Abstract 2266
Background
PT-112, a novel platinum pyrophosphate agent under development in solid tumors and hematological malignancies, is a potent inducer of damage associated molecular patterns (DAMPs) characteristic of ICD. It also affects G1/S cell cycle transition independent of DNA damage or repair pathways. Here we present a clinical update and analysis of single-agent activity in heavily pre-treated pts.
Methods
We treated 62 pts in an all-comer 3x3 Phase I dose escalation study. PT-112 was given IV for 1hr on days 1,8,15 (28d cycle) at dose levels 12 – 420 mg/m2.
Results
All dose levels completed were deemed safe, with dose-linear pharmacokinetics, and MTD was not reached. Fatigue was the most common side effect. No significant acute neurotoxicity was reported in 533 infusions. Grade 1-2 peripheral neuropathy was seen in 8/62 pts (13%), and Grade 3 in 2 pts (3%) with cumulative doses of 3.1 and 4.3 g/m2. Neutropenia (6 pts) and thrombocytopenia (8 pts) were limited with no infections or bleeding. Median prior lines of therapy = 5. Tumor control, metabolic and biomarker responses were observed at doses at / above 125 mg/m2, with PSA reduction in 4 / 8 prostate pts. A non small cell lung cancer pt previously unresponsive to anti-PD-1 immunotherapy achieved a 6+ month RECIST PR at 250 mg/m2 and complete PET response in liver / bone sites. A small cell lung pt who rapidly progressed on CTLA4 + PD-1 immunotherapy achieved PR at 360mg/m2, progression free at 7.5 months. Marked tumor reduction at 360 mg/m2 is ongoing after 6 mos. in a malignant thymoma pt with bulky thoracic disease. Time to response was 5-8 wks in all 3 pts. PFS at 6 mos. was reached in 8 / 46 evaluable pts at / above 125 mg/m2 (17.4%). The ORR in 28 evaluable pts at / above 250mg/m2 was 10.7%. At the provisional RP2D, now under confirmation (360 mg/m2), 2 of 3 pts experienced durable tumor shrinkage.
Conclusions
PT-112 is a novel ICD inducing agent that is safe and well tolerated. Single-agent activity occurred in heavily pre-treated pts. Neither acute neurotoxicity nor kidney damage occurred. Fatigue was the most common side effect. Beneficial activity was observed at a range of doses, indicative of a broad therapeutic index, lack of cross-resistance with standard agents and feasibility for combinations.
Clinical trial identification
NCT: 2266745 IND: 118577.
Legal entity responsible for the study
Phosplatin Therapeutics LLC.
Funding
Phosplatin Therapeutics LLC.
Editorial Acknowledgement
Disclosure
D.D. Karp: Member of the scientific advisory board: Phosplatin Therapeutics. T.D. Ames, J.M. Jimeno: Employee and part owner: Phosplatin Therapeutics. All other authors have declared no conflicts of interest.
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