SYN818 Shows Favorable Safety Profile in Locally Advanced or Metastatic Solid Tumors

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The DNA polymerase theta (POLQ) inhibitor SYN818 demonstrated an acceptable toxicity profile when administered as a single agent at doses of 50 mg, 100 mg, and 200 mg in patients with locally advanced or metastatic solid tumors enrolled in a first-in-human, phase 1 study (NCT06666270).1

Early data, shared at the 2025 AACR Annual Meeting, indicated that in the first 3 dosing cohorts, the most common adverse effects (AEs) reported with the monotherapy were grade 1 in severity, and no dose-limiting toxicities were reported. Moreover, no hematological toxicities that are typically experienced with DNA damage repair inhibitors were observed.

“[The] pharmacokinetic [PK] and safety profile [of SYN818] supports its potential value in combination with [a] PARP [inhibition] and/or rational therapeutic modalities,” Yiqun Du, MD, PhD, of Fudan University Shanghai Cancer Center, in Shanghai, China, and colleagues, wrote in a poster of the data.

A Preview of the Path That Led to the Phase 1 Study

DNA double-strand breaks are extremely harmful genomic lesions that can be repaired through homologous recombination, nonhomologous end-joining, and microhomology-mediated end-joining, the latter of which is mediated by POLQ. POLQ is also crucial for filling gaps in single-stranded DNA (ssDNA) that occur during or after replication. When cells harbor genetic mutations in proteins involved in ssDNA gap recognition and facilitation—such as BRCA1, BRCA2, and RAD51—the ssDNA gap filling depends on PARP1-mediated PARlyation and POLQ. As such, investigators hypothesized that POLQ inhibition, either as monotherapy or paired with PARP inhibition, could offer a synergistic strategy capable of killing cancer cells devoid of key factors in the ssDNA gap-filling pathway.

Preclinical data with the POLQ inhibitor SYN818 have suggested that the agent has over 8000-fold selectivity in DLD1 parental vs BRCA2 KO cells; an acceptable PK profile with robust in vivo efficacy when paired with PARP inhibition; low risk for CYP450 inhibition and TDI; and a favorable safety profile. Specifically, there was a low risk of QT prolongation, and no impact on central nervous system, respiratory, and cardiovascular systems. Moreover, the agent “has robust and strong synergy with PARP [inhibitors], chemo[therapy], and TOPi-based [antibody-drug conjugates (ADCs)],” the authors wrote.

Delving Into the Phase 1 Study Design

The early-phase study enrolled patients with locally advanced or metastatic solid tumors who were at least 18 years of age, had an ECOG performance status of 0 or 1, and a life expectancy of at least 3 months. They were not selected for BRCA mutation or homologous recombination deficient (HRD) status; however, the trial protocol is being amended to select for these subsets at dose level 4.

For the phase 1a dose-escalation portion of the research, patients (n = ~30) received SYN818 monotherapy at 50 mg, 100 mg, or 200 mg. The examination of the agent at dose level 4, which is 300 mg, is currently ongoing; this will be followed by dose levels 5 and 6. The key objective of this portion of the research is safety and tolerability, identification of the recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD), and PK profile.

The phase 1b portion of the study will be comprised of 2 parts: dose-escalation and dose-expansion. Part 1 plans to enroll approximately 18 patients with locally advanced or metastatic solid tumors with BRCA mutations or HRD. Part 2 plans to include about 75 patients organized into different cohorts of locally advanced or metastatic solid tumors harboring BRCA mutations or HRD. In this portion of the trial, SYN818 will be evaluated in combination with olaparib (Lynparza) at 300 mg twice daily. The key objectives for phase 1b were safety and tolerability, to determine the RP2D/MTD, and efficacy in the form of objective response rate, disease control rate, duration of response, and progression-free survival. “Phase 1b will be conducted in the second half of 2025,” the study authors wrote.

Looking at the Current Dataset

As of the April 2, 2025, data cutoff, a total of 7 patients were enrolled to the first 3 dose-escalation cohorts. The median patient age was 56 years (range, 48-62), all were female, all had an ECOG performance status of 1, and all were Asian. Tumor types included breast (n = 3), ovarian (n = 1), and colorectal cancer (n = 3).

Patients were heavily pretreated, with a median of 4 prior line of therapy (range, 2-6). Most patients (85.7%) had received a least 3 prior lines of systemic therapies for metastatic disease; this treatment included platinum chemotherapy for 71.4% of patients, PARP inhibitors for 14.3% of patients, and endocrine therapy for 28.6% of patients. Moreover, 28.6% of patients had prior HER2 inhibition, 57.1% had prior exposure to VEGF inhibitors, 14.3% had ADCs, and 28.6% had immune therapy.

PK Profile: Key Takeaways

Plasma exposure of the drug increased dose proportionally from 50 mg to 200 mg once daily. Moreover, the profile of the agent was noted to have “exceeded expectations from preclinical studies, demonstrating more favorable outcomes than the predicted human PK profiles,” the study authors wrote. They added that the initial PK profiles at dose levels 1 to 3 showcase “robust target coverage, supporting continued evaluation in the phase 1 trial.”

Looking Ahead

They concluded by stating that a peripheral blood-based pharmacodynamic marker is under development and will be applied for planned retrospective analyses.

Reference

Du Y, Wang HH, Yan M, et al. A phase I study of POLQ inhibitor SYN818 as monotherapy in adult patients with locally advanced or metastatic solid tumors. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT152.