Phase 3 SIGMA Trial of Safusidenib Initiated for IDH1-Mutant Glioma

A protocol amendment expanding the global SIGMA study (G203; NCT05303519) into a pivotal phase 3 trial has been finalized. This registrational trial will evaluate the efficacy and safety of safusidenib, a novel, oral, brain-penetrant inhibitor of mutant IDH1 as maintenance therapy for patients with IDH1-mutant astrocytoma. The study focuses on high-risk or high-grade tumors following standard-of-care (SOC) treatment, addressing a significant therapeutic gap in neuro-oncology.¹

The phase 3 portion of the SIGMA trial is a randomized, double-blind, placebo-controlled study designed to enroll approximately 300 participants across the United States, Australia, and China.^1,2 Patients with histologically confirmed IDH1-mutant grade 2, 3, or 4 astrocytoma who have completed radiotherapy or chemoradiotherapy and adjuvant temozolomide without evidence of progression will be randomized 1:1 to receive safusidenib 250 mg twice daily or placebo. The primary end point is progression-free survival (PFS) as determined by blinded independent central review using RANO 2.0 criteria. Secondary end points include overall survival, objective response rate (ORR), and duration of response.

Safusidenib is an isoform-selective inhibitor specifically designed to address the challenges of treating central nervous system malignancies.¹ IDH1 mutations occur in nearly 2400 new glioma cases annually in the US, primarily affecting patients in their 30s and 40s. While these patients typically experience longer survival than those with IDH-wild type tumors, high-grade IDH-mutant astrocytomas inevitably recur after surgical and adjuvant therapies, at which point salvage options are limited. Unlike earlier generations of targeted therapies, safusidenib was engineered for high blood-brain barrier penetration, a critical pharmacokinetic requirement for reaching infiltrative glioma cells.

The transition to a pivotal phase 3 trial follows promising clinical data from earlier phases. Results from a phase 2 study of safusidenib in treatment-naive patients with grade 2 IDH1-mutant gliomas, published in Neuro-Oncology in late 2025, demonstrated a confirmed ORR of 44.4% and a clinical benefit rate of 81.5% per RANO-LGG criteria. Notably, the median PFS had not been reached after a median follow-up of 28 months, with an 87.9% probability of remaining progression-free at 24 months. These data suggested that potent IDH1 inhibition can significantly delay the need for toxic radiation and chemotherapy.³

The safety profile of safusidenib remains consistent with earlier reports. Treatment-emergent adverse events were primarily grade 1 or 2, including alopecia, arthralgia, and manageable elevations in alanine aminotransferase. Grade 3 or higher treatment-related adverse events occurred in approximately 18.5% of patients, with low rates of discontinuation due to toxicity.

The current therapeutic landscape for IDH-mutant glioma recently shifted with the August 2024 FDA approval of vorasidenib (Voranigo), a dual IDH1/2 inhibitor, for patients with grade 2 tumors in the "watch-and-wait" setting.⁴ The SIGMA trial aims to build upon this momentum by targeting high-risk and higher-grade astrocytomas (grades 3 and 4) in the maintenance setting.¹ By introducing safusidenib after standard chemoradiotherapy, investigators hope to extend the duration of response and prevent the rapid recurrence typically seen in high-grade disease.

“These SIGMA protocol updates reflect alignment with US regulators to support the potential approval of safusidenib as swiftly as possible for a patient population that is in dire need of options,” said David Hung, MD, founder, president, and CEO of Nuvation Bio, in a press release. “Following discussions with regulatory agencies, advocacy groups and physicians, we substantially expanded the study to include most patients with an IDH1-mutant glioma who currently have no approved targeted therapies available. We are encouraged by the promising results seen in the phase 2 study, which included both astrocytoma and oligodendroglioma, and are eager to explore the potential of safusidenib across multiple settings through this registrational trial. We expect initial data for the separate oligodendroglioma cohort in 2027.”

REFERENCES

1. Nuvation Bio announces pivotal global phase 3 SIGMA Trial (G203) for safusidenib in IDH1-mutant glioma. News release. Nuvation Bio. February 9, 2026. Accessed February 11, 2026. https://tinyurl.com/m5wzn3tj

2. SIGMA (Safusidenib in IDH1 Mutant Glioma Maintenance) (SIGMA). ClinicalTrials.gov. Updated February 3, 2026. Accessed February 11, 2026. https://clinicaltrials.gov/study/NCT05303519

3. Arakawa Y, Saito R, Kanemura Y, et al. Phase II study of safusidenib erbumine in patients with chemotherapy- and radiotherapy-naïve isocitrate dehydrogenase 1-mutated WHO grade 2 gliomas. Neuro Oncol. 2025 Nov 8:noaf258. doi: 10.1093/neuonc/noaf258. Epub ahead of print. PMID: 41206766.

4. FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. News release. FDA. August 6, 2024. Accessed February 11, 2026. https://tinyurl.com/3jv48wa9