First-in-human dose-finding study of venadaparib (IDX-1197), a potent and selective PARP inhibitor, in patients with advanced solid tumors.

Abstract

3107 Background: Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for ovary, breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or homologous recombinant repair mutation (g/sHRRmt). In this phase 1 dose finding study of venadaparib, we determined the maximum tolerated dose for venadaparib monotherapy and explored the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of venadaparib in patients with advanced solid tumor which progressed after an attempt of standard-of-care therapy and for which effective therapy does not exist. Methods: Subjects who satisfied all of the inclusion/exclusion criteria and provided written informed consent were enrolled in this study. The investigational product was administered orally once daily continuously in a 3 weekly cycle. Enrolled subjects were assessed for safety and evaluated on tumor response using RECIST 1.1. The study was carried out in a conventional 3+3 design, starting from 2 mg up to 240 mg. Dose limiting toxicities (DLTs) and pharmacokinetics were assessed during the first cycle. Results: As of 08 Feb 2021, enrollment is completed with 32 patients enrolled. Most common tumor types enrolled are breast cancer (16 patients) and ovarian cancer (11 patients). Other tumor types include cancers of endometrium, fallopian tube, uterus and prostate. No DLTs were observed up to the maximum tested dose of 240 mg. Frequently observed adverse drug reactions were as follows – Anemia (56%), nausea (38%) and neutropenia (25%). Overall objective response rate (ORR) was 16% and clinical benefit rate (CBR) was 47%. Partial response was observed starting from 40 mg and clinical benefit was observed from the lowest dose of 2 mg. From optional tumor tissue samples, venadaparib exhibited ≥ 90% PAR inhibitory effect in pharmacodynamic analysis from 10 mg. For patients with known germline or somatic BRCA status either from local lab results or examined at a central lab retrospectively, ORR and CBR was 22% and 44% respectively for BRCAm(+) (9) patients. Interestingly, clinical efficacy was observed in BRCAm(-) (18) patients also, with ORR and CBR of 17% and 50% respectively. Conclusions: Safety and tolerability of the venadaparib monotherapy was confirmed with preliminary efficacy signals observed, even in BRCAm(-) patients. Clinical benefit was observed from the lowest tested dose, suggesting the potential to combine with other chemotherapeutic agents. Further studies to explore efficacy and safety of venadaparib in other tumor types and combinations, as well as to explore adequate biomarkers are warranted. Clinical trial information: NCT03317743.