The FDA has placed a partial clinical hold on the phase 1/2 VELA trial due to visual adverse effects observed in select patients who received the investigational treatment BLU-222.
The FDA has placed a partial clinical hold on the phase 1/2 VELA trial (NCT05252416) due to visual adverse effects (AEs) observed in select patients who received the investigational treatment BLU-222. Patients who are already enrolled in the trial will continue to receive BLU-222, but additional patients will not be allowed to enroll until the hold is lifted.1
The agent is currently under evaluation in the phase 1 dose-escalation portion of the VELA trial. To date, patients have been treated with BLU-222 at doses ranging from 50 mg twice daily to 800 mg twice daily, with evidence of clinical benefit and no discontinuations due to AEs.
Preliminary visual AEs included transient, reversible episodes of light sensitivity and blurred vision. Most events were low grade (grade 1), apart from 1 grade 3 event involving light sensitivity and blurred vision in a patient treated at 600 mg twice daily. All events resolved with dose interruption or reduction. Investigators observed no treatment-emergent abnormal findings, including uveitis, in patients who have undergone thorough ophthalmologic exams.
Blueprint Medicines, the developer of the drug, plans to present initial dose-escalation findings from the trial in the first half of 2023 in accordance with prior guidance.
“Patient safety is our first priority, and we are working closely with the FDA to investigate the reported visual adverse events as well as amend the VELA trial protocol to provide specific guidance to investigators on how to monitor for and manage these events should they occur,” Becker Hewes, MD, chief medical officer at Blueprint Medicines, said in a press release. “We have confidence in the benefit-risk profile of BLU-222 based on the activity and safety data we have seen to date in the dose escalation study. In addition, we recognize the urgency to treat patients with CDK2-vulnerable cancers, many of whom have seen their disease progress after exhausting all other options, and we aim to resume enrollment as expeditiously and responsibly as possible.”
CDK regulates cell growth and proliferation. Solid tumors may harbor cyclin E1 gene (CCNE1) amplification, while activated CDK4/6 complex increases expression of cyclin E1 and E2. Although CDK4/6 inhibitors are effective in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer, treatment resistance generally occurs.2
BLU-222 is an oral, investigational, potent, selective CDK2 inhibitor. Preclinically, BLU-222 has shown potent CDK2 inhibition and antitumor activity,3 and tumor regression in combination with carboplatin and paclitaxel.
The first-in-human, open-label VELA trial is studying the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of BLU-222 in adult patients with CCNE1-amplified tumors or ER-positive, HER2-negative breast cancer following progression on a CDK4/6 inhibitor.
The primary end points of phase 1 include the maximum tolerated dose and recommended phase 2 dose of the agent. Phase 2 will evaluate the overall response rate of the agent. The safety of BLU-222 as monotherapy and in combination with carboplatin, ribociclib (Kisqali), and/or fulvestrant (Faslodex) will be evaluated in both study portions.
The phase 1 dose-escalation portion will be divided into 3 cohorts:
Similarly, the phase 2 dose-expansion portion will be divided into 3 cohorts:
Investigators expect approximately 50 sites to enroll patients across North America, Europe, and Asia/Pacific.