Abstract
Safety, pharmacokinetics and anti-tumor activity of RP12146, a PARP1/2 inhibitor, in patients with locally advanced or metastatic solid tumors.
Author
Piotr Jan Wysocki
Jagiellonian University Hospital, Kraków, Poland
info_outline
Piotr Jan Wysocki, Maciej Tadeusz Lubaś, Mateusz Łobacz,, Ewa Kalinka-Warzocha, Piotr Tomczak, Michal Kwiatek, Iwona A. Lugowska, Martin Smakal, Dominik Chraniuk, Bohuslav Melichar, Beate Markiewicz-Bialek, Kasi V. Routhu, Prajak J. Barde, Ajit Nair
Full text
Authors
Piotr Jan Wysocki
Jagiellonian University Hospital, Kraków, Poland
info_outline
Piotr Jan Wysocki, Maciej Tadeusz Lubaś, Mateusz Łobacz,, Ewa Kalinka-Warzocha, Piotr Tomczak, Michal Kwiatek, Iwona A. Lugowska, Martin Smakal, Dominik Chraniuk, Bohuslav Melichar, Beate Markiewicz-Bialek, Kasi V. Routhu, Prajak J. Barde, Ajit Nair
Organizations
Jagiellonian University Hospital, Kraków, Poland, Kraków University Hospital, Krakow, Poland, Polish Mother's Memorial Hospital - Research Institute, Warszawa, Poland, Pratia Poznań Medical Center, Poznan, Poland, Maria Sklodowska-Curie National Research Institute and Oncology Centre (MSCI), Warsaw, Poland, Multiscan s.r.o, Prague, Poland, Clinical Trials Site Nasz Lekarz, Toruń, Poland, FNOL - Oncology Clinic, Olomouc, Poland, Centrum Medyczne Medyceusz, Lodz, Czech Republic, Rhizen Pharmaceuticals AG, Basel, Switzerland
Abstract Disclosures
Research Funding
Pharmaceutical/Biotech Company
Rhizen Pharmaceuticals AG
Background:
RP12146 is an orally bioavailable, potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and PARP 2. Pre-clinically, RP1246 demonstrated anti-proliferative activity in both
BRCA
and non-
BRCA
mutant cancer cell lines of different tumor types as well as in xenograft models. The first-in-human of RP12146 as a single agent is underway to determine the safety, pharmacokinetics and anti-tumor activity.
Methods:
The phase I/Ib study was designed as two-part study. Phase I was a dose escalation, 3+3 design, MTD determination study and would enroll pts who have tumors which are known to harbour DNA repair deficiencies. Phase Ib is dose expansion at the MTD/ optimal dose and would enroll thirty-six pts (12 pts each of advanced/metastatic ovarian cancer (OC), breast cancer (BC), and castration-resistant Prostate cancer (mCRPC) having a confirmed deleterious HRR mutation. RP12146 was administered orally in a 28-days cycles until disease progression. Safety were the primary outcome and the investigator-assessed ORR, CBR and PFS assessed using RECIST v1.1, are the secondary outcomes. Predictive biomarker analysis included inhibition of PARP enzyme as measured by gH2AX levels in PMBCs.
Results:
As of 31-Jan-2023, 9 pts in the dose escalation at 3 dose levels (100 mg QD, 200mg BID and 400 mg BID) and 13 pts (with 5 CHEK2, 4 BRCA2, 2 ATM, 1 CDK12, and 1 RAD51C mutations) in dose expansion have been enrolled. No DLTs were reported in dose escalation. The dose of 400mg BID was considered for dose expansion. Out of 22 pts enrolled, 13 pts had PC, 3 pts had OC, and 2 pts had BC. Most of the related AEs reported were mild in severity except one event of Grade 3 anaemia which resolved, and patient continues to be on therapy. None of the pts developed related SAEs or discontinued due to an AE. Eleven patients (50%) in the expansion group continue to be on RP12146 treatment. RP12146 exhibited rapid absorption achieving maximum concentrations in 1 hr, with an elimination half-life of ~ 4 hrs. Out of the 7 efficacy evaluable PC patients, 5pts showed stable disease and 2pts showed progressive disease. Out of 3 OC pts, 2 pts showed stable disease, and one pt had progressive disease. Among two BC pts, one showed stable disease and the other had progressive disease. Overall, out of 16 efficacy evaluable patients, 8 patients (50%) showed stable disease.
Conclusions:
RP12146 showed a differentiated safety profile so far with limited hematological toxicities reported as compared to the first-generation PARP inhibitors. Updated safety and efficacy data will be provided at the time of presentation. Clinical trial information: NCT05002868.
Clinical status
Clinical
1 clinical trial
20 organizations
1 drug
2 targets
Clinical trial
A Multi-center, Open-label, Phase I/Ib Study to Assess the Safety, Pharmacokinetics and Anti-tumor Activity of RP12146, a Poly (ADP-ribose) Polymerase (PARP) Inhibitor, in Patients With Locally Advanced or Metastatic Solid TumorsStatus: Completed, Estimated PCD: 2024-04-25
Organization
Jagiellonian University HospitalOrganization
Kraków, PolandOrganization
Kraków University HospitalOrganization
Krakow, PolandOrganization
Warszawa, PolandOrganization
Pratia Poznań Medical CenterOrganization
Poznan, PolandOrganization
Maria Sklodowska-Curie National Research Institute and Oncology Centre (MSCI), Warsaw, PolandOrganization
Warsaw, PolandOrganization
Multiscan s.r.oOrganization
Prague, PolandOrganization
Clinical Trials Site Nasz LekarzOrganization
Toruń, PolandOrganization
FNOL - Oncology ClinicOrganization
Olomouc, PolandOrganization
Centrum Medyczne MedyceuszOrganization
Lodz, Czech RepublicOrganization
Rhizen Pharmaceuticals AGOrganization
Basel, SwitzerlandDrug
RP12146Target
PARP 1Target
PARP 2