Randomized phase 2 trial of ruxolitinib in combination with radiation and temozolomide compared to radiation and temozolomide for newly diagnosed glioblastoma.

Abstract

TPS2094 Background: Glioblastoma is the associated with poor outcomes despite treatment with radiation and temozolomide. Therapeutic resistance and disease recurrence are driven in part by glioma stem cell populations and activation of oncogenic signaling pathways, including the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Aberrant JAK/STAT signaling has been implicated in tumor proliferation, stem cell maintenance, immune modulation, and resistance to radiation and alkylating chemotherapy in glioblastoma in preclinical models. Ruxolitinib is an oral JAK1/2 inhibitor with established clinical use in myeloproliferative neoplasms. Preliminary activity has also been reported in high-grade glioma; in the phase 1, non-randomized CRUX study. Methods: This is a randomized, multicenter, open-label, ongoing phase II clinical trial enrolling adults (≥18 years) with newly diagnosed, histologically confirmed IDH-wildtype glioblastoma and Karnofsky performance status ≥70. Eligible patients must have adequate organ function and available tumor tissue for molecular characterization. Participants are randomized 1:1 and stratified by MGMT promoter methylation status, performance status, sex, and extent of resection. Patients assigned to the experimental arm receive oral ruxolitinib 20 mg administered twice daily in combination with standard radiation therapy (60 Gy delivered in 30 fractions) and concurrent temozolomide at 75 mg/m 2 , followed by adjuvant temozolomide at 150-200 mg/m 2 with continuous ruxolitinib at 20 mg bid. Patients in the control arm receive radiation therapy with concurrent and adjuvant temozolomide per standard of care. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or completion of protocol-defined therapy. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety. Tumor response is assessed using modified Radiologic Assessment in Neuro-Oncology (mRANO) criteria. Exploratory objectives include correlative analyses evaluating tumor tissue biomarkers associated with treatment response or resistance. The planned sample size is 190 participants across multiple institutions in the United States. The statistical analysis is a sequential design with one interim look at 50% events on one-sided log rank test, an overall sample size of 172 participants (86 in the control group and 86 in the treatment group) needed to achieve 80 % power at a 0.1 significance level to detect a hazard ratio of 0.68182 when the control group median survival time is 15 months. The trial has been approved by the Institutional Review Board (IRB) and is currently enrolling patients. Clinical trial information: NCT06991101 .