This study will assess the therapeutic efficacy of the combination of Laser Interstitial Thermal Therapy (LiTT) with adjuvant cemiplimab compared to the therapeutic efficacy of the combination of LiTT with physician's choice of adjuvant chemotherapy in patients with recurrent glioblastoma. Patients will be enrolled and randomized on a 2:1 ratio to either the experimental arm (LiTT + cemiplimab) or the control arm (LiTT + physician/s choice chemotherapy).
Histologically confirmed WHO grade 4 GBM (IDH-wt). Note: GBM variants, including histone-mutant and molecular-defined gliomas per WHO 2021 are allowed. Any number of recurrences are permitted.
Unequivocal evidence of tumor progression as documented on the screening biopsy.
At least 12 weeks post-completion of standard frontline therapy. Standard frontline therapy in this population includes maximal feasible surgical resection (biopsy alone is allowed), radiotherapy, and temozolomide chemotherapy. There is no restriction on the number of adjuvant temozolomide cycles.
Candidate for LITT based on the size, location, and shape of the recurrent tumor as determined by the performing neurosurgeon. Surgical resection/debulking prior to LITT is allowed per standard of care but is not required; if the patient undergoes resection or debulking, it must have occurred at least 3 weeks prior to the start of any study treatment.
Received prior treatment with any anti-angiogenic agent (including bevacizumab) within 3 months of date of surgery (LITT). (Note: bevacizumab is otherwise permitted when used outside this window for cerebral edema.)
Received prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD127, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
Received prior treatment with a monoclonal antibody within 4 weeks prior to the first day of study treatment.
Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first day of study treatment.
Parallel
NeuroBlate® Laser Ablation Laser Interstitial Thermal Therapy
DeviceLiTT, or magnetic resource imaging (MRI)-guided laser ablation, is a minimally invasive surgery approved for cytoreductive treatment of brain tumors. It employs a small incision in the scalp and skull, through which a thin laser probe is inserted and guided by MRI imaging to the core of a tumor mass where it delivers hyperthermic ablation from the core to the rim.
Cemiplimab
DrugCemiplimab is a programmed death receptor-1 (PD-1)-blocking antibody that is administered intravenously at 350mg over 30 minutes every 3 weeks on an outpatient basis.
Chemotherapy
DrugAdjuvant chemotherapy will be decided by the physician's choice of best fit by patient, including the agent(s), dosing, and schedule.
Progression-free survival (PFS) at Month 6 (PFS6)
PFS6 as defined from the time of treatment start to the time of progression (based on clinical assessment and imaging per Immunotherapy Response Assessment in Neuro-Oncology (iRANO)) or death, whichever is earlier, or last follow-up if neither progression nor death event is observed. PFS6 will be estimated as the empirical PFS probability at Month 6 using the Kaplan-Meier method.
Overall survival (OS) at Month 18 (OS18)
OS as defined from the time of treatment start to the time of death or last follow up if surviving; OS-18 is further estimated as the empirical OS probability at Month 18 using the Kaplan-Meier method.
Median Progression-Free Survival (PFS) as determined using the Kaplan-Meier method
PFS as defined from the time of treatment start to the time of progression (based on clinical assessment and imaging per Immunotherapy Response Assessment in Neuro-Oncology (iRANO)) or death, whichever is earlier, or last follow-up if neither progression nor death event is observed.
Median Overall Survival (OS) as determined using the Kaplan-Meier method
OS as defined from the time of treatment start to the time of death or last follow up if surviving.
Objective Response Rate (ORR)
Proportion of patients achieving Complete Response (CR) or Partial Response (PR) by iRANO criteria. CR - Requires all of the following: complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. No new lesions; stable or improved non-enhancing (T2/FLAIR) lesions. Patients must be off corticosteroids (or on physiologic replacement doses only) and stable or improved clinically. PR - Requires all of the following: ≥ 50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. No progression of nonmeasurable disease. Stable or improved nonenhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater than the dose at time of baseline scan. Stable or improved clinically.
Disease control rate (DCR)
DCR, defined as proportion of patients achieving Complete Response (CR), Partial Response (PR), or Stable Disease (SD) by iRANO criteria.
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Washington University School of Medicine
Lead sponsor
Regeneron Pharmaceuticals
Collaborator
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