P17.04.B A PHASE 2 STUDY OF NIRAPARIB CONCOMITANT WITH TUMOR TREATING FIELDS (TTFIELDS) IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMA (HGG)

Abstract

Abstract BACKGROUND Preclinical data have demonstrated that application of TTFields reduces gene expression within the FA-BRCA DNA-damage response pathway, thus inducing potential sensitivity to PARP inhibition. We conducted a phase 2 trial of TTFields concomitant with niraparib in patients with recurrent HGG. MATERIAL AND METHODS This single-center trial enrolled patients with recurrent grade 4 glioma, including both rGBM (IDH-wt) and IDH-mutant grade 4 astrocytoma. The study included a single-arm, primary efficacy cohort (A) and a window-of-opportunity cohort (B) for patients needing surgical resection. In Cohort A, TTFields therapy was administered for 5 - 7 days prior to start of niraparib (300mg daily, 28-day cycles). Cohort B received TTFields therapy starting 5 - 7 days prior to surgery and stopped 1 hour before incision. TTFields therapy was resumed post-operatively with niraparib added 5-7 days thereafter. Primary endpoint: disease control rate (DCR) in Cohort A, defined as achievement of either objective response (CR or PR) or stable disease (SD) lasting at least 16 weeks, using Modified Response Assessment in Neuro-Oncology criteria. Cohort A had a Simon two-stage design: null hypothesis, DCR 30%; alternative hypothesis, DCR 60%; n = 24 for 80% power, one-sided α = 0.05. After enrollment of n=8 in Stage 1, advancement to Stage 2 (n=16) was allowed if ≥ 4 patients in Stage 1 met the primary endpoint. Secondary endpoints: safety, progression-free survival (PFS), overall survival (OS). Exploratory endpoints: pre- vs. post-TTFields 18F FluorThanatrace (18F-FTT) PET imaging for PARP-1 expression, and assessment of homologous recombination deficiency (HRD) in TTFields-treated tumor tissue. RESULTS Nine patients were enrolled: Cohort A, n=8 (n=6 rGBM, n=2 grade 4 IDH-mutant astrocytoma); Cohort B, n=1 (rGBM). Median age 53; all patients were male; 6/9 (67%) were MGMT unmethylated. All patients received prior radiation/temozolomide; 3/9 (33%) received prior bevacizumab. Most common treatment-related adverse events (trAEs): grade 1-2 dermatologic AEs (scalp, n=6) grade 1-2 nausea (n=5), grade 1-2 vomiting (n=4), grade 2 anorexia (n=2), grade 1 constipation (n=2). Grade 3-4 trAEs included fatigue (n=1), thrombocytopenia (n=1), cerebral edema (n=1). Mean TTFields usage at niraparib initiation was 80.7% (19.4 hours/day). In Cohort A, there were no objective responses and 1/8 patients (12.5%) achieved SD. The efficacy benchmark to proceed to Stage 2 was not met. Median PFS and OS in Cohort A were 1.3 months (95% CI, 0.8 - 3.0 months) and 6.5 months (95% CI, 2.3 - 16.4 months), respectively. Cohort B was terminated early due to slow accrual. Correlative data (18F-FTT PET imaging, HRD assessment in TTFields-treated tumor tissue) will be presented. CONCLUSION Niraparib concomitant with TTFields therapy for recurrent HGG was safe and well tolerated but did not demonstrate a signal of efficacy.