FDA clears IND for 225Ac-J591 in advanced prostate cancer

The FDA has granted clearance to an investigational new drug (IND) application for 225Ac-J591 (CONV01-α), a prostate-specific membrane antigen-targeted monoclonal antibody under investigation for the treatment of patients with advanced prostate cancer, announced Convergent Therapeutics, the developer of the therapy, in a news release.¹

"CONV01-α's design increases delivery of tumor-killing radiation to malignant cells while greatly reducing both off-tumor effects and the amount of radiation delivered per dose, thereby improving both treatment efficacy and safety," says Neil Bander, MD.

"Receiving clearance of our IND is a significant milestone for Convergent Therapeutics," said Convergent's co-founder and CEO, Philip Kantoff, MD, in the news release.¹ "While we have already treated well over 100 prostate cancer patients in the context of investigator INDs, this new IND will allow us to rapidly advance CONV01-α into phase 3 studies and expand the scope of clinical development of CONV01-α as a monotherapy and in combination with other cancer therapies."

Convergent plans to conduct phase 2 clinical trials of the therapy in 2024, with a registrational program set to begin in 2025.

In a previous phase 1 multi-dose, dose escalation study (NCT04506567) presented at the 2023 American Association of Cancer Research Annual Meeting in Orlando, Florida,² 225Ac-J591 demonstrated safety and preliminary efficacy across all dose levels in predominantly 177Lu-naïve patients with metastatic castration-resistant prostate cancer (mCRPC).

Specifically, among the patients who were evaluable for a prostate-specific antigen (PSA) change (n = 22), 21 patients (95%) in the study experienced a PSA decline. Of these, 14 (67%) patients experienced a decline of at least 50%, and 6 (27%) experienced a decline of at least 90%.

Circulating tumor cell (CTC) samples were collected from 13 of 21 patients at baseline and 12 weeks. At baseline, 5 patients had unfavorable (≥ 5/7.5 mL) CTC counts. At 12 weeks, 10 patients remained favorable or converted from unfavorable to favorable, 6 patients experienced at least a 50% decline in CTC count, and 5 patients converted from detectable to undetectable levels of CTC.

Regarding safety, treatment with 225Ac-J591 was well-tolerated across all dose levels. No dose-limiting toxicities (DLTs) were observed in cohorts 1 or 2. In cohort 3, 2 of 6 patients experienced a DLT, one being grade 2 and the other grade 3. The most common low-grade non-hematologic treatment-emergent adverse events were fatigue (95%), xerostomia (69%), and nausea (57%).

Neil Bander, MD, Convergent's co-founder and CSO, added in the news release,¹ "Importantly, patients also showed minimal [adverse] effects in phase 1/2 trials. CONV01-α's ideal biodistribution delivers potent alpha particles while avoiding immediate and significant salivary gland toxicity as well as the potential delayed renal toxicity.CONV01-α's design increases delivery of tumor-killing radiation to malignant cells while greatly reducing both off-tumor effects and the amount of radiation delivered per dose, thereby improving both treatment efficacy and safety."

In total, the study included 24 patients with predominantly 177Lu-naïve mCRPC. The median age of patients was 73.5 years. To be included in the study, patients had to have adequate organ function, an ECOG performance status of 0 to 2, and progressive mCRPC after treatment with a potent AR pathway inhibitor and chemotherapy.

The primary objective for the study was to assess DLTs and determine a recommended phase 2 dose. Secondary objectives were exploratory efficacy measures such as PSA decline, radiographic response rate, biochemical/radiographic progression-free survival, overall survival, change in CTCs, and patient reported outcomes, as well as safety and correlatives (plasma and tissue genomics, PSMA imaging).

References

1. Convergent Therapeutics announces FDA clearance of IND application for CONV01-α, a best-in-class radioantibody targeting prostate-specific membrane antigen. News release. Convergent Therapeutics. Published online April 2, 2024. Accessed April 3, 2024. https://www.prnewswire.com/news-releases/convergent-therapeutics-announces-fda-clearance-of-ind-application-for-conv01--a-best-in-class-radioantibody-targeting-prostate-specific-membrane-antigen-302106271.html

2. Nauseef JT, Sun M, Thomas C, et al. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer. Presented at the 2023 American Association for Cancer Research Annual Meeting. Orlando, Florida. April 14-19, 2023. Abstract CT014