What question did this study set out to answer?

The primary objective is to determine the recommended phase 2 dose (RP2D) of CX-5461 and assess its safety.

May 29, 2026

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

Key Points

The primary objective is to determine the recommended phase 2 dose (RP2D) of CX-5461 and assess its safety.
Administered CX-5461 intravenously at 250 mg/m² and 325 mg/m² in a 28-day cycle
Included patients with advanced pancreatic, breast, or ovarian cancers with DNA repair deficiencies
Evaluated the Relative Dose Intensity (RDI) and safety in 54 treated patients.
The RP2D of CX-5461 was established at 250 mg/m² based on clinical data and RDI of 91% (Arm A) and 88% (Arm B)
Among response-evaluable patients, the overall disease control rate was 39% in Arm A and 38% in Arm B
Twelve patients experienced grade ≥3 treatment-related adverse events, highlighting issues like proteinuria and fatigue.

Abstract

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 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%)

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