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Onvansertib is a highly selective PLK1 inhibitor. PLK1 is a protein which serves as a master regulator of cancer cell division.
It is for patients who are about to start treatment for their metastatic cancer; that is, for those who have not received first line chemotherapy in the metastatic setting.
KRAS or NRAS mutated metastatic CRC required. Patients with BRAF mutation are excluded. Only for MSS.
No prior bevacizumab (Avastin) allowed.

Patients will be randomized to receive standard of care (Folfox or Folfiri with bevacizumab), or the experimental agent onvansertib (oral, a pill), at two different doses, added to standard of care (Folfox or Folfiri with bevacuzumab).

Data from a previos trial (2022) show that the the addition of the PLK1 inhibitor onvansertib to FOLFIRI/bevacizumab shows very promising efficacy results with response rates of over 30% and PFS over 9 months in second-line mCRC KRAS-mutant colon cancer. The treatment is well-tolerated.
Onvansertib overcomes irinotecan resistance in RAS-mutated metastatic CRC

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Inclusion Criteria

Inclusion Criteria:

* Histologically confirmed metastatic colorectal cancer.
* Documented KRAS or NRAS mutation.
* No previous systemic therapy in the metastatic setting.
* Participants must be willing to submit archival tissue or undergo fresh biopsy.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Women of childbearing potential must use contraception or take measures to avoid pregnancy.
* Imaging computed tomography (CT) or magnetic resonance imaging (MRI) of chest/abdomen/pelvis and other scans as necessary to document all sites of disease performed within 28 days prior to the first dose of onvansertib.
* Must have acceptable organ function

Exclusion Criteria

Exclusion Criteria:

* Concomitant KRAS or NRAS and BRAF-V600 mutation or microsatellite instability high/deficient mismatch repair.
* Prior treatment with a VEGF inhibitor, including bevacizumab or biosimilars.
* Previous oxaliplatin treatment within 12 months prior to randomization, when arm open.
* Known dihydropyrimidine dehydrogenase (DPD) deficiency.
* Anticancer chemotherapy or biologic therapy administered within 28 days prior to the first dose of study drug.
* Untreated or symptomatic brain metastasis.
* Gastrointestinal (GI) disorder(s) that would significantly impede the absorption of an oral agent.
* Unable or unwilling to swallow study drug.
* Uncontrolled intercurrent illness.
* Known hypersensitivity to fluoropyrimidine or leucovorin, irinotecan, or oxalipatin.
* Abnormal glucuronidation of bilirubin; known Gilbert's syndrome.
* Use of strong CYP3A4 or CYP2C19 inhibitors or strong CYP3A4 inducers.
* QTc >470