FDA Lifts Partial Hold on Phase 1/2 VELA Trial of BLU-222 for Solid Tumors

The FDA ​has lifted the partial clinical hold previously placed on the phase 1/2 VELA trial (NCT05252416) evaluating BLU-222, a selective inhibitor of CDK2, as a treatment for patients with solid tumors.¹

Previously in February 2023, Blueprint Medicines Corporation announced the FDA placed a partial clinical hold on the VELA trial because visual adverse events (AEs), consisting of transient, reversible episodes of light sensitivity and blurred vision were reported in some patients. Patients who were already enrolled in the trial continued to receive BLU-222 but additional patients were not allowed to enroll.

Although there was 1 grade 3 AE involving light sensitivity and blurred vision observed in a patient who was treated with BLU-222 600 mg twice daily, all other AEs were grade 1.² Each of the observed AEs resolved with dose interruption or reduction. Further, no treatment-emergent abnormal findings have been reported in patients given detailed ophthalmologic examinations.

As of March 28, 2023, the partial clinical hold is lifted, and Blueprint Medicines has started working with trial sites to reinitiate patient enrollment in the VELA trial.¹

"With a focus on patient safety, we have worked diligently with the FDA over the last several weeks to resolve the partial clinical hold by updating adverse event monitoring and management procedures. We will now collaborate closely with investigators to resume patient enrollment," said Becker Hewes, MD, chief medical officer at Blueprint Medicines, in a press release.

The phase 1/2 VELA trial is an international, open-label, first-in-human study in which investigators are evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and anticancer activity of BLU-222.³

In the dose-escalation portion of the study, patients with advanced/relapsed tumors were treated with BLU-222 at doses ranging from 50 to 800 mg twice daily alone or in combination with other agents including fulvestrant (Faslodex), carboplatin, or ribociclib (Kisqali).

The phase 1 dose-escalation portion will be divided into 3 cohorts: part 1A with patients who have any advanced solid tumor and progression on standard of care (SOC) will be administered BLU-222 monotherapy, part 1C in which patients with gastric or endometrial cancer who have received ≥2 prior therapies (≥1 platinum-based therapy) or with platinum-resistant/refractory ovarian cancer will receive BLU-222 and carboplatin, and part 1D in which patients with estrogen receptor (ER)-positive, HER2-negative breast cancer with progression on a CDK4/6 inhibitor will receive BLU-222, ribociclib, and fulvestrant.

In a similar fashion, the phase 2 dose-expansion portion will be divided into 3 cohorts. Part 2A will include patients with CCNE1-amplified tumors, including endometrial cancer (≥2 prior therapies), platinum-resistant/refractory ovarian cancer, or other advanced solid tumors who have progressed on SOC. Patients in this part will will receive BLU-222, while in part 2B and 2D, which will include patients with CDK4/6 inhibitor–resistant ER-positive, HER2-negative breast cancer, BLU-222 and fulvestrant with/without ribociclib will be administered to patients. Part 2C which will consist of patients with CCNE1-amplified platinum-resistant/refractory ovarian cancer who will be administered BLU-222 and carboplatin.

For the phase 1 portion of the study, the primary end points will determine the maximum tolerated dose and recommended phase 2 dose of BLU-222, and assess the rate and severity of AEs. Secondary end points undergoing evaluation include overall response rate, treatment-induced modulation of cyclin E/CDK2 pathway biomarkers, duration of response, disease control rate, PK, PD, clinical benefit rate, progression-free survival, and overall survival.

Patients aged 18 years and older with advanced solid tumors that have progressed beyond standard of care, patients with estrogen receptor-positive/ HER2-negative breast cancer ER-positive that has progressed following treatment with a CDK4/6 inhibitor, endometrial and gastric cancer that has progressed after at least 2 prior therapies, including 1 prior platinum therapy, or platinum refractory or platinum resistant ovarian cancer CCNE1-amplified tumors that have progressed beyond treatment with the standard of care.

Approximately 50 sites are expected to enroll patients across North America, Europe, and Asia/Pacific.

"We are confident in the potential of BLU-222 to improve outcomes in patients with cancers vulnerable to CDK2 inhibition, and we look forward to presenting initial dose escalation data from the VELA trial in the second quarter of 2023," added Hewes, in a press release.¹

REFERENCES

1. Blueprint Medicines announces lift of partial clinical hold on phase 1/2 VELA trial of BLU-222. News release. Blueprint Medicines Corporation. March 28, 2023. Accessed March 29, 2023. https://bit.ly/3M0E9HA

2. Blueprint medicines announces partial clinical hold for phase 1/2 VELA trial of BLU-222. News release. Blueprint Medicines Corporation. February 10, 2023. Accessed March 29, 2023. https://prn.to/3DXbpdM

3. (VELA) study of BLU-222 in advanced solid tumors. ClinicalTrials.gov. Updated January 10, 2023. Accessed March 29, 2023. https://clinicaltrials.gov/ct2/show/NCT05252416