This is a single center, single arm, phase 1 surgical dose escalation clinical trial with a preliminary efficacy study at the recommended safe maximal resection. Total duration of subject participation will be two years. Total duration of the study is expected to be 5 years.
Patients with suspected newly diagnosed or recurrent isocitrate dehydrogenase wild-type (IDH-WT) glioblastoma will be enrolled in this study if within the selection criteria (see inclusion and exclusion criteria below). Prior to surgery, patients will undergo: 1) standard pre-operative medical clearance 2) standard of care pre-operative magnetic resonance imaging (MRI) 34 with gadolinium contrast with thin cut T1 with and without contrast and diffusion tensor imaging and 3) amine chemical exchange saturation transfer echoplanar (CEST-EPI) MRI. 3,18,19,33 Pre-operative post-processing of CEST-EPI regions to identify areas of potential infiltrating tumor will be carried out as previously described. 3 In addition, resection constraints will be added based (starting at 0.7cm and increasing in 0.7cm intervals over 4 intervals to a maximum constraint of 2.8cm). This maximum constraint will reach the theorized threshold for significant infiltrating tumor cell burden based on preliminary data. 3,14 This data will be converted into a intraoperative object through our intraoperative neuronavigation system (BrainLab Surgical Navigation System, Munich, Germany).
On day of surgery, subjects will undergo standard of care procedures for craniotomy for brain tumor resection at Ronald Reagan UCLA Medical Center. Upon initial tumor resection, a biopsy specimen will be sent to neuro-pathology to confirm diagnosis. 5-aminolevulinic acid (5-ALA), a safe FDA approved fluorescence molecule used to increase extent of resection in glioma surgery will be administered for comparision with CEST imaging in surgery. 17 Areas of 5-ALA positivity and areas of CEST-EPI positivity will be biopsied for further comparision as described in the secondary objective. This will be followed by resection using the intraoperative CEST-EPI identified region with resection constraint using the intraoperative neuronavigation object. After completion of surgery, standard of care procedures for craniotomy will be completed.
To assess for short and long term complications related to surgery alone, patients will be admitted post-operatively with standard post-op care. There will be a immediate within 24-hr MRI while patient is inpatient, followed by 2 week post-operative visit alongside a 4 week MRI 35 to evaluate for rapid early progression. This will be followed with standard of care 8 week MRI and initiation of standard of care (temolozolomide and radiotherapy). The window of monitoring for surgery related complications will be the 4 week MRI and office visit as the resection limiting toxicities (described below) all fall within this window.
Given this protocol, safety constraints and analysis will follow a pre-determined statistical and methodological protocol. Using standard of care resection of contrast enhancement as the baseline, we will begin with 3 subjects with maximal CEST positive resection 0.7 cm from the contrast enhancing edge. The resection levels up to (0.7cm, 1.4 cm, 2.1cm or 2.8cm) from areas of CE tumor ("doses") escalation within each cohort will occur following a rule-based approach based on a i3+3 design 2 with a target resection level limiting toxicity (RLT) probability of 0.25 and an equivalence interval (EI) of 0.20 to 0.30, meaning that the RLT rate must not exceed the upper bound of the equivalence interval (EI) in order to extend the distance from contrast enhancing edge or for a distance to be selected for validation/expansion in "dose" escalation (if already at the highest dose level). Given that variability in the data can be large in a small cohort, the i3+3 design requires 2 criteria are met when determining whether to stay at the current distance or to reduce. First, the RLT rate must exceed the upper bound of the EI (ie, ≥1 RLTs occur in 3 patients). Next, if subtracting 1 from the number of RLTs results in a RLT rate within the EI, then the i3+3 rules state to stay at the current level and enroll 3 additional patients (Note: if a cohort in Dose Escalation is expanded to 6 patients and the adjusted RLT rate remains within the EI, this dose may be further expanded/validated in dose expansion following discussion with the Independent Data Monitoring Committee \[IDMC\]/Safety Monitoring Committee \[SMC\]). However, if the adjusted RLT rate still exceeds the EI, the rules state to enroll 3 patients at the next lower level.
Decision Rule Table (source https://i3design.shinyapps.io/i3plus3/) :
Following the completion of resection level escalation, a recommended maximum resection (MR) will be calculated using all available RLT data. The recommended MR will be calculated using an isotonic regression. Under this framework, the MR is the resection for which the isotonic estimate of the RLT rate is closest to the target RLT rate of 0.25. The recommended MR or a lower recommended level will be selected as the primary recommendation or resection.
As a secondary objective, if the MR is greater than the standard of care resection, (the DSMB recommendation is that a certain interval of CEST-EPI resection is safe) the MR will be used for a single-arm preliminary efficacy analysis compared to propensity matched historical controls of resection of IDH-WT GBM. If this expansion is carried out, we will carry out CEST-EPI resections at the MR in 16 patients using the same protocol and follow up as described above. Follow up will additionally include interval MRI as recommended by RANO 2.0 1 to calculated PFS and OS. Comparisions with historical controls will be carried out with cox regression analyses.
As additional secondary data, an objective measure of tumor burden will be evaluated. Tumor tissue will be collected from each resection. The secondary endpoint of this study is to determine the dependence of pH-sensitive amine CEST-EPI contrast on "active" tumor density. This will be measured through immunohistochemical staning of tumor (via H\&E, anti-EGFR for EGFR amplified tumors), and proliferative tumor (anti-Ki67) which will be reviewed by blinded neuro-pathologist. Comaprisions of tumor burden across CEST-EPI and 5-ALA metrics will be compared with paired sample chi square tests and linear regression analysis. A study timeline is shown below.
5 CRITERIA FOR EVALUATION 5.1 Primary Efficacy Endpoint The primary endpoint for this study will be the safety of resecting CEST-EPI positive regions of glioblastoma.
5.2 Safety Evaluations This is an additional risk study and all safety evaluations will be reviewed as described below by JCCC DSMB and at multidisciplinary brain tumor board including neurosurgeons, neuro-oncologists, neuro-radiologists, and neuro-pathologists. Safety will be evaluated by "resection limited toxicities" (RLTs) and are pre-defined and are listed in detail below.
