Enrollment complete in phase 2 study of PT-112 in mCRPC

The target enrollment has been met in a phase 2 study (NCT02266745) exploring PT-112, a small-molecule conjugate of pyrophosphate, in patients with late-stage metastatic castration-resistant prostate cancer (mCRPC), according to a news release from Promontory Therapeutics, the developer of the therapy.¹

Data from the phase 1 dose escalation portion of the trial were published in May 2022, showing safety and tolerability of PT-112 among heavily pre-treated patients with advanced solid tumors.

"This clinical trial is the largest study to date of PT-112 and will establish the optimal dose in line with the FDA's Project Optimus, as well as proof of concept in our late-line mCRPC patient population," said Promontory Therapeutics Chief Medical Officer Johan Baeck, MD, in the news release.¹ "Data from our earlier Phase 1/2 studies have shown that PT-112 is clinically safe and active, and promotes immunogenic cancer cell death induced by the inhibition of ribosomal biogenesis, which is a promising mechanism of action for late-stage patients with prostate cancer—an 'immune-cold' disease with no broadly approved and effective immunotherapy."

Overall, the phase 2, open-label, non-randomized, dose expansion study is composed of 2 cohorts: cohort D, exploring PT-112 in patients with mCRPC, and cohort A, exploring PT-112 in patients with thymoma and thymic carcinoma.The thymoma cohort is complete and no longer enrolling.The mCRPC cohort will be assessing the safety and efficacy of PT-112 in this patient population, in addition to the immune activation by PT-112 as a monotherapy, as determined by the propogation of new T cell populations and reductions in circulating tumor cells and ctDNA.

In total, cohort D of the study has enrolled 109 patients across clinical trial sites in the US and France. All patients included in the study have been treated with at least 3 life-prolonging therapies for mCRPC and exhibited radiographic evidence of disease progression at study entry. Those with bone-only metastatic disease were also eligible for inclusion.

Additional inclusion criteria for the study included an ECOG performance status of 0-1, adequate organ function, and stable disease if there is a history of treated or untreated brain metastases.²

The primary outcome for the study is to define the recommended dose level and schedule for pivotal studies. Secondary outcomes include disease control rate, objective response, and duration of response.

Data from the phase 1 dose escalation portion of the trial were published in eClinicalMedicine in May 2022, showing safety and tolerability of PT-112 among heavily pre-treated patients with advanced solid tumors, including mCRPC.³ In total, the study enrolled 66 patients treated across 11 dose levels (12 to 420 mg/m²). The median number of prior therapies was 4 (IQR, 2-6).

Overall, findings from the study showed that 17% of patients included in the efficacy analysis achieved a progression-free survival of 6 months or longer. Among the patients with mCRPC, 10 patients demonstrated radiographic and serum marker reductions, 4 of whom survived for 2 years or longer.

Regarding safety, 27% of patients experienced a grade 3 adverse event (AE), and no grade 4-5 AEs were observed. Treatment-related AEs included fatigue (35%), nausea (24%), and peripheral neuropathy (21%).

Based on these data, the investigators determined the recommended phase 2 dose to be 360 mg/m² for patients with advanced solid tumors.

According to the news release on the current phase 2 portion of the study,1 Promontory Therapeutics is planning to have a Type C meeting with the FDA in the second half of 2024, followed by an end-of-phase 2 meeting. The company also plans to further engage with the European regulatory authorities.

Robert Fallon, CEO of Promontory Therapeutics, concluded in the news release,¹ "Promontory is grateful to our clinical partners across the US and France, including Gustave Roussy Paris, for completing enrollment of this critical phase 2 study. We are confident in PT-112's potential as an effective treatment for patients with mCRPC who have progressed on androgen receptor directed therapy, chemotherapy or radioligand therapy and who lack any effective immunotherapy. We look forward to presenting topline safety, efficacy, and correlative data at relevant research and medical conferences later this year."

References

1. Promontory Therapeutics completes enrollment of phase 2 trial of PT-112 in late-line patients with metastatic castration-resistant prostate cancer. News release. Promontory Therapeutics. Published online and accessed March 8, 2024. https://www.prnewswire.com/news-releases/promontory-therapeutics-completes-enrollment-of-phase-2-trial-of-pt-112-in-late-line-patients-with-metastatic-castration-resistant-prostate-cancer-302083644.html

2. A study evaluating the safety, pharmacokinetics, and clinical effects of intravenously administered PT-112 injection in subjects with advanced solid tumors and subsequent dose expansion cohorts. ClinicalTrials.gov. Last updated August 14, 2023. Accessed March 8, 2024. https://clinicaltrials.gov/study/NCT02266745

3. Karp DD, Camidge DR, Infante JR, et al. Phase I study of PT-112, a novel pyrophosphate-platinum immunogenic cell death inducer, in advanced solid tumours. EClinicalMedicine. 2022:49:101430. doi:10.1016/j.eclinm.2022.101430