January 5, 2021 – The FDA has granted permission for a phase 1 study evaluating ON 123300, a first-in-class multikinase CDK4/6 inhibitor to proceed under the agent’s investigational new drug application.
The FDA has granted permission for a phase 1 study evaluating ON 123300, a first-in-class multikinase CDK4/6 inhibitor to proceed under the agent’s investigational new drug application, according to a press release from Onconova Therapeutics, Inc.1
“We are grateful to receive this timely, favorable response from the FDA to initiate a phase 1 trial with ON 123300,” said Steven M. Fruchtman, MD, president and chief executive officer of Onconova Therapeutics, Inc. “We are advancing the process to secure Institutional Review Board approval and affirm our expectation that the first patient will be enrolled during the first half of 2021.”
The phase 1 trial, which will be conducted in the United States, will evaluate the safety, tolerability, and pharmacokinetics of ON 123300 in patients with relapsed/refractory advanced cancers, including hormone receptor (HR)–positive, HER2-negative breast cancer that is resistant to approved second-generation CDK4/6 inhibitors.2
Patients on the study will receive increasing doses starting at 40 mg or higher of daily, single-agent ON 123300 administered orally in 28-day cycles.
Upon establishment of the recommended phase 2 dose of ON 123300 from the dose-escalation portion of the study, additional postmenopausal patients with metastatic HR-positive, HER2-negative breast cancer will be enrolled. Additional cohorts of patients with advanced colorectal cancer and non-Hodgkin lymphoma, such as mantle cell lymphoma, are being considered for potential enrollment should the dose-expansion portion lend positive findings.
Additionally, the agent may have utility in tumor types such as multiple myeloma, advanced hepatocellular carcinoma, and inoperable glioblastoma. Preclinical research has also suggested that ON 123300 crosses the blood-brain barrier.
ON 123300 targets tumor-driving kinases, including CDK4/6 and ARK5 and appears to simultaneously inhibit cell cycle and cellular energy metabolism through these kinases. In vitro studies have suggested that ON 123300 has utility as a cytotoxic agent against cancer cells.
The study plans to begin enrollment in the first half of 2021, pending approval from the Institutional Review Board.
Additionally, an ongoing study of ON 123300 is being conducted in China by Onconova Therapeutics, Inc.’s partner company, HanX Biopharmaceuticals, Inc. In that study, patients will be dosed in 21-day cycles. To date, the study has enrolled 4 patients and will continue recruitment until a phase 2 dose is established.
Regarding approved CDK4/6 inhibitors, palbociclib (Ibrance) and ribociclib (Kisqali) are dosed in 21-day cycles, and abemaciclib (Verzenio) is dosed continuously. Notably, the 3 currently approved agents require concomitant administration with an aromatase inhibitor. Additionally, unlike the cytotoxic effects of ON 123300, the currently approved CDK4/6 inhibitors are cytostatic, inhibiting cancer growth rather than leading to cell death.
The differing mechanisms of action between these established CDK4/6 inhibitors and ON 123300 suggests that the first-in-class agent could yield specific benefit to patients with breast cancer who have progressed on a CDK4/6 inhibitor and could fulfill a significant unmet need in the space.