ARX517 demonstrates continued safety and efficacy in mCRPC

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The investigators observed no dose limiting toxicities or serious adverse events among all patients who received an ARX517 dose of 3.4 mg/kg, the highest dose tested in the trial.

Updated findings from the phase 1/2 APEX-01 trial (NCT04662580) show continued safety and anti-tumor activity with the prostate-specific membrane antigen (PSMA)-targeting antibody drug conjugate ARX517 in patients with metastatic castration-resistant prostate cancer (mCRPC), announced Ambrx, the developer of the therapy, in a news release.1

APEX-01 is a first-in-human, phase 1/2, multicenter, dose escalation and dose expansion study evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517 in patients with mCRPC.

APEX-01 is a first-in-human, phase 1/2, multicenter, dose escalation and dose expansion study evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517 in patients with mCRPC.

Reported results follow completion of the 21-day dose limiting toxicity (DLT) period for cohort 9 of the dose escalation study. Patients in cohort 9 received an ARX517 dose of 3.4 mg/kg, the highest dose tested in the trial at the time of data report.

Overall, the investigators observed no DLTs or serious adverse events (SAEs) among the 3 patients included in the cohort. Among those patients, 2 experienced a rapid prostate-specific antigen (PSA) reduction of 91% and 33% at first PSA assessment, conducted at 3 weeks post-treatment following 1 dose of ARX517. The third patient did not experience a PSA decrease due to having non-PSA secreting mCRPC.

As a result of these findings, the safety monitoring committee voted to escalate the dosage to 4.5 mg/kg for cohort 10 as well as to expand the patients in cohort 9 receiving the 3.4 mg/kg dosage. Additional expansion cohorts in the study include cohort 4 (1.4 mg/kg, n = 23), cohort 6 (2.0 mg/kg, n = 23), and cohort 8 (2.88 mg/kg, n = 20), all of which are now fully enrolled.

A recommended phase 2 dose is expected by early 2024.

“We continue to observe no DLTs or SAEs at the highest ARX517 dose tested. We believe this is a direct result of the stability of conjugation supported by PK data presented at [the European Society for Medical Oncology Annual Congress] last month. While we are opportunely positioned to explore higher doses, we have already observed significant PSA50 decline and long duration on treatment at 2.0 mg/kg,” said Sandra Aung, PhD, Chief Clinical Officer of Ambrx, in the news release.1 “The high interest in our PSMA-targeting ADC and pace of enrollment in the APEX-01 study has been outstanding, and based on this we are anticipating to reach a recommended phase 2 dose by early next year.”

Additional data from APEX-01

APEX-01 is a first-in-human, phase 1/2, multicenter, dose escalation and dose expansion study evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517 in patients with mCRPC.2

Findings on earlier cohorts from the trial were presented at the 2023 ESMO Congress in Madrid, Spain.3 Regarding higher doses, among the 23 patients included in cohorts 6 to 8 (2.0 mg/kg – 2.88 mg/kg) at the time of data report, 61% experienced a PSA reduction of at least 30% (PSA30), 52% experienced a PSA reduction of at least 50% (PSA50), and 26% experienced a PSA reduction of at least 90% (PSA90). In addition, 81% of evaluable patients (n = 21) experienced at least a 50% reduction in circulating tumor DNA (ctDNA).

In cohorts 4 to 8 (1.4 mg/kg – 2.88 mg/kg), target lesion reduction by RECIST v1.1 criteria was observed in 5 of 9 evaluable patients. Among those, 2 patients achieved confirmed responses.

No DLTs or treatment-related SAEs were reported at any dose up to 2.88 mg/kg. Additionally, no grade 4 or 5 treatment-related AEs were observed.

Overall, patients were included in the APEX-01 study if their tumors had progressed following at least 2 FDA approved treatments for prostate cancer, including at least 1 second-generation androgen receptor pathway inhibitor. Participants also had to have either PSA progression defined by a minimum of 2 rising PSA values or radiographic progression by RECIST v 1.1 or disease progression by the presence of new bone lesions.

In APEX-01, ARX517 is delivered via intravenous infusion every 3 or 4 weeks. In phase 2 of the study, patients will be randomly assigned to receive the recommended phase 2 dose of ARX517, expected to be determined early next year, or to the investigator’s choice of treatment.

References

1. Ambrx provides update on APEX-01, an on-going phase 1/2 dose escalation study evaluating ARX517, a proprietary PSMA-targeting ADC, in metastatic castration-resistant prostate cancer. News release. November 28, 2023. Accessed November 29, 2023. https://www.globenewswire.com/news-release/2023/11/28/2786934/0/en/Ambrx-Provides-Update-On-APEX-01-an-On-Going-Phase-1-2-Dose-Escalation-Study-Evaluating-ARX517-a-Proprietary-PSMA-Targeting-ADC-in-Metastatic-Castration-Resistant-Prostate-Cancer.html

2. ARX517 as monotherapy and in combination regimens in subjects with metastatic castration-resistant prostate cancer (ARX517). ClinicalTrials.gov. Last updated November 22, 2023. Accessed November 29, 2023. https://clinicaltrials.gov/study/NCT04662580

3. Shen J, Pachynski R, Nordquist LT, et al. APEX-01: First-in-human phase I/II study of ARX517 an anti- prostate-specific membrane antigen (PSMA) antibody-drug conjugate (ADC) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2023;34(suppl 2):S974-S975. doi:10.1016/j.annonc.2023.09.2752

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