A phase 1/2 dose escalation study of the oral DNA polymerase theta inhibitor (POLQi) GSK4524101 ± niraparib in adults with advanced or metastatic solid tumors.
Bibliographic record
Abstract
TPS3174 Background: In homologous recombination-deficient (HRd) tumors, use of a PARP inhibitor (PARPi) leads to generation of DNA breaks that cannot be effectively repaired, thus selectively killing cancer cells via synthetic lethality. An alternative DNA repair mechanism, microhomology-mediated end joining, is mediated by DNA polymerase theta (encoded by POLQ ). In preclinical studies, POLQi + PARPi demonstrated superior efficacy vs PARPi alone in preventing HRd tumor growth. To evaluate the clinical potential of this combination, this first-in-human study investigates treatment with GSK4524101, an investigational POLQi, and niraparib, a PARPi, in patients with solid tumors. Methods: This open-label, phase 1/2, multicenter study opened in October 2023 and includes a phase 1a/b, dose-escalation portion (part 1; potential enrollment to n≈75). Sites in the US and Canada are enrolling patients for part 1, which aims to assess the maximum tolerated dose, pharmacokinetics (PK), and safety of oral GSK4524101 ± oral niraparib. Eligibility criteria include age ≥18 years, Eastern Cooperative Oncology Group performance status of 0–2, life expectancy ≥3 months, and diagnosis of advanced or metastatic solid tumor with all standard-of-care treatment options exhausted. Exclusion criteria include unresolved chemotherapy-induced adverse events (AEs) or symptomatic uncontrolled brain or leptomeningeal metastases, uncontrolled hypertension, history of myelodysplastic syndrome or acute myeloid leukemia, or another malignancy that has progressed or required active treatment in the past 2 years. Outcome measures include dose-limiting toxicity (DLT) incidence during the DLT observation periods (up to 28 days; primary); treatment-emergent AEs (TEAEs) and serious AEs (SAEs); percentage of patients receiving all planned doses; and percentage of patients requiring AE-related dose interruptions, reductions, and discontinuations in the DLT observation period. Secondary endpoints include the PK of niraparib and the metabolite of GSK4524101 and incidence and duration of TEAEs and SAEs beyond the DLT observation period. The study is currently recruiting, with 17 patients having received doses across 9 sites in 2 countries as of January 10, 2025. Clinical trial information: NCT06077877 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".