Abstract 483P
Background
RP12146 is an orally bioavailable, potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and PARP 2 with an IC50 of 0.62nM and 0.44nM respectively and with PARP trapping activity. A phase I/Ib study of RP12146 as a single agent is underway to determine the safety, pharmacokinetics, and anti-tumor activity.
Methods
The phase I/Ib study is designed as a two-part study. Part 1 is a dose-escalation, 3+3 design, MTD determination study and will enroll pts who have tumors that are known to harbour DNA repair deficiencies. Part 2 is dose expansion at the MTD (or optimal dose) and will enroll ovarian, breast cancer, and prostate cancer pts with a confirmed deleterious HRR mutation. Thirty-six pts (12 pts in each expansion group) are planned to be enrolled. Safety is the primary outcome and ORR, CBR, and PFS assessed using RECIST v1.1, would be the secondary outcomes. Biomarker analysis includes the measurement of gammaH2AX in PMBCs.
Results
RP12146 exhibited anti-tumor potential with TGI of 28% as a single agent and 95.19% with gemcitabine combination in the OVCAR-3 xenograft model. In the phase I study, as on 27 Apr 2022, 9 pts of median age 68 years and with 3 median prior therapies have been enrolled at 3 dose levels (100 mg QD, 200 and 400 mg BID) in the dose escalation part. Tumor types included biliary tract, colorectal, breast, prostate, and ovarian cancers. No related TEAEs were reported except for a mild event of neuropathy. None of the patients reported related Grade 3/ 4 AEs. No DLT’s have been reported thus far. None of the pts developed related SAEs or discontinued due to an AE. An ovarian cancer patient who had CDK12 mutation has shown stable disease at C3D1. Five out of 9 patients (55%) are ongoing in the study. RP12146 exhibited rapid absorption achieving maximum concentrations in about 1 hr, with an elimination half-life of ∼ 5 hrs.
Conclusions
RP12146 inhibited tumor growth as a single agent and in combination with gemcitabine in xenograft model of ovarian cancer. In the on-going clinical study, RP12146 has been well-tolerated in the first two cohorts and further evaluation at higher doses in dose escalation is underway. Updated safety and preliminary efficacy data will be provided at the time of presentation.
Clinical trial identification
NCT05002868.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.