Updated results of phase I study of senaparib (IMP4297) in Australian patients with advanced solid tumours

Abstract

BACKGROUND: PARP inhibitors are promising anti-cancer agents with proven clinical activity based on mechanism of synthetic lethality. Senaparib (previously known as IMP4297) is a novel highly potent and selective oral PARP1/2 inhibitor with strong antitumor activity in preclinical studies. This first in study investigated the tolerability, safety, PK, and preliminary antitumor activity of senaparib in Australia. METHODS: Adults with advanced, refractory solid tumours received senaparib orally QD, starting at 2mg. Dose escalation used a traditional 3+3 design and a modified Fibonacci sequence with 3-6 patients per cohort. DLT was evaluated in the first cycle. Dose expansion cohort enrolled patients with BRCA mutated (BRCA+) advanced solid tumors. RESULTS: As of Feb 25, 2020, 39 patients were enrolled in 10 dose levels (2 to 150mg). No DLTs were observed. The most frequent treatment emergent adverse events (TEAE) were headache (25.6%), fatigue (25.6%), constipation (17.9%), diarrhea (15.4%), nausea (12.8%), vomiting (12.8%) and anemia (10.3%). Treatment-related adverse events (TRAE) were observed in 8 (21%) patients starting from 40mg dose group. The most frequent TRAEs were nausea (8%), thrombocytopenia (5%) and fatigue (5%). An event of grade 4 thrombopenia in 80mg was the only serious TRAE. Four (10%) patients interrupted and 6 (15%) patients discontinued therapy due to AEs. The overall ORR and DCR was 15% and 85% respectively. In 8 evaluable ovarian cancer patients, ORR was 38% and DCR was 75%. A prolonged (> 20 months) PR response was observed in one BRCA+ ovarian cancer patient and a > 50% decrease of PSA for 11 months was observed in one BRCA- prostate cancer patients. The plasma exposure increased proportionally with doses ranging from 2mg to 80mg and became nonlinear ranging from 80mg to150mg cohorts. CONCLUSIONS: Senaparib demonstrated encouraging clinical benefit and a favorable tolerability profile in patients with advanced solid tumour. The 100 mg orally QD was selected as the RP2D in Australia based on safety, pharmacokinetics and clinical activity.