On June 8, 2022 Promontory Therapeutics Inc., a clinical stage pharmaceutical company focused on oncology therapeutics, reported the peer-reviewed publication of its first-in-human Phase 1 study of lead therapeutic candidate, PT-112 in the July 2022 issue of eClinicalMedicine, part of The Lancet’s Discovery Science (Press release, Promontory Therapeutics, JUN 8, 2022, View Source [SID1234615787]). The study, entitled "Phase I Study of PT-112, a novel Pyrophosphate-Platinum Immunogenic Cell Death Inducer, in Advanced Solid Tumours," showed that PT-112 was safe and well-tolerated in heavily pre-treated patients with advanced cancers, and demonstrated prolonged responses against thymoma and lung cancers, along with radiographic and serum marker improvement in prostate cancer.
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PT-112 has been validated as an immunogenic cell death inducer in pre-clinical models, and is under active Phase 2 clinical development. In the first-in-human dose escalation study PT-112 was given as monotherapy to eligible patients with progressing, advanced solid tumors via intravenous infusion on days 1, 8, 15 of a 28-day cycle in a 3+3 dose-escalation trial. The primary endpoint was to assess safety and pharmacokinetics, and to identify a recommended Phase 2 dose. The secondary objective was exploratory assessment of anti-tumor activity.
Study findings from 66 heavily pre-treated patients treated across 11 dose levels of PT-112 (12-420 mg/m2) include:
The recommended phase 2 dose was determined to be 360 mg/m2
The most common treatment-related adverse events included fatigue (35%), nausea (24%), and peripheral neuropathy (21%)
Treatment-related Grade 3 adverse events were experienced by 27% of patients, with no grade 4-5 events observed.
Durable, confirmed RECIST partial responses were induced in non-small cell lung cancer, small cell lung cancer, and thymoma, some of which persisted for prolonged periods even after treatment discontinuation. Two additional unconfirmed RECIST responses were observed.
Radiographic and serum marker reductions were observed among ten patients with metastatic castration resistant prostate cancer, four of whom survived two years or longer
"We are pleased to publish the results of our first Phase 1 study of PT-112 in The Lancet’s eClinicalMedicine," said Matthew Price, Executive VP & COO of Promontory Therapeutics. "The evidence supports our belief that PT-112’s immunogenic cell death induction makes it a promising future treatment option in several possible cancer indications, and that its foundational safety allows us to consider numerous ways to deploy it. The experience we gained in this study underlies the direction taken by the company in our current Phase 2 studies of PT-112."
The study is registered under NCT02266745 and the full dose-escalation results are available in eClinicalMedicine and online here.
About PT-112
PT-112 is the first small-molecule conjugate of pyrophosphate in oncology, and possesses a unique pleiotropic mechanism of action that promotes immunogenic cell death (ICD) through the release of damage associated molecular patterns (DAMPs) that bind to dendritic cells and lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a highly potent inducer of this immunological form of cancer cell death. Further, PT-112 harbors a property known as osteotropism, or the propensity of the drug to reach its highest concentrations in certain areas of the bone, making it a candidate for treatment of patients with cancers that originate in, or metastasize to, the bone. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) Annual Congress. The combination Phase 1b dose escalation study of PT-112 with PD-L1 checkpoint inhibitor avelumab in solid tumors was reported in an oral presentation at the ESMO (Free ESMO Whitepaper) 2020 Virtual Congress. A Phase 1 study in patients with relapsed or refractory multiple myeloma was presented at ASH (Free ASH Whitepaper) 2020. Monotherapy Phase 2 development is ongoing in mCRPC, and in a Phase 2 proof of concept study in thymic epithelial tumors under the company’s formal collaboration with the National Cancer Institute (NCI).