FDA Pauses Trial Investigating BLU-222 in Advanced Solid Tumors

The FDA has placed a partial clinical hold on patient enrollment in the phase 1/2 VELA trial (NCT05252416) evaluating BLU-222 in advanced solid tumors following reports of visual adverse effects, according to a press release from Blueprint Medicines.¹

Previous data on the anti-cancer activity of BLU-222 in ovarian cancer models were presented at the 2022 American Association for Cancer Research Annual Meeting (AACR).

The reported AEs included transient, reversible instances of light sensitivity and blurred vision. All AEs were grade 1 except for a single incidence of grade 3 light sensitivity in a patient receiving 600 mg of BLU-222 twice per day, which investigators resolved with dose interruption or reduction. There were no treatment-emergent AEs including uveitis in patients who underwent detailed ophthalmologic examinations.

“Patient safety is our first priority, and we are working closely with the FDA to investigate the reported visual [AEs] 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 the press release.

Investigators previously shared findings regarding BLU-222’s anti-cancer activity in CCNE1-amplified ovarian cancer models at the 2022 American Association for Cancer Research Annual Meeting (AACR).² According to the investigators, the data provided rationale for the development of single-agent BLU-222 and in combination with standard-of-care agents in CCNE1-amplified tumors.

In the open-label, first-in-human, phase 1/2 VELA trial, investigators are evaluating the safety, tolerability, pharmacokinetics, and anti-cancer activity of BLU-222, a selective inhibitor of CDK2. In the phase 1 dose escalation portion of the trial, patients received BLU-222 received at doses ranging from 50 mg to 800 mg twice per day alone or in combination with other agents including fulvestrant (Faslodex), carboplatin, or ribociclib (Kisqali).

Primary end points include identifying the maximum tolerated dose and recommended phase 2 dose in the first phase and the overall response rate and AEs in the second phase. Secondary end points include progression-free survival, overall survival, clinical benefit rate, disease control rate, and duration of response.

Patients 18 years and older with advanced solid tumors who have progressed beyond stand-of-care therapy or estrogen receptor–positive, HER2-negative breast cancer that has progressed after treatment with a CDK4/6 inhibitor were eligible for enrollment. Additional inclusion criteria included having endometrial and gastric cancer that has progressed after at least 2 prior therapies or refractory/resistant ovarian cancer that has progressed beyond standard-of-care treatment.

Patients who had visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis were not eligible for enrollment. Patients were also unsuitable for enrollment if they had central nervous system metastases, intracranial hemorrhage or bleeding diatheses, unresolved toxicities form any prior therapy, grade III or IV cardiovascular disease, a history of another primary malignancy other than completely resected carcinomas in situ, or active infection.

Patients were also unable to enroll on the trial if they had planned major surgical procedures within 14 days prior to beginning study treatment, were unwilling to comply with scheduled visit, or pregnant.

References

1. Blueprint Medicines announces partial clinical hold for phase 1/2 VELA trial of BLU-222. News release. February 10, 2023. Accessed February 14, 2023. bit.ly/3jWT3D0
2. Brown V, Ramsden P, House N, et al. BLU-222, an investigational, potent, and selective CDK2 inhibitor, demonstrated robust antitumor activity in CCNE1-amplified ovarian cancer models. Presented at AACR Annual Meeting 2022, April 8-13, 2022. Poster Number 2306.