Novel CDK4/6 ARK5 Inhibitor Explored as a Treatment for Advanced Cancers

The investigational CDK4/6 ARK5 inhibitor, ON 123300, has been dosed in the first time in a patient whose is enrolled in a phase 1 trial of ON 123300 for the treatment of advanced cancers.

The investigational CDK4/6 ARK5 inhibitor, ON 123300, has been dosed for the first time in a patient whose is enrolled in a phase 1 trial of ON 123300 for the treatment of advanced cancers including but not limited to, HR+ HER2- breast cancer patients who are refractory to or progressing on approved cyclin dependent kinase (CDK) 4/6 inhibitors, according to a press release by Onconova Therapeutics.1

ON 123300 has low nanomolar potency that may improve second-generation compounds. Preclinical models have found the compound effective in inhibiting CDK4/6 ARK5.2

The interventional, sequential assignment trial has an estimated enrollment of 36 participants and utilizes a 3 + 3 dose escalation design with an expansion cohort at the recommended phase 2 dose. The estimated completion date is October 2023. The primary outcomes of the study are the incidence of dose limiting toxicities (DLT) within the first 28 days of dosing, the incidence of adverse events (AEs), and abnormal laboratory test results. Secondary outcomes include recommended phase 2 dose and the pharmacokinetics of ON 123300, The other outcome measured is preliminary efficacy. 

During the study, each cohort received an increasing dose of ON 123300. Dosing started at 40 mg.

In order to participate, patients must be 18 years old or older, have histological or cytological evidence of advanced and/or metastatic cancer, have received and failed at least one prior approved treatment, have a life expectancy of 3 more or greater, be able to swallow oral capsules, and have an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2. Patients that have any significant medical condition, are at a risk for Torsades de pointes, a diagnosis of a hematological malignancy except for non-Hodgkin lymphoma, any chemotherapy within 14 days of the planned first dose, or a recent history of venous thromboembolic events are not eligible to participate.

“We are excited to begin dosing patients in this Phase 1 study and are pleased to be advancing ON 123300’s clinical development in the United States,” said Steven M. Fruchtman, MD, president, and chief executive office of Onconova Therapeutics, in a press release. “Our goal is to provide an innovative treatment option for patients with advanced breast cancer who have become resistant to the commercial CDK 4/6 inhibitors, and other refractory solid tumors driven by the overexpression of tyrosine kinases targeted by ON 123300. Notably, ON 123300’s ability to target multiple kinase pathways that are overexpressed in cancer may allow for single-agent efficacy and better tolerability compared to existing treatment regimens.”

Questions remain if CDK4/6 inhibitors can be optimized for the treatment of breast cancer. Trials such as monarchE (NCT03155997) and PENELOPE-B (NCT01864746) aim to determine if breast cancer patients can benefit from the treatment. Many clinicians agree that patients with high-risk disease would benefit, however, when to administer therapy is still undetermined. Some trials found that there is a high rate of late recurrence when used in earlier setting lines, suggesting that they be used in later treatments.

For breast cancer patients, acquired resistance to CDK4/6 inhibition remains a serious problem. Success has been seen with CDK4/6 inhibitors in this patient population, but sequencing is needed in order to determine and inhibit resistance. Ribociclib (Kisqali) and abemaciclib (Verzenio) are 2 approved CDK4/6 inhibitors showing promise in this regard.

1.Onconova Therapeutics announces the initial dosing of the first patient in the US phase 1 clinical trial of ON 123300. News release. Onconova Therapeutics. May 21, 2021. Accessed May 26, 2021.
2.Patel S, Pancholi P, Visal T, et al. ON 123300, an Orally Administered Novel CDK4/6 + ARK5 Inhibitor, Exhibits Potent Antitumor Activity In Vivo: Comparative Studies with Palbociclib. Abstract. Accessed May 26, 2021.