onvansertib plus paclitaxel for the treatment of mTNBC."

P1 data • Triple Negative Breast Cancer

CRDF-004: Study of Onvansertib in Combination With FOLFIRI and Bevacizumab or FOLFOX and Bevacizumab Versus FOLFIRI and Bevacizumab or FOLFOX and Bevacizumab for First-Line Treatment of Metastatic Colorectal Cancer in Adult Participants With a KRAS or NRAS Mutation (clinicaltrials.gov) - P2 | N=113 | Active, not recruiting | Sponsor: Cardiff Oncology | Recruiting ➔ Active, not recruiting

Enrollment closed • Colorectal Cancer • Oncology • Solid Tumor • KRAS • NRAS

Onvansertib inhibits cell proliferation and increases sensitivity to paclitaxel in uterine serous cancer cells. (PubMed, Am J Cancer Res) - "The combination of onvansertib with paclitaxel demonstrated a synergistic effect in cell proliferation inhibition via inducing cell apoptosis and DNA damage. Our results provide preclinical evidence that onvansertib may be an effective strategy to treat USC and deserves further evaluation in animal models and clinical trials."

Journal • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Oncology • Solid Tumor • Uterine Cancer • AURKA

Cardiff Oncology Reports First Quarter 2025 Results and Provides Business Update (GlobeNewswire) - "Upcoming expected milestones: Additional clinical data from the ongoing CRDF-004 trial in mCRC expected in 1H 2025."

P2 data • Colorectal Cancer

Combination therapy with onvansertib and carboplatin demonstrate anti-tumorigenic effects in endometrioid endometrial cancer cell lines (AACR 2025) - "Combination therapy with onvansertib and carboplatin demonstrate compelling anti-tumorigenic effects in endometrioid EC cell lines. Ongoing investigation is merited for pursuit of possible translation into clinical treatment options of this novel drug combination in EC."

Combination therapy • Preclinical • Breast Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Oncology • Solid Tumor • CASP3 • CCND1 • CDK4 • CTNNB1 • SNAI2

Onvansertib in combination with carboplatin demonstrates enhanced anti-tumorigenic effects in pre-clinical models of serous endometrial cancer (AACR 2025) - "The combination of onvansertib and carboplatin demonstrated potent anti-tumorigenic effects in serous EC cells compared with onvansertib or carboplatin alone. Further studies are warranted to evaluate if this combination may translate into a novel clinical therapeutic option for serous EC."

Combination therapy • Preclinical • Breast Cancer • Colon Cancer • Colorectal Cancer • Endometrial Cancer • Oncology • Solid Tumor • AURKA • CASP3 • CCND1 • CDK2 • CDK4 • CTNNB1 • SNAI2

The impact of cell cycle inhibitors on bladder cancer with low NECTIN-4 expression (AACR 2025) - "Enfortumab-vedotin (EV) links a monoclonal antibody targeting NECTIN-4 with the cytotoxic agent monomethyl auristatin E (MMAE)...Drug sensitivity was assessed by a CCK-8 assay over 72 hours following treatment with the PLK1 inhibitor (onvansertib)... This study underscores the therapeutic potential of cell cycle inhibitors, notably PLK1 inhibitors, in bladder cancer cells with low NECTIN-4 expression, showing an inverse relationship between NECTIN-4 expression and sensitivity to PLK1 inhibitors. NECTIN-4 levels could predict PLK1 inhibitor treatment response. NECTIN-4 knockdown experiments confirmed that reduced NECTIN-4 expression disrupted cell cycle regulation and increased PLK1 inhibition efficacy."

Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • CCND1 • NECTIN4