Temozolomide, with or without WSD0922-FU, for the Treatment of EGFR-Mutant, IDH-Wildtype Glioblastoma
This phase II trial compares the effect of adding WSD0922-FU to temozolomide versus temozolomide alone in slowing disease progression in patients with EGFR-mutant, IDH-wildtype glioblastoma. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid and may kill tumor cells and slow down or stop tumor growth. WSD0922-FU is a targeted treatment which blocks EGFR. It is able to get into the brain and spinal cord and help treat those types of tumors. Adding WSD0922-FU to the usual treatment with temozolomide may be more effective in slowing disease progression, compared to temozolomide alone, in patients with EGFR-mutant, IDH-wildtype glioblastoma.
Inclusion Criteria
- Age >= 18 years
- Histopathologic diagnosis of glioblastoma, IDH-wildtype (as defined by the 2021 World Health Organization [WHO] classification of central nervous system [CNS] tumors) on primary pathology review * NOTE: MGMT promoter methylation status must have been performed
- Glioblastomas must have a pathogenic EGFR mutation, with or without EGFR amplification, detected by Clinical Laboratory Improvement Act (CLIA)-certified next-generation sequencing * EGFR mutation includes both deoxyribonucleic acid (DNA) sequence variants (e.g. point mutations, etc.) and transcript variants (e.g. EGFRvIII, etc.) * EXCEPTIONS: Glioblastomas which are EGFR wildtype with amplification are excluded. Glioblastomas which only have EGFR variants of unknown significance (without any pathogenic EGFR mutations) are also excluded
- Patients must have completed standard radiation (60 Gy in 30 fractions) with concurrent temozolomide (missing no more than 2 weeks of temozolomide), and adequately recovered from treatment related toxicities * NOTE: Adjuvant temozolomide must not have been initiated
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
- Hemoglobin > 9.0 g/dL (obtained =< 14 days prior to registration)
- Leukocytes > 3.0 x 10^9/L (obtained =< 14 days prior to registration)
- Absolute neutrophil count (ANC) > 1.5 x 10^9/L (obtained =< 14 days prior to registration)
- Platelet count > 100 x 10^9/L (obtained =< 14 days prior to registration)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (< 3 x ULN for patients with Gilbert's disease) (obtained =< 14 days prior to registration)
- Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (obtained =< 14 days prior to registration)
- Prothrombin time (PT)/international normalized ratio (INR)/activated partial thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant therapy and INR or aPTT is within target range of therapy (obtained =< 14 days prior to registration)
- Calculated creatinine clearance >= 45 mL/min using the Cockcroft-Gault formula (obtained =< 14 days prior to registration)
- Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only
- Provide written informed consent
- Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study)
- Must be willing to take light-protective measures during the study and for two weeks after last dose of WSD0922-FU
- Willingness to provide mandatory tissue specimens for correlative research
Exclusion Criteria
- Patients deemed to have progressive disease based on clinical deterioration after chemoradiation or radiographic progression outside of the radiation field * EXCEPTION: Patients deemed to have pseudoprogression are eligible; however, this should be controlled on =< 4 mg of dexamethasone and should not require bevacizumab at study onset
- Any of the following because this study involves an investigational agent, the genotoxic, mutagenic and teratogenic effects of which on the developing fetus and newborn are unknown: * Pregnant persons * Nursing persons * Persons of childbearing potential (and persons able to father a child) who are unwilling to employ adequate contraception
- Any of the following prior therapies: * Surgery for glioblastoma =< 3 weeks prior to registration * Radiation therapy =< 2 weeks prior to registration * Systemic therapies intended for the management of the glioblastoma, including but not limited to: ** Targeted therapies ** EGFR inhibitors ** Alkylating chemotherapy ** Adjuvant temozolomide (note that temozolomide administered concurrent with radiation is NOT an exclusion criterion) ** Immunotherapy ** Biologics ** Any other systemic therapies (Food and Drug Administration [FDA] approved, off-label, investigational) ** Bevacizumab * Non-enzyme-inducing anticonvulsants < 2 weeks prior to registration * Strong inducers and strong inhibitors of CYP3A < 14 days prior to registration
- Failure to adequately recover from any adverse events or complications related to any of the following therapies received prior to registration: * Craniotomy and resection of tumor * Stereotactic biopsy of tumor * Other major surgical procedure * Radiation therapy < 2 weeks prior to registration
- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens. Examples include (but are not limited to) refractory nausea and vomiting (if not controlled by supportive therapy), inability to swallow the formulated product, previous significant bowel resection, other chronic gastrointestinal diseases, etc
- Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection * Severe skin lesions such as skin/pressure ulcers, chronic leg ulcers or non-healing wounds. * Active history of keratitis * Symptomatic CNS complications that require urgent neurosurgical or medical (e.g. mannitol) intervention * Known intracranial hemorrhage which is unrelated to tumor * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Dyspnea at rest due to complications of advanced malignancy or other disease that requires continuous oxygen therapy * Or psychiatric illness/social situations that would limit compliance with study requirements
- Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy * NOTE: Patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial
- Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm
- Other active malignancy within the last 3 years that would interfere with treatment on this protocol * EXCEPTIONS: non-melanoma skin cancer, carcinoma in situ of the cervix, patients on hormonal therapy for treated breast or prostate cancer
- History of myocardial infarction =< 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07708961.
Locations matching your search criteria
United States
Arizona
Scottsdale
Florida
Jacksonville
Minnesota
Rochester
PRIMARY OBJECTIVE:
I. To assess if adding EGFR/EGFRvIII inhibitor WSD0922-FU (WSD0922-FU) to adjuvant temozolomide improves progression-free survival (PFS) compared to standard of care (SOC) treatment without WSD0922-FU in patients with EGFR mutant glioblastoma.
SECONDARY OBJECTIVES:
I. To assess the safety and tolerability of WSD0922-FU when combined with temozolomide.
II. To assess if adding WSD0922-FU to adjuvant temozolomide improves overall survival compared to SOC treatment without WSD0922-FU in patients with EGFR mutant glioblastoma.
EXPLORATORY OBJECTIVES:
I. To explore differences in WSD0922-FU efficacy based on MGMT status.
II. To explore differences in WSD0922-FU efficacy based on specific EGFR mutations.
III. To explore differences in WSD0922-FU efficacy based on EGFR variant allele fraction.
IV. To explore the impact of tumor treating field therapy on WSD0922-FU efficacy.
V. To identify spatial patterns of recurrence after WSD0922-FU therapy using advanced magnetic resonance imaging (MRI).
VI. To explore the impact of tumor EGFRvIII spatial heterogeneity on WSD0922-FU efficacy.
VII. To explore the impact of AXL-mediated resistance mechanisms on WSD0922- FU efficacy.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5 of cycles 1-6 and WSD0922-FU PO twice daily (BID) on days 1-5, 8-12, 15-19, and 22-26 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease recurrence while on therapy and are planning to undergo tumor resection or stereotactic biopsy prior to starting alternative treatment continue receiving WSD0922-FU PO BID on days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle until the time of surgery. Patients also undergo echocardiography (ECHO) and magnetic resonance imaging (MRI) throughout the trial and undergo chest x-ray and collection of tissue samples on study. Patients may undergo optional collection of blood and/or cerebrospinal fluid (CSF) samples throughout the trial.
ARM B: Patients receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients who experience disease recurrence while on therapy and are planning to undergo tumor resection or stereotactic biopsy prior to starting alternative treatment may initiate WSD0922-FU PO BID on days 1-5, 8-12, 15-19, and 22-26 of each cycle. Cycles repeat every 28 days until the time of surgery. Patients also undergo ECHO and MRI throughout the trial and undergo chest x-ray and collection of tissue samples on study. Patients may undergo optional collection of blood and/or CSF samples throughout the trial.
After completion of study treatment, patients are followed up at 30 days then every 2 months for 3 years and every 4 months for 2 years in clinical follow up, followed by every 2 months until disease progression and then every 6 months after disease progression in survival follow-up, for up to 5 years after registration.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMayo Clinic in Rochester
Principal InvestigatorSani Haider Kizilbash
- Primary IDMC250711
- Secondary IDsNCI-2026-04965, 26-000481
- ClinicalTrials.gov IDNCT07708961