Abstract Background: Pidnarulex (CX-5461) is a first-in-class G-quadruplex-stabilizing agent that induces replication-dependent DNA damage, inhibits RNA polymerase I and topoisomerase II (Top2). Pidnarulex has demonstrated safety and preliminary efficacy in a prior phase I study (NCT02719977), with partial responses in 4 of 32 patients and stable disease in 11 patients, including 4 with responses ≥6 months. The National Cancer Institute’s (NCI) preclinical in vitro studies in homologous recombination (HR) -proficient (, OVCAR3) and HR-deficient (HRD) (A2780, IGROV1) cell lines show that pidnarulex (1 µM or 3 µM in vitro;) significantly increased percentage of RPA32, pSer33-RPA32, 53BP1 and Rad51 nuclear foci 24 hours post-treatment, indicating DNA damage response activation. G4 stabilization (BG4 antibody) was observed in all 3 cell lines at both concentrations. This pilot study (NCT06606990) aims to determine whether pidnarulex induces a Rad51 response, defined as the percentage of cells with ≥5 Rad51 positive nuclear foci in post-treatment tumor biopsies. Methods: This single-center pilot study aims to enroll 40 adult patients (age ≥18) distributed equally between 2 cohorts: with or without HRD-associated alterations (deleterious BRCA1/2; Fanconi anemia gene mutations; functional alterations in ARID1A, ATM, ATR, BRIP1, BAP1, BARD1, CDK12, CHK1, CHK2, IDH1/2, MRE11A, NBN, PALB2, RAD50, RAD51, RAD51B/C/D, RAD54L). The primary objective is assessing Rad51 response following pidnarulex treatment. Secondary objectives include safety (CTCAE v5. 0), objective response rate (RECIST v1. 1), pharmacokinetics (PK) of pidnarulex, and additional tumor DNA-damage and repair markers RPA32, pSer33-RPA32, γH2AX, 53BP1, pSer8-RPA32, pKap1, and pNBS1) associated with clinical response. Eligible adults must have histologically confirmed solid tumors, ECOG ≤2, adequate organ function, and tumor amenable to biopsy. Pidnarulex is administered at 325 mg/m² IV on days 1 and 8 of each 28-day cycle. Dose reductions occur for grade ≥3 non-hematologic toxicities, with a maximum of 2 reductions (DL-1: 250 mg/m²; DL-2: 200 mg/m²). Mandatory tumor biopsies are collected at baseline and on cycle 1 day 2 (24 ± 2 hours post-dose) for pharmacodynamic assessment. Blood samples are collected for PK analyses (mandatory) and ctDNA (optional). Study success requires 16 evaluable biopsies per cohort, with ≥3 patients (19%) showing a Rad51 response, providing 90% power to detect a true 30% Rad51-positive response rate at a 5% false-positive rate. Funded by NCI Contract No. HHSN261201500003I. Citation Format: Jibran Ahmed, Brian Ko, Sarah J. Shin, Murielle Hogu, Lawrence Rubinstein, Himabindu Gali, Deborah F. Wilsker, Ralph E. Parchment, Laura Kuhlmann, Steven Gore, James H. Doroshow, Alice P. Chen. Pilot study of pidnarulex pharmacodynamics in patients with advanced solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT293.
Ahmed et al. (Fri,) studied this question.