FDA Grants Orphan Drug Designation to Novel CDK2/4/6 Inhibitor in Malignant Gliomas

The FDA granted orphan drug designation to the CDK2/4/6 inhibitor, NUV-422, for the treatment of patients with malignant gliomas, according to a press release from Nuvation Bio.

"We are pleased to receive the FDA's orphan drug designation, which underscores the potential of NUV-422 to address the significant unmet need of patients with high-grade gliomas," said David Hung, MD, founder, and chief executive officer of Nuvation Bio, in a statement. "We look forward to continuing the development of NUV-422 through our ongoing phase 1/2 study."

NUV-422 is currently being evaluated as a treatment of adult patients with recurrent or refractory high-grade gliomas, including glioblastoma multiforme (GBM) in a first-in-human, open-label, phase 1/2 dose escalation and multiple expansion cohort study (NCT04541225).

The study is actively recruiting up to 80 patients with histologically confirmed disease, evidence of recurrence after treatment or who are refractory to treatment, adequate bone marrow and organ function, and a life expectancy of at least 3 months. Patients are required to be recovered from toxicity caused by prior anti-cancer therapy prior to receiving NUV-422 in the study. The protocol includes cohort-specific inclusion criteria which state that patients in phase 1 dose-escalation cohorts must have measurable or non-measurable disease at baseline as well as a Karnofsky Performance Status (KPS) score ≥ 60. In the 2 dose-expansion cohorts, the requirements for inclusion include available tumor tissue, receipt of prior therapy with radiation or radiation plus temozolomide (Temodar), radiographic proof of progression and measurable disease, a KPS score ≥ 70, and resectable tumors (expansion cohort 2).

Patients with recurrent or refractory high-grade gliomas are excluded from the study if they received chemotherapy, radiation, or biological anti-cancer therapy within 14 days of NUV-422 dosing, are currently using or previously used bevacizumab (Avastin) as therapy for brain cancer, received an investigational cancer therapy of any kind within 14 days of NUV-422 dosing, require systemic corticosteroid therapy > 4 mg/day, requires anti-seizure medication or has uncontrolled seizures, and are pregnant or breastfeeding.

Participants will self-administer NUV-422 orally in 28-day cycles continuously until disease progression, toxicity, withdrawal of consent, or study termination.

In phase 1 of the study, the primary end point is the incidence of treatment-emergent adverse events (TEAEs), serious TEAEs, and dose-limiting toxicities (DLTs). These end points are explored to determine the safety and tolerability of the novel agent and to determine the recommended phase 2 dose. In the phase 2 portion of the study, the primary end point is the objective response rate.

Currently, 4 sites in the United States are recruiting patients for the study of NUV-422, including Dana-Farber Cancer Institute in Boston, Memorial Sloan Kettering Cancer Center in New York, The University of Texas MD Anderson Cancer Center in Houston, and the University of Utah Huntsman Cancer Institute in Salt Lake City. The leading oncologists for the clinical trial at these cancer centers include Patrick Y. Wen, MD; Thomas Kaley, MD; Jordi Rodon, MD, PhD; and Howard Colman, MD.

The initial data from the trial will be from the phase 1 portion, the findings from which are planned to be reported in 2022.

NUV-422 is a potent and selective small molecule that inhibits CDK 2, 4, and 6. In preclinical research, the agent demonstrated the ability to penetrate the blood-brain barrier. This earlier research suggests that NUV-422 may be helpful for the difficult-to-treat primary tumor in the central nervous system, including the malignant gliomas that make up 755 of all primary brain tumors in adult patients.

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_{Nuvation Bio granted Orphan Drug Designation for NUV-422 for the treatment of patients with malignant gliomas. News release. Nuvation Bio. March 11, 2021. Accessed March 11, 2021. https://bit.ly/3l6dNEg}