This phase I/II trial tests the safety, side effects and best dose of selinexor given in combination with the usual chemotherapy (temozolomide) and compares the effect of this combination therapy versus the usual chemotherapy alone (temozolomide) in treating patients with glioblastoma that has come back (recurrent). Selinexor is in a class of medications called selective inhibitors of nuclear export (SINE). It works by blocking a protein called CRM1, which may keep cancer cells from growing and may kill them. 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. Giving selinexor in combination with usual chemotherapy (temozolomide) may shrink or stabilize the tumor better than the usual chemotherapy with temozolomide alone in patients with recurrent glioblastoma.
Patients must have histologically confirmed glioblastoma (IDH wild-type, MGMT promoter methylated) that has undergone resection or biopsy upon first recurrence. Recurrence at site of prior involvement is defined by histopathological evidence of viable neoplastic cells associated with any of the following: mitotic activity, increased proliferation rate, micro-endothelial proliferation, or pseudo-palisading necrosis
Prior to resection or biopsy, patients must have measurable disease, defined as at least one bi-dimensional contrast-enhancing lesion with clearly defined margins, with 2 perpendicular diameters of at least 10 mm, visible on >= 2 axial slices
Patients must have received first-line treatment of temozolomide plus radiotherapy
Patients must not have received any prior therapy aside from resection or biopsy for their recurrent disease
Patients who have had chemotherapy must have full recovery of organ and marrow function following the nadir of the last chemotherapy cycle
Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia
Patients who are receiving any other investigational agents
Patients who have previously received bevacizumab
Parallel
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Magnetic Resonance Imaging
Procedure/SurgeryUndergo MRI
Placebo Administration
DrugGiven PO
Selinexor
DrugGiven PO
Temozolomide
DrugGiven PO
Recommended phase 2 dose (RP2D) (Phase I)
Any eligible patient who receives at least one dose of protocol-defined therapy will be considered evaluable for dose-limiting toxicity (DLT) if either of the following occurs: (1) the patient experiences a DLT during cycle 1 of therapy; or (2) the patient receives at least 4 doses of temozolomide and 1 dose of selinexor. All other patients enrolled during the phase 1 portion of the study will be considered inevaluable for DLT and may be replaced for the purposes of establishing the RP2D.
Progression-free survival (PFS) (Phase II)
Patients who experience disease progression or death will be considered to have experienced a PFS-event; otherwise the patient is considered censored at last contact.
Response according to response assessment in neuro-oncology criteria (RANO) criteria
A patient who is evaluated as complete response, partial response, or stable disease will be considered a RANO-responder. All other patients will be considered RANO-non-responders. Response rate will be calculated and comparisons made using categorical data methods.
Six-month progression-free survival (PFS-6)
Any patient considered evaluable for RANO response will be considered evaluable for PFS-6. Any evaluable patient who is considered progression free for the primary analysis will be considered a PFS-6 responder. All other evaluable patients will be considered PFS-6 non-responders.
Median overall survival
Will be calculated from the Kaplan-Meier estimate of the probability of death as a function of time since enrollment. Ninety-five percent (95%) confidence intervals will be calculated as well.
Molecular signatures of vulnerability
Will be assessed using logistic regression for the outcome measure (RANO response) and using proportional hazard regression with the biological characteristic of interest as the predictor variable for risk for PFS event. Patients considered evaluable for RANO response and PFS, respectively, will contribute to the analyses for these exploratory outcomes. Two-sided statistical testing will be employed, and a p-value of 0.05 or less will be considered as indicating significant evidence of association between the particular signature and the outcome of interest.
Click on the lead sponsor to view all of their trials.
