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Safusidenib in IDH1-Mutant Glioma Maintenance

Patients with high-grade IDH-mutant astrocytomas have a better prognosis than those with glioblastoma, but their tumors almost invariably recur. No maintenance therapies known to extend progression-free survival or overall survival are currently available to these patients. Although the National Comprehensive Cancer Network guidelines recommend the IDH inhibitor vorasidenib for grade 3 or grade 4 recurrent or progressive tumors, this recommendation is not supported by the results of a randomized controlled trial. 

This study will evaluate the safety and efficacy of safusidenib in newly diagnosed grade 3 IDH-mutant astocytoma with high-risk features and all grade 4 IDH-mutant astrocytoma.

Safusidenib is an investigational IDH inhibitor that is being developed as an oral anti-tumor drug for the potential treatment of adult patients with IDH-mutant gliomas. Tumor with a mutation in the IDH1 gene produce a mutated form the IDH protein, which in turn produces a metabolite that contributes to tumor growth and disrupts immune cell function. IDH inhibitors are a new type of targeted therapy that slow tumor grow by blocking the activity of the mutant IDH protein. 

Inclusion Criteria
  1. Must be ≥18 years old at the time of signing the informed consent form.
  2. Must have a KPS score ≥60.
  3. Expected survival of ≥6 months.
  4. Diagnosis of histologically confirmed IDH-mutant Grade 3 or Grade 4 astrocytoma, per WHO 2021 classification and Investigator assessment.
  5. Have an IDH1 mutation (R132H/C/G/S/L) based on immunohistochemistry (IHC) (R132H only), polymerase chain reaction (PCR), or next-generation sequencing (NGS). CDKN2A/B status and at least 1 of the following must be confirmed: absence of 1p19q co-deletion by fluorescence in situ hybridization, array comparative genomic hybridization, or NGS; presence of an ATRX loss of function mutation by NGS; or loss of normal ATRX expression by IHC. A validated assay performed in a CLIA- certified/CAP-accredited (or local equivalent) clinical laboratory must be used for all of the aforementioned results. Documentation of biomarker status, including redacted molecular pathology and NGS reports, must be provided during screening.
  6. Participants with Grade 3 astrocytoma must have one or more of the following risk factors:
    1. Unequivocal contrast enhancement on an MRI prior to resection, per Blinded Independent Central Review (BICR).
    2. Residual tumor, defined as a tumor resection with a minimum of 1×1 cm of measurable disease, per BICR.
    3. A hemizygous deletion of, or known/predicted pathogenic mutation in, CDKN2A/B; result must be based on a CLIA-certified/CAP-accredited (or local equivalent) clinical laboratory assay and documentation must be provided.
  7. Have received a resection and/or biopsy; additional resections are only allowed for reasons not relating to disease recurrence or progression (e.g. removal of residual tumor).
  8. Must not have experienced disease recurrence or progression.
  9. Participants must have completed radiation therapy with a minimum of 90% of planned treatment completed (with or without concurrent temozolomide) and between 6 and 12 cycles of adjuvant temozolomide and have no evidence of disease progression. Randomization must occur at least 28 days and not more than 75 days after the final dose of temozolomide.
  10. Must agree to submit sufficient tumor tissue for retrospective biomarker and histological analyses. This requirement may be waived in rare circumstances with approval by the Sponsor.
  11. Recovered to Grade ≤1 from clinically relevant toxicity due to prior anticancer therapy. Irreversible changes associated with radiation therapy are allowed.
  12. Has adequate hematologic and organ functions as defined below:
    1. Absolute neutrophil count: ≥1500/mm3 or ≥1.5×109/L
    2. Hemoglobin: ≥9.0 g/dL
    3. Platelet count: ≥100,000/mm3 or ≥100×109/L
    4. Serum total bilirubin ≤1.5×the upper limit of normal (ULN) (participants with Gilbert's syndrome can be included if total bilirubin ≤2.5×ULN)
    5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN
    6. Alkaline phosphatase (ALP) ≤2.5×ULN
    7. Creatinine clearance ≥60 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) × (weight in kg) × (0.85 if female)/72 × serum creatinine
  13. Female participants who engage in heterosexual intercourse must be of nonchildbearing potential, defined as either surgically sterile (e.g., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), OR be postmenopausal with at least 1 year of amenorrhea, OR must agree to use a highly effective method of contraception from the beginning of screening until at least 90 days after the last dose of study drug. Acceptable highly effective methods of contraception include:
    1. Desogestrel-based progestin-only contraception associated with consistent inhibition of ovulation; this includes oral, injectable, and implantable methods
    2. Intravaginal and transdermal hormone delivery methods
    3. Intrauterine device (with or without hormone elution)
    4. Bilateral tubal occlusion or ligation (must be documented)
    5. Vasectomized partner (must be documented)

    6. Sexual abstinence (only when it is the usual and preferred lifestyle of the participant)

      Male participants should agree to use a condom when sexually active with a female partner of childbearing potential from Screening until at least 90 days after the last dose of study drug (or be surgically sterile [e.g., vasectomy with documentation]; or remain abstinent [when this is in line with the preferred and usual lifestyle]). Male participants should also agree to not donate sperm for the duration of the study and until at least 90 days after the last dose of study drug.

  14. Must have a signed and dated Institutional Review Board/Independent Ethics Committee approved ICF before any protocol-directed Screening procedures are performed. A legally authorized representative may consent on behalf of a participant who is otherwise unable to provide informed consent.
  15. Must be able to undergo MRI assessments as specified in the protocol.
  16. Must be able to comply with all requirements of the study.

 

Exclusion Criteria
  1. Participants may not have received any anticancer treatments other than surgery, radiation, concurrent/adjuvant temozolomide, and tumor-treating fields. Tumor-treating fields must be discontinued prior to randomization.
  2. Participants with prior or anticipated treatment with anti-angiogenic agents such as Avastin (bevacizumab), agents known to target IDH1 or IDH2, or investigational agents for glioma are excluded.
  3. Have brainstem or spinal cord involvement either as primary location, site of multifocal involvement, or by significant tumor extension.
  4. Significant functional or neurocognitive deficits, including uncontrolled seizures, that would preclude participation in protocol-defined study activities, as assessed by Investigator.
  5. Evidence of diffuse leptomeningeal disease by MRI.
  6. Participants with human immunodeficiency virus (HIV) are ineligible unless the following criteria are met: have been receiving effective antiretroviral therapy for at least 4 weeks; viral load <400 copies/mL, CD4+ T-cell (CD4+) counts ≥350 cells/µL, an absence of opportunistic infections for the last 12 months, and participant agrees to be treated with anti-viral therapy for the duration of the study, if indicated.
  7. Have a corrected QT interval by Fredericia’s formula (QTcF) ≥470 milliseconds (msec) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome).
  8. History of significant cardiac disease within 12 months prior to randomization including myocardial infarction, New York Heart Association Class II/III/IV heart failure, left ventricular ejection fraction <35%, unstable angina, unstable cardiac arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation), syncope of cardiovascular etiology, or cardiac arrest unless the cardiac disease has been corrected (e.g., coronary artery bypass graft, valve replacement), in which case at least 6 months must have passed since the corrective procedure.
  9. Participants with known history and/or serological evidence of chronic hepatitis B virus infection will be included only if the following criteria are met: hepatitis B- deoxyribonucleic acid (DNA) viral load is below the limit of quantification, liver function tests meet inclusion criteria (AST, ALT, ALP, bilirubin), and participant agrees to be treated with anti-viral therapy for the duration of the study, if indicated.
  10. Participants with known history and/or serological evidence of hepatitis C virus infection will be included only if the following criteria are met: hepatitis C-ribonucleic acid (RNA) viral load is below the limit of quantification, liver function tests meet inclusion criteria (AST, ALT, ALP, bilirubin), and participant agrees to be treated with anti-viral therapy for the duration of the study, if indicated.
  11. If taking corticosteroids, must be on a stable or decreasing dose for the 14 days prior to randomization.
  12. Major surgical procedure within 2 weeks prior to randomization or anticipation of need for major surgical procedure during the course of the study.
  13. Participants with other malignancies must have received curative treatment and been disease-free for at least 3 years. Curatively resected non-melanoma skin cancer or curatively treated carcinoma in situ is allowed.
  14. Have had an active infection that requires systemic therapy or have had a fever >38.5°C within 7 days of randomization.
  15. Any active disease or condition that impairs the participant's ability to take study drug, including difficulty swallowing or malabsorption syndrome, refractory nausea and vomiting, chronic gastrointestinal disease, or previous bowel resection with clinically significant sequelae.
  16. Have any other clinical or psychiatric condition or laboratory abnormality that, in the opinion of the Investigator, would interfere with, or increase the risk of, study participation.
  17. Are pregnant or breastfeeding or plan to become pregnant during the study.

  18. Known hypersensitivity to safusidenib, to any drug with similar chemical structure, or to any other excipient present in the pharmaceutical form of safusidenib.

     

Investigator(s)

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