FDA Places Partial Clinical Hold on Phase 1 Study of NUV-422 in Solid Tumors

The FDA has placed a partial clinical hold on the phase 1/2 NUV-422-02 trial (NCT04541225) evaluating the selective small molecule CDK2/4/6 inhibitor NUV-422 in patients with solid tumors such as high-grade glioma, hormone receptor–positive advanced breast cancer, and metastatic castration-resistant prostate cancer (mCRPC).¹

The action follows reports of uveitis in certain patients receiving the agent. In response to this observation, Nuvation Bio, Inc. proactively paused enrollment to further evaluate these cases with investigators and uveitis experts. The company also reached out to the regulatory agency for guidance on determining an acceptable path forward.

Although no new patients can enroll to the trial, current participants are permitted to continue treatment with NUV-422.

“We are committed to patient safety across all our studies and to working collaboratively with the FDA to develop, as efficiently as possible, new medicines where existing therapies are inadequate,” David Hung, MD, founder, president, and chief executive officer of Nuvation Bio, Inc., stated in a press release. “Based upon the recent development of uveitis as a potential safety signal, we will conduct an overall risk/benefit analysis of the NUV-422 program. Our goal is always to ensure that we deploy our resources on programs that have the highest probability of success and of generating value for patients and our investors.”

Preclinical data with NUV-422 have suggested that the agent has favorable blood–brain barrier penetration.² Moreover, the agent is designed to limit CDK1 inhibition, which is known to be a possible cause of toxicity with other second-generation inhibitors.

The first-in-human, open-label, phase 1/2 trial was launched to examine the safety and efficacy of NUV-422 in adult patients with recurrent or refractory high-grade gliomas, metastatic breast cancer with and without brain metastases, and metastatic castration-resistant prostate cancer.

To be eligible for enrollment to all phases and cohorts, patients must have recovered from toxicity to previous anticancer therapies.³ Moreover, they needed to be eligible to receive single-agent NUV-422, have a life expectancy of greater than 3 months, and have acceptable bone marrow and organ function.

The phase 1 portion of the trial started to enroll patients in December 2020. In recent months, investigators were examining higher doses of the agent to identify a maximum tolerated dose of treatment.

On the trial, study participants received self-administered, oral NUV-422 in 28-day treatment cycles. Treatment was continued until progressive disease, toxicity, withdrawn consent, or study termination.

The primary outcome measures in the dose-escalation portion of this research were to examine the safety and tolerability of the agent and to identify the recommended phase 2 dose. The primary outcome measure of the phase 1 surgical sub study was to evaluate the pharmacokinetic profile of NUV-422.

For cohort 1 in the phase 2 dose-expansion portion of the research, the primary outcome measure will be to evaluate objective response rate and duration of response with NUV-422 in those with IDH wild-type glioblastoma. In cohorts 2, 3, and 4 of the expansion portion of the trial, the primary outcome measure is to evaluate the same efficacy measures in those with hormone receptor–positive, HER2-negative metastatic breast cancer; mCRPC; and hormone receptor–positive, HER2-negative metastatic breast cancer with brain metastases, respectively.

The company shared that they plan to provide updates on the direction of the NUV-422 program following the completion of an internal risk-benefit analysis that will consider feedback from the FDA.

NUV-422 will also be explored in combination with fulvestrant (Faslodex) in those with hormone receptor–positive, HER2-negative advanced breast cancer who previously received a hormonal therapy combined with an approved CDK4/6 inhibitor, as part of the phase 1b/2 NUV-422-03 trial (NCT05191004).² The agent is also being paired with enzalutamide (Xtandi) in the phase 1b/2 NUV-422-04 trial (NCT05191017), as a potential regimen for patients with mCRPC who previously received abiraterone acetate (Zytiga).

References

1. Nuvation Bio announces FDA partial clinical hold for phase 1 study of NUV-422 in solid tumors. News release. Nuvation Bio, Inc. June 27, 2022. Accessed June 27, 2022. https://bit.ly/3A8v7Sz
2. Pipeline: CDK 2/4/6. Nuvation Bio, Inc. Accessed June 27, 2022. https://bit.ly/3u5vE3Q
3. Study of NUV-422 in adults with recurrent or refractory high-grade gliomas and solid tumors. ClinicalTrials.gov. Updated March 11, 2022. Accessed June 27, 2022. https://clinicaltrials.gov/ct2/show/NCT04541225