Investigational Drug
CX-5461
TrialFetch AI Analysis
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Overview
Pidnarulex (CX-5461) is an investigational small molecule being developed for tumors with homologous recombination repair defects (for example, BRCA1/2 or PALB2 alterations). Early human studies include a completed multicenter Phase I trial in DNA repair–deficient solid tumors and a separate first‑in‑human Phase I trial in advanced hematologic malignancies. Multiple NCI‑supported trials are ongoing or planned. (pubmed.ncbi.nlm.nih.gov)
Mechanism of action
- Originally described as a selective inhibitor of RNA polymerase I–mediated rRNA transcription, inducing nucleolar stress and p53 activation. (pubs.acs.org)
- Subsequent work indicates CX‑5461 also stabilizes G‑quadruplex DNA structures and induces replication stress; clinical proof‑of‑concept has focused on synthetic lethality in homologous recombination–deficient tumors. (pubmed.ncbi.nlm.nih.gov)
- Additional preclinical data suggest TOP2B poisoning is a major pharmacologic activity at relevant concentrations, highlighting that multiple mechanisms may contribute to antitumor effects. (pubmed.ncbi.nlm.nih.gov)
- Recent reviews summarize these converging mechanisms (Pol I blockade, G‑quadruplex stabilization, replication stress/DDR activation, and potential TOP2 interactions). (pmc.ncbi.nlm.nih.gov)
Efficacy
Solid tumors (Phase I, CCTG IND.231; NCT02719977) - Population: 40 patients with advanced solid tumors, enriched for homologous recombination defects. (pubmed.ncbi.nlm.nih.gov) - Activity: Objective responses were observed in 14% of patients, mainly among those with homologous recombination deficiency; emergence of BRCA2/PALB2 reversion mutations at progression supported the synthetic‑lethal mechanism. (pubmed.ncbi.nlm.nih.gov)
Hematologic malignancies (Phase I, dose‑escalation) - Population: Advanced hematologic cancers treated IV q3w. (pubmed.ncbi.nlm.nih.gov) - Activity: One prolonged partial response in anaplastic large‑cell lymphoma; five patients (myeloma and DLBCL) achieved stable disease as best response. (pubmed.ncbi.nlm.nih.gov)
Ongoing/expansion studies - A Phase Ib expansion in BRCA2/PALB2‑mutant solid tumors is ongoing; early company‑reported data (ESMO 2024 abstract) describe clinical benefit (stable disease) in 40% of 15 evaluable patients, including some post‑PARP inhibitor cases. Peer‑reviewed outcomes are not yet available. (senhwabio.com) - Additional NCI‑sponsored trials (including a pharmacodynamic pilot and combination studies) have been initiated or announced. (prnewswire.com)
Safety
- In solid tumors (CCTG IND.231), pidnarulex was “generally well tolerated”; the recommended Phase II dose (RP2D) was 475 mg/m² IV on days 1, 8, and 15 of a 28‑day cycle. Dose‑limiting toxicity was phototoxicity/UV photosensitivity. (pubmed.ncbi.nlm.nih.gov)
- In hematologic cancers, the maximum tolerated dose was 170 mg/m² IV every 3 weeks. Dose‑limiting toxicity was palmar‑plantar erythrodysesthesia; dose‑independent photosensitivity occurred and was preventable with measures. (pubmed.ncbi.nlm.nih.gov)
- Nonclinical genomic safety signal: an in‑vitro study reported extensive collateral mutagenesis across human cell lines exposed to CX‑5461, warranting careful monitoring in clinical development. (pubmed.ncbi.nlm.nih.gov)
Key trial identifiers
- NCT02719977 — Phase I in advanced solid tumors (CCTG IND.231); completed. (ichgcp.net)
- NCT04890613 — Phase Ib expansion in BRCA2/PALB2‑mutant solid tumors; ongoing. (translational-medicine.biomedcentral.com)
- NCT06606990 — NCI pilot pharmacodynamic study in advanced solid tumors; recruiting. (translational-medicine.biomedcentral.com)
Further reading
- Hilton et al., Nature Communications 2022: Phase I results in solid tumors (RP2D, phototoxicity, 14% responses, HRD link). (pubmed.ncbi.nlm.nih.gov)
- Khot et al., Cancer Discovery 2019: First‑in‑human Phase I in hematologic malignancies (MTD, response and SD data, dermatologic AEs). (pubmed.ncbi.nlm.nih.gov)
- Pan et al., Nature Communications 2021: Evidence that TOP2B is a primary target in preclinical models. (pubmed.ncbi.nlm.nih.gov)
- Review of mechanisms and pathways engaged by CX‑5461. (pmc.ncbi.nlm.nih.gov)
- In‑vitro mutagenesis assessment of CX‑5461. (pubmed.ncbi.nlm.nih.gov)
- Trial listings and status summaries (NCT02719977, NCT04890613, NCT06606990). (ichgcp.net)
Notes: Pidnarulex/CX‑5461 remains investigational; efficacy and safety profiles are still being defined in ongoing trials, and mechanistic interpretations continue to evolve across Pol I inhibition, G‑quadruplex stabilization, and TOP2B interaction. (pubmed.ncbi.nlm.nih.gov)
Last updated: Oct 2025
Active trials using CX-5461
Found 2 active trials using this drug:
TrialFetch AI summary: Enrolling adults with locally advanced/unresectable or metastatic HER2-expressing solid tumors (dose escalation includes HER2+ and breast cancer across HER2-positive/low/ultralow; expansion limited to HER2-low breast cancer [IHC 1+ or 2+/ISH−] or HR+ HER2-ultralow) who have had at least one prior cytotoxic chemotherapy line and have ECOG ≤2, adequate organ function, and LVEF ≥50% (selected stable/treated brain metastases allowed; ILD/pneumonitis risk excluded). Treatment is single-arm trastuzumab deruxtecan IV day 1 every 21 days plus pidnarulex (CX-5461; investigational G-quadruplex–stabilizing DNA-damage/DDR-targeting agent) IV day 8, continued until progression or unacceptable toxicity.
ClinicalTrials.gov ID: NCT07137416
TrialFetch AI summary: This trial enrolls adults with advanced pancreatic, prostate, breast, or ovarian cancers harboring pathogenic or likely pathogenic germline BRCA2 and/or PALB2 mutations (with an exploratory cohort for other HRD-associated ovarian/fallopian/peritoneal cancers), treating them with intravenous CX-5461, a G-quadruplex DNA stabilizer that selectively targets homologous recombination–deficient tumor cells. Prior PARP inhibitor and systemic therapies are allowed, and patients must have measurable disease and ECOG ≤2.
ClinicalTrials.gov ID: NCT04890613
