Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors

Weiss, Glen J.; Jameson, Gayle; Hoff, Daniel D. Von; Valsasina, Barbara; Davite, Cristina; Giulio, Claudia Di; Fiorentini, Francesco; Alzani, Rachele; Carpinelli, Patrizia; Sanzo, Alessandro Di; Galvani, Arturo; Isacchi, Antonella; Ramanathan, Ramesh K.

doi:10.1007/s10637-017-0491-7

Cited by 24 publications

(27 citation statements)

References 36 publications

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“…The relative lack of toxicity is due to the relatively low dosage of both drugs used, which again underscores the synergistic activity of the combination. In addition, even with the use of higher doses in a clinical setting, the spectrum of the reported side effects of the single drugs (hamatological toxicity for onvansertib and neurotoxicity for paclitaxel) [43,44] are not overlapping, fostering this drug combination. We also reported a synergistic activity when PLK1 inhibitors were combined with both eribulin and PI3K inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Affatato

Carrassa

Chilà

et al. 2020

Cancers

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Mucinous epithelial ovarian cancer (mEOC) is a rare subset of epithelial ovarian cancer. When diagnosed at a late stage, its prognosis is very poor, as it is quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using a siRNA library directed against human protein kinases in a mEOC cell line, and polo-like kinase1 (PLK1) was identified as the kinase whose downregulation interfered with cell proliferation. Both PLK1 siRNA and two specific PLK1 inhibitors (onvansertib and volasertib) were able to inhibit cell growth, induce apoptosis and block cells in the G2/M phase of the cell cycle. We evaluated, in vitro, the combinations of PLK1 inhibitors and different chemotherapeutic drugs currently used in the treatment of mEOC, and we observed a synergistic effect of PLK1 inhibitors and antimitotic drugs. When translated into an in vivo xenograft model, the combination of onvansertib and paclitaxel resulted in stronger tumor regressions and in a longer mice survival than the single treatments. These effects were associated with a higher induction of mitotic block and induction of apoptosis, similarly to what was observed in vitro. These data suggest that the combination onvansertib/paclitaxel could represent a new active therapeutic option in mEOC.

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Section: Discussionmentioning

confidence: 99%

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Affatato

Carrassa

Chilà

et al. 2020

Cancers

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“…The primary objectives were to evaluate DLTs and the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of onvansertib. The first dose of onvansertib was 12 mg/m 2 , which was half of RP2D established in the phase 1 single agent study for solid tumors (18). Each arm followed a standard 3+3 dose-escalation design in which onvansertib dose was escalated by 50% increments.…”

Section: Treatment Plan and Study Designmentioning

confidence: 99%

“…A phase 1, first-in-human, dose escalation study of onvansertib in patients with advanced/metastatic solid tumors identified neutropenia and thrombocytopenia as the primary doselimiting toxicities (DLTs) (18). These hematologic toxicities were anticipated based on the mechanism of action of the drug and were reversible, with recovery occurring within 3 weeks.…”

Section: Introductionmentioning

confidence: 99%

“…These hematologic toxicities were anticipated based on the mechanism of action of the drug and were reversible, with recovery occurring within 3 weeks. The half-life of onvansertib was established between 20 and 30 hours (18). The oral bioavailability of onvansertib plus its short half-life provide the opportunity for convenient, controlled and flexible dosing schedules with the potential to minimize toxicities and improve the therapeutic window.…”

Section: Introductionmentioning

confidence: 99%

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A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Zeidan

Ridinger²,

Lin

et al. 2020

Clinical Cancer Research

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Purpose: The Polo-like kinase 1 (PLK1) is a master regulator of mitosis and overexpressed in acute myeloid leukemia (AML). We conducted a phase 1b study of the PLK1 inhibitor onvansertib in combination with either low-dose cytarabine (LDAC) or decitabine in relapsed or refractory (R/R) AML patients. Experimental Design: Onvansertib was administered orally, in escalating doses, on days 1-5 in combination with either LDAC (20 mg/m 2 ; days 1-10) or decitabine (20 mg/m 2 ; days 1-5) in a 28-day cycle. The primary endpoint was to evaluate first-cycle dose-limiting toxicities and the maximum tolerated dose (MTD). Secondary and exploratory endpoints included safety, pharmacokinetics, antileukemic activity and response biomarkers. Results: Forty patients were treated with onvansertib (12-90 mg/m 2) in combination with LDAC (n=17) or decitabine (n=23). Onvansertib was well tolerated with most grades 3 and 4 adverse events related to myelosuppression. In the decitabine arm, the MTD was established at 60 mg/m 2 , and 5 (24%) of the 21 evaluable patients achieved complete remission with or without hematologic count recovery. Decrease in mutant circulating tumor DNA (ctDNA) during the first cycle of therapy was associated with clinical response. Engagement of the PLK1 target, TCTP, was measured in circulating blasts and was associated with greater decrease in bone marrow blasts. Conclusions: The onvansertib and decitabine combination was well tolerated and had anti-leukemic activity particularly in patients with target engagement and decreased mutant ctDNA following treatment. This combination will be further investigated in the ongoing phase 2 trial. Research.

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“…Despite these promising preclinical results, there are no clinical trials examining combination treatments with PLK1 inhibitors in (pediatric) patients with rhabdomyosarcoma. However, based on the preclinical data and the tolerable toxicity of the PLK1 inhibitor NMS-1286937 in adult patients with solid tumor, such trials would be of interest (69).…”

Section: Cell Cyclementioning

confidence: 99%

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Erp¹,

Graaf

Fleuren

2018

Molecular Cancer Therapeutics

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Targeted therapies have revolutionized cancer treatment; however, progress lags behind in alveolar (ARMS) and embryonal rhabdomyosarcoma (ERMS), a soft-tissue sarcoma mainly occurring at pediatric and young adult age. Insulin-like growth factor 1 receptor (IGF1R)-directed targeted therapy is one of the few single-agent treatments with clinical activity in these diseases. However, clinical effects only occur in a small subset of patients and are often of short duration due to treatment resistance. Rational selection of combination treatments of either multiple targeted therapies or targeted therapies with chemotherapy could hypothetically circumvent treatment resistance mechanisms and enhance clinical efficacy. Simultaneous targeting of distinct mechanisms might be of particular interest in this regard, as this affects multiple hallmarks of cancer at once. To determine the most promising and clinically relevant targeted therapy-based combination treatments for ARMS and ERMS, we provide an extensive overview of preclinical and (early) clinical data concerning a variety of targeted therapy-based combination treatments. We concentrated on the most common classes of targeted therapies investigated in rhabdomyosarcoma to date, including those directed against receptor tyrosine kinases and associated downstream signaling pathways, the Hedgehog signaling pathway, apoptosis pathway, DNA damage response, cell-cycle regulators, oncogenic fusion proteins, and epigenetic modifiers. .

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Phase I dose escalation study of NMS-1286937, an orally available Polo-Like Kinase 1 inhibitor, in patients with advanced or metastatic solid tumors

Cited by 24 publications

References 36 publications

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

Identification of PLK1 as a New Therapeutic Target in Mucinous Ovarian Carcinoma

A Phase Ib Study of Onvansertib, a Novel Oral PLK1 Inhibitor, in Combination Therapy for Patients with Relapsed or Refractory Acute Myeloid Leukemia

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

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