A perioperative study of Safusidenib in patients with <i>IDH1</i>-mutated glioma
Creators: name: Cain, Sarah A
name: Topp, Monique
name: Rosenthal, Mark
name: Tobler, Robert
name: Freytag, Saskia
name: Best, Sarah A
name: Whittle, James R
name: Drummond, Katharine J
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: Pharmacology
subject: Biotechnology
subject: Cancer

description: This is a single arm, open label perioperative trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with safusidenib following biopsy, and prior to surgical resection in patients with <i>IDH1</i> mutated glioma who have not received radiation therapy or chemotherapy. Fifteen participants will receive treatment in two parts. First, biopsy followed by one cycle (28 days) of safusidenib, an orally available, small molecular inhibitor of mutated IDH1, then maximal safe resection of the tumor (Part A). Second, after recovery from surgery, safusidenib until disease progression or unacceptable toxicity (Part B). This research will enable objective measurement of biological activity of safusidenib in patients with <i>IDH1</i> mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention. <b>Clinical Trial Registration:</b>NCT05577416 (ClinicalTrials.gov) Adult low-grade gliomas (aLGG) are primary brain cancers, defined by mutations in <i>IDH1</i> or <i>IDH2</i>. When the <i>IDH</i> gene becomes abnormal (mutated), production of a metabolite that causes cancer cells to grow is increased. These tumors grow slowly but invade the normal functioning brain, making them nearly impossible to cure. The current standard of care treatment includes surgery, followed by radiation therapy and chemotherapy, the timing of which depends on the risk of cancer regrowth. Some patients may be suitable for monitoring with MRI scans alone, however recurrences will inevitably occur. Recently developed targeted mutant IDH inhibitors for aLGG patients may be beneficial both at diagnosis and recurrence. Notably, early treatment prior to radiation therapy and chemotherapy delays growth of aLGG and the need for subsequent radiation therapy and chemotherapy. Nevertheless, most patients will eventually suffer further tumor growth and the optimal timing and sequencing of these therapies remains an area of active research. This research investigates the mutant <i>I</i>DH1 inhibitor safusidenib. The researchers are conducting an innovative clinical trial where patients with aLGG, who have not received radiation therapy or chemotherapy, are treated with safusidenib following a biopsy and prior to surgical removal of their tumor. In this study they investigate whether this trial design is safe and feasible, and how safusidenib works; with the goal to better understand the optimal use of IDH inhibitors for patients with aLGG. Adult low-grade gliomas (aLGGs) are defined by <i>IDH1/2</i> mutations which lead to accumulation of 2-HG, an oncometabolite affecting tumorigenesis. 2-HG inhibits α-KG-dependent enzymes, affecting epigenetic regulation, collagen synthesis and cell signaling, hindering progenitor cell differentiation and promoting cancer. In addition, 2-HG promotes angiogenesis, an immunosuppressive tumor microenvironment and oxidative damage. aLGGs grow slowly, diffusely infiltrating the brain and are difficult to cure. Emergence of targeted mutant IDH inhibitors has shifted focus toward identifying prognostic markers and future combination studies. Treatment includes maximal safe surgical resection, radiation therapy and sequential chemotherapy. Early, extensive surgery improves overall survival. Active surveillance with MRI is suitable for some patients to delay side effects. Multiple mutant IDH inhibitors have shown promise in glioma. Vorasidenib (IDH1/2 inhibitor) improved progression-free survival in the INDIGO Phase III trial. Safusidenib (DS-1001b, AB-218) is an orally available small molecule inhibitor of mutant IDH1 with demonstrated brain penetration and clinical activity in Phase I trials. There have been few therapeutic advances in glioma due to challenges in measuring drug penetration and pharmacodynamic (PD) evaluation. Perioperative trials, including biopsy to obtain pre-treatment tissue, are feasible and offer a means to examine the direct effects of new drugs. These studies allow evaluation of drug pharmacokinetics (PK) and PD outcomes. Hypothesis: Treatment with safusidenib following biopsy and prior to resection in newly diagnosed <i>IDH1</i> mutated glioma is feasible. Estimate: &gt;60% of screened patients completing planned investigations and procedures. Primary objective: Assess feasibility and acceptability of a perioperative study in <i>IDH1</i> mutated aLGG patients. Secondary end points: Determine safusidenib toxicity, safety of two-stage surgery and biological activity by changes in 2-HG levels. Key inclusion: Adults ≥18 years with aLGG diagnosis not requiring urgent resection. Key exclusion: prior chemotherapy/radiation, cerebellar/brainstem tumors. Procedures: Open biopsy, oral safusidenib, second-stage resection, continued safusidenib post-resection. Data collection: tumor tissue, CSF and blood samples processed per protocols. PK/PD relationships: Evaluated by blood, tumor and CSF samples. Biological activity: Assessed by changes in 2-HG levels and <i>IDH1</i> ctDNA. Tumor tissue, CSF and blood samples collected for research. Safusidenib PK will be investigated to evaluate PK/PD relationships. Translational end points include paired whole-genome transcriptome profiling, single nuclei RNA sequencing, bulk metabolomics and DNA methylation. Spatial transcriptomics using <i>in situ</i> digital sequencing and spatial metabolomics on sections pre- and post-safusidenib treatment. Descriptive statistics for demographics, safety, PK, PD, efficacy and biomarker data by dose and time. Toxicity: Monitored by adverse events, clinical tests and vital signs. Safety of surgery: 30-day morbidity and mortality recorded post-biopsy and resection. Radiological response: Determined by MRI changes and LGG-RANO criteria. Progression-free survival and time to treatment failure: Calculated from biopsy date. Perioperative studies in aLGG offer a unique opportunity to study drug effects and are feasible, ethical and acceptable to patients.