Phase Ib expansion and dose optimization study of CX-5461 in patients with solid tumours enriched for DNA-repair deficiencies.

3091 Background: G-quadruplexes (G4) are guanine-rich DNA/RNA structures that contribute to DNA damage and genomic instability. Pidnarulex (CX-5461) is a first-in-class G4 stabilizer that induces synthetic lethality in Homologous Recombination-deficient (HRD) cells. Previous phase 1 study showed safety and preliminary activity. Here we report dose optimization for recommended phase 2 dose (RP2D) of CX-5461 and confirm safety. Methods: CX-5461 was administered intravenously on Days 1 and 8 of a 28-day cycle at 2 dose levels (250 and 325 mg/m²) in patients (pts) with advanced pancreatic adenocarcinoma (PA), breast cancer (BC), or ovarian cancer (OC). The main cohort (Arms A: 250 mg/m² & B: 325 mg/m²) included pts with HRD or DNA damage response (DDR) alterations and has completed accrual. An exploratory cohort (Arms C: 250 mg/m² & D: 325 mg/m²) of OC pts with BRCA or other HRD genes enrolled simultaneously. Primary objective is to determine RP2D of CX-5461 using Relative Dose Intensity (RDI). Secondary objectives are safety, tolerability and efficacy. Results: 54 pts were treated and evaluable for toxicity (Arm A = 18, Arm B = 18, Arm C = 10, Arm D = 8). Patients’ characteristics and efficacy results are detailed in table 1. The median number of prior lines of treatment were 6 (1-14). The median number of CX-5461 cycles received were 2 (1-30) and weeks on treatment were 8 (4-120). Grade ≥3 Treatment-Related Adverse Events (TRAEs) occurred in 12 pts (22%), including proteinuria, thrombocytopenia, and fatigue; 6 (11%) were AEs of special interest: 1 (2%) palmar-plantar erythrodysesthesia, 4 (7%) photosensitivity, and 1 (2%) phototoxic drug eruption. Among 29 response-evaluable pts in main cohort, 1 had PR (3%) and 10 had SD (34%),median duration 16 weeks (wks) (8-84). In evaluable OC (n=29), 2 had PR (7%), 13 SD (44%), median duration 16 wks (8-84). OC pts with BRCA mutations (n=25) had 2 PR (8%) and 11 SD (44%); all had prior PARPi exposure. 3/ 5 non-BRCA HRD had SD (60%). Prolonged clinical benefit was observed in 4 pts with treatment durations of 14 (OC, gBRCA1), 17 (OC, gBRCA2), 21 (OC, sBRCA1) and 30 cycles (PA, gPALB2). RDI was 91% in Arm A and 88% in Arm B. RDI and clinical data support 250 mg/m² as the RP2D. Conclusions: CX-5461 was tolerable and showed evidence of durable disease control in heavily pretreated pts, enriched for HRD/DDR alterations and post exposure to PARPi. The 250 mg/m² dose is established as the RP2D based on clinical data and RDI. Correlative studies are ongoing. Clinical trial information: NCT04890613 . Arm A (N=18) Arm B (N=18) Arm C (N=10) Arm D (N=8) Tumor Type BC 7 (39%) 2 (11%) - - OC 5 (28%) 9 (50%) 10 (100%) 8 (100%) PC 6 (33%) 7 (39%) - - Molecular alterations gBRCA1/2 12 (67%) 9 (50%) 3 (30%) 3 (38%) sBRCA1 0 (0%) 1 (6%) 6 (60%) 3 (38%) Other 6 (34%) 8 (44%) 1 (10%) 2 (25%) Efficacy (evaluable pts only) PR 1/13 (8%) 0 (0%) 0 (0%) 1/7 (14%) SD 4/13 (31%) 6/16 (38%) 5/9 (56%) 3/7 (43%) Disease control rate 5/13 (39%) 6/16 (38%) 5/9 (56%) 4/7 (57%)