First-in-human, phase 1/2 study of GSK4524101, an oral DNApolymerase theta inhibitor (POLQi), alone or combined with the poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) niraparib in adults with solid tumors.

TPS3174 Background: Double-stranded DNA breaks (DSBs) in human cells are typically repaired via nonhomologous end joining (NHEJ) or homologous recombination (HR). Deficiency of HR-mediated DNA repair plays a role in the initiation and progression of many tumor types. In tumors with HR deficiency, PARP inhibition leads to generation of DSBs that cannot be effectively repaired because of the HR defect, resulting in synthetic lethality. This finding has led to the clinical development and approval of several PARPi for the treatment of various tumors including certain ovarian, breast, prostate, and pancreatic cancers that are prone to display HR deficiency (HRd). DNA polymerase theta (encoded by POLQ) mediates an alternative DNA repair mechanism, microhomology-mediated end joining (MMEJ). DNA polymerase theta is generally not detectable in normal tissues but is upregulated in many tumor types. In preclinical studies, POLQi plus PARPi treatment demonstrated superior efficacy to PARPi alone in preventing the growth of HRd tumors. To evaluate the clinical potential of combining POLQi and PARPi, this first-in-human study investigates treatment with GSK4524101, an investigational POLQi, with or without the PARPi niraparib, in patients with solid tumors. Methods: This open-label, multicenter, phase 1/2 study (NCT06077877) opened in October 2023 and comprises dose-finding (part 1, including a food-effect cohort) and dose-expansion (part 2) parts. This trial aims to assess the maximum-tolerated dose, pharmacokinetics, safety, and preliminary antitumor activity of oral GSK4524101 with or without niraparib. The primary endpoints are safety (part 1) and confirmed objective response rate (part 2). Secondary endpoints include pharmacokinetics, safety, progression-free survival (part 2), and response duration (part 2). Up to 135 patients may be enrolled. To be eligible, patients must be aged ≥18 years; have an advanced or metastatic solid tumor, an Eastern Cooperative Oncology Group performance status score of 0–2, and a life expectancy of ≥3 months; and have exhausted all standard treatment options. Individuals are ineligible if they have not recovered from chemotherapy-associated adverse events or have symptomatic uncontrolled brain or leptomeningeal metastases, a history of myelodysplastic syndrome or acute myeloid leukemia, uncontrolled hypertension, or a second malignancy that has progressed or required active treatment in the previous 2 years. The study is actively recruiting in the US and Canada; as of January 1, 2024, 1 patient has been dosed. Patients enrolled in part 1 will receive GSK4524101 alone or GSK4524101 plus niraparib; patients enrolled in part 2 will be randomized to either GSK4524101 plus niraparib or niraparib alone. Part 1 of this study is expected to complete in 2025. Data presented on behalf of the original authors with their permission. Presented at the American Association for Cancer Research (AACR) Annual Meeting 2024; April 5-10, 2024; San Diego, CA. Final publication number: 9686. Reused with permission. Clinical trial information: NCT06077877 .