Phase 1/2 dose escalation study of NUV-422, a potent inhibitor of cyclin-dependent kinases 2, 4, and 6, in recurrent or refractory (r/r) high-grade gliomas (HGG) and solid tumors.

TPS3173 Background: CDKs that govern the G1-S transition of the cell cycle (CDK2, CDK4 and CDK6) are deregulated in many cancers. CDK2 expression, in particular, is associated with worse overall survival in glioblastoma (GB), disease-free recurrence in prostate cancer, and resistance to approved CDK4/6 inhibitors (CDK4/6i) in breast cancer. These provide rationale for inhibition of CDK2/4/6 as a potential novel therapeutic strategy in these cancers. NUV-422 is a potent (low nM) small molecule CDK2/4/6i with limited activity against CDK1, a target potentially associated with toxicities in other CDKi. Preclinical studies have shown that NUV-422 has favorable blood-brain barrier penetration, inhibited growth of multiple glioma cell lines in vitro, and exhibited antitumor activity in GB xenograft models. NUV-422 also exhibited antitumor activity in multiple patient-derived xenograft (PDX) models of HR+ HER2- mBC resistant to CDK4/6i, and PDX models of prostate cancer resistant to anti-androgens. Methods: NUV-422-02 (NCT04541225) is a phase 1/2, first in human, open label, multicenter study to evaluate single-agent NUV-422 (given orally) in patients with advanced solid tumors (r/r HGG, r/r HR+ HER2- mBC, or r/r mCRPC). The Ph 1 dose escalation will use a 3+3 design to evaluate safety, tolerability, and PK of NUV-422 and establish the recommended phase 2 dose (RP2D). Ph 1 also includes a randomized surgical substudy to characterize PK and pharmacodynamics (PD) of preoperative NUV-422 in resected GB tumor tissue. After the RP2D is identified, parallel enrollment into phase 2 expansion cohorts will begin. Cohort 1 will evaluate isocitrate dehydrogenase wild type (IDH-WT) GB. Cohort 2 will evaluate HR+ HER2- mBC (without active brain metastases); Cohort 3 will evaluate mCRPC; and Cohort 4 will evaluate HR+ HER2- mBC with active brain metastases. The Ph 2 primary endpoint is objective response rate. Secondary efficacy endpoints include clinical benefit rate, duration of response, progression-free survival, and overall survival. Response assessments will be based on response criteria appropriate to the tumor type (HGG [RANO]; HR+HER2- mBC [RECIST 1.1 or RANO-Brain Metastases]; mCRPC [RECIST 1.1, PCWG3, prostate-specific antigen decrease]). Blood, urine, or tumor tissue will be obtained to assess safety, PK, PD, and for additional exploratory analyses to characterize NUV-422 mechanism of action. Enrollment was initiated in December 2020, and dose escalation is ongoing. The NUV-422 program will also be expanded in 2022 to include additional studies in mBC and mCRPC in combination with standard of care treatments. Clinical trial information: NCT04541225.