FDA Grants Fast Track Designation to BNT324/DB-1311 in mCRPC

The FDA has granted fast track designation to the antibody-drug conjugate (ADC) BNT324/DB-1311 as a potential treatment option for patients with unresectable advanced or metastatic castration-resistant prostate cancer (mCRPC) who have progressed on or after standard systemic regimens.¹

The next-generation ADC is designed to target the transmembrane glycoprotein B7-H3, which is an immune checkpoint protein overexpressed in a variety of solid tumors and is associated with disease progression and poor prognosis. An ongoing phase 1/2 trial (NCT05914116) is evaluating BNT324/DB-1311 in patients with advanced solid tumors.

“The FDA’s decision is a recognition of the potential of our B7-H3–targeting ADC candidate for the treatment of [patients with] advanced CRPC. [Although] patients with metastatic prostate cancer initially respond to hormone therapy, most patients progress after 18 to 24 months and develop CRPC, an advanced form of prostate cancer, leading to a poor prognosis for these patients. The 5-year survival rate for patients with mCRPC is only around 36%,” Özlem Türeci, MD, chief medical officer and co-founder of BioNTech, stated in a news release. “We are committed to further advancing BNT324/DB-1311 with our partner DualityBio and believe that a targeted ADC immunotherapy approach has the potential to improve outcomes for patients at advanced stages of the disease.”

Along with targeting B7-H3, BNT324/DB-1311 features a topoisomerase I inhibitor payload. Preclinical studies showed that the ADC produced antitumor activity in a variety of solid tumor models, and preliminary data from the phase 1/2 trial have shown efficacy with manageable toxicity.

The first-in-human, multicenter, open-label dose-escalation and -expansion study is enrolling patients at least 18 years of age with histologically or cytologically confirmed, unresectable advanced or metastatic solid tumors that have relapsed or progressed on or after standard systemic treatments; are intolerable to standard treatment; or have no standard treatment available.²

Key inclusion criteria for all patients include at least 1 measurable lesion per RECIST v1.1 criteria; a life expectancy of at least 3 months; an ECOG performance status of 0 or 1; and a left ventricular ejection fraction of at least 50%.

Patients with CRPC being enrolled into cohort 4 of phase 2a are required to have pathologically documented metastatic adenocarcinoma of the prostate, where progressive mCRPC is defined as castrate levels of serum testosterone less than 50 ng/dL and progressive disease per Prostate Cancer Working Group 3 criteria. Prior docetaxel, either before or after androgen receptor–targeted therapy, is required, and docetaxel rechallenge is also permitted. Prior novel hormone therapy is also needed for enrollment.

Prior treatment with B7-H3–targeted therapy will exclude patients from participation, and those who received prior treatment with an ADC containing a topoisomerase I inhibitor will not be included. Other key exclusion criteria include a medical history of symptomatic congestive heart failure or serious cardiac arrhythmia requiring treatment; a medical history of myocardial infarction or unstable angina within 6 months before enrollment; or an average QTcF prolongation to greater than 470 ms.

During dose escalation, BNT324/DB-1311 is being administered at 1 of 5 dose levels on day 1 of each 3-week cycle. Dose expansion will feature tumor-specific cohorts, including mCRPC, small cell lung cancer, non–small cell lung cancer, esophageal squamous cell carcinoma, melanoma, and other tumors.

In phase 1, the primary end points are identifying the proportion of patients with dose-limiting toxicities; identifying the proportion of patients with treatment-emergent adverse effects (TEAEs) and serious AEs; and determining the maximum tolerated dose and recommended phase 2 dose. Phase 2’s primary end points consist of the rate of TEAEs and serious AEs; and objective response rate per RECIST v1.1 criteria. Pharmacokinetics are a secondary end point.

References

1. BioNTech and DualityBio receive FDA fast track designation for antibody-drug conjugate candidate BNT324/DB-1311 in prostate cancer. News release. BioNTech. June 24, 2024. Accessed July 8, 2024. https://investors.biontech.de/news-releases/news-release-details/biontech-and-dualitybio-receive-fda-fast-track-designation
2. A study of DB-1311 in advanced/​metastatic solid tumors. ClinicalTrials.gov. Updated September 13, 2023. Accessed July 8, 2024. https://clinicaltrials.gov/study/NCT05914116