bluuebunny/crossref_metadata_2025 huggingface dataset:
CTIM-41. ONCOLYTIC IMMUNOTHERAPY LINKS IMMUNOACTIVATION TO SUBJECT SURVIVAL IN PHASE I TRIAL OF RECURRENT GLIOBLASTOMA
Authors: Ling Alexander , Solomon Isaac , Nakashima Hiroshi , Santos Andres , Barone Francesca , Reardon David , Chiocca E Antonio
Published: November 2023

A “first-in-human” phase 1 trial of intralesional injection of CAN-3110, an immunotherapeutic oncolytic based on herpes simplex virus 1 (HSV1), was conducted in 41 subjects with recurrent high-grade glioma (rHGG). The impact of CAN-3110 on the tumor immune microenvironment was assessed using immunohistochemistry, multiplexed immunofluorescence, TCR-beta DNA sequencing, and bulk RNA sequencing of paired pre- and post-treatment samples. These analyses were combined with patient features to identify potential biomarkers of therapy response in rHGG. In IDH wild type recurrent glioblastoma (IDHwt rGBM) patients, post-treatment survival times were positively associated with positive pre-treatment HSV1 serology after controlling for additional covariates such as tumor volume, age, gender, CAN-3110 dose, etc. (HR = 0.16, p < 0.001, n = 32, CoxPH). Positive HSV1 serology was also significantly associated with clearance of CAN-3110 from injected tumors. Interestingly, increased intratumoral CD8 and CD4 T cell numbers following treatment were positively associated with prolonged survival in HSV1 seropositive patients (p = 0.017 and 0.026, respectively), but not when analyses were conducted including HSV1 seronegative patients. Likewise, post-treatment immune expression signatures (such as for antitumor cytokines, T cell traffic, etc.) were more strongly associated with prolonged survival for HSV1 seropositive patients than for seronegative patients, and most assessed immune signatures only became associated with survival after CAN-3110 treatment. Extended survival was also associated with increased TCR-beta diversity following therapy in both the tumor and in PBMCs. Combined with a lack of observed dose-limiting toxicities and a median post-treatment survival of 14.2 months (95% CI: 9.5-15.7) in IDHwt rGBM patients with positive HSV1 serology, these data provide evidence that intralesional CAN-3110 treatment can instigate immune activation in a traditionally immunologically cold tumor and that this immune activation may influence survival time—particularly when patients have had prior exposure to HSV1. (clinicaltrials.gov NCT03152318).
CTNI-01. LONG-TERM RESULTS FROM A PHASE 1 TRIAL OF SPINE SBRT IN INOPERABLE PATIENTS WITH CORD COMPRESSION
Authors: Ghia Amol , Guha-Thakurta Nandita , Li Jing , McAleer Mary Frances , Briere Tina , Tatsui Claudio , Brown Paul , Beckham Thomas , Wang Chenyang , Yeboa D Nana , Chang Eric , Rhines Laurence
Published: November 2023

PURPOSE/OBJECTIVE

We seek to establish the feasibility of using spine stereotactic radiosurgery (SSRS) allowing for spinal cord dose constraint relaxation as the primary management of metastatic epidural spinal cord compression (MESCC) in inoperable patients monitoring for radiation myelopathy (RM) and radiographic local control (LC).

MATERIAL/METHODS

Patients with radiation naïve MESCC were enrolled on this prospective Phase 1 trial. Single fraction SSRS was delivered to a dose of 18 or 24 Gy. Spinal cord constraint relaxation was performed in sequential cohorts from an initial allowable Dmax cohort of 10 Gy up to 16 Gy only if tumor progression occurred without RM.

RESULTS

Thirty two patients enrolled on the trial of which 4, 12, 8 and 8 were in the 10 Gy, 12 Gy, 14 Gy and 16 Gy cord Dmax cohorts, respectively. At baseline, there were 10 sites with MESCC Grade 1B, 10 sites with Grade 1C, 9 sites with Grade 2, 2 sites with Grade 1A, and 1 site with Grade 3 disease. Of the 28 evaluable patients, the median overall survival was 32.3 months (range 5.8-122.6 mo). The 1-year and 5-year LC was 84.5% and 79.5%. The 2-year LC did not statistically differ between the 14-16 Gy cord Dmax combined cohorts and the 10-12 Gy cord Dmax combined cohorts (92.9% vs. 62.9%, p = 0.15). With a median clinical follow-up of 22.7 months (range 3-122.3 mo), there were no cases of RM including in the 13 patients who survived at least 3 years. In the cohort receiving a cord Dmax of 16 Gy, there were no cases of RM with a median follow-up of 18.6 mo (range 9.0-97.1 mo).

CONCLUSION

With long-term follow-up, these data demonstrate that SSRS is a safe and effective tool in patients with MESCC. Cord constraint relaxation may be considered in inoperable patients with MESCC.
CTNI-02. A LONGITUDINAL THERAPY RESPONSE MONITORING STUDY IN SUBJECTS WITH LEPTOMENINGEAL METASTASES USING CNSIDE COMPARED TO STANDARD OF CARE (CSF CYTOLOGY, CLINICAL EVALUATION, IMAGING)
Authors: Nagpal Seema , Youssef Michael , Beruti Sue , Gillis Laura , Gordon Kelly , Blouw Barbara , Kumthekar Priya
Published: November 2023

LM is diagnosed via clinical evaluation, neuroaxis neuroimaging (MRI brain and spine), and CSF cytology. These methods have limited sensitivity and specificity, and lack the ability to quantitatively measure the LM’s response to treatment. These hindrances create challenges in LM diagnosis and management for physicians. CNSide is a commercially available Laboratory Developed Test (LDT) that is analytically validated for the detection and characterization of tumor cells in the CSF, and run commercially in Biocept’s CLIA-certified, CAP-accredited laboratory. Physicians order CNSide testing at their discretion for patients that have a suspicion of LM. To evaluate the performance of CNSide for LM disease management in a controlled setting, Biocept is conducting a prospective, multi-center clinical study (FORESEE, NCT05414123) involving patients previously diagnosed with NSCLC or Breast Cancer and a suspicion or diagnosis of LM per standard of care (SOC) management, including clinical assessment, radiographic evaluation, and CSF cytology. At baseline and at designated time points throughout treatment, matched CSF samples will be analyzed in parallel with standard of care CSF cytology and CNSide at Biocept along with time matched neuroimaging and clinical evaluation. The primary end point of the trial is the proportion of decision points during LM treatment in which physicians indicated that CNSide aided in their decision making. Physicians will also indicate which component of the test aided in management, modeling other similar studies that measure the effect of serum biomarker results on clinical management of cancer. Secondary end points include diagnostic comparison to clinical evaluation, cytology, and radiographic results, and determining the sensitivity, specificity, PPV and NPV of CNSide in the detection of CSF tumor cells (cytology being the reference standard).
CTNI-04. PHASE I STUDY OF RADIATION THERAPY (RT) FOLLOWED BY INTRATHECAL (IT) TRASTUZUMAB/PERTUZUMAB IN THE MANAGEMENT OF HER2+ BREAST LEPTOMENINGEAL DISEASE (LMD)
Authors: Ahmed Kamran , Kumthekar Priya , Pina Yolanda , Kim Youngchul , DeJesus Michelle , Evernden Brittany , Oliver Daniel , Vogelbaum Michael A , Tran Nam , Liu James , Etame Arnold , Armaghani Avan , Costa Ricardo , Soyano Aixa , Lee Kimberley , Arrington John , Rosa Marilin , Soliman Hatem , Yu Hsiang-Hsuan Michael , Han Hyo , Forsyth Peter
Published: November 2023

BACKGROUND

IT trastuzumab is used in the management of HER2+ breast LMD. The monoclonal antibody pertuzumab is used with trastuzumab in the management of metastatic and localized HER2+ breast cancer.

METHODS

The study is a multi-institutional, phase I/II trial of RT followed by IT trastuzumab/pertuzumab. HER2+ LMD patients with a life expectancy >8 weeks were eligible. Treatment was initiated with RT, whole brain and/or focal brain/spine RT followed by IT trastuzumab/pertuzumab. The dose of IT trastuzumab was fixed at 80 mg with a dose escalation of IT pertuzumab. An mTPI-2 design was used to determine the recommended phase II dose (RP2D). Each cycle was 4 weeks with 2x/week treatment in cycle 1, weekly in cycle 2, and every two weeks thereafter. Clinical trial information: NCT04588545.

RESULTS

A total of 9 patients were enrolled. Median age was 51 (range: 34-63). Seven patients (78%) were hormone receptor (HR)-/HER2+ and two were HR+/HER2+. Four dose cohorts were treated 10, 20, 40, each with one patient and 80 mg pertuzumab with six patients. Study therapy was well tolerated with no dose limiting toxicities identified. Toxicities at least partially attributable to study therapy included fatigue [grade 1 (n = 2); grade 2 (n = 1)], grade 1 extremity pain (n = 1), and grade 1 headaches (n = 1). Two patients were noted to have infected Ommaya reservoirs after which one patient resumed treatment while one patient stopped therapy after noting stable LMD for approximately 24 months. Median survival has not been reached with a 12 month OS of 86%. Best leptomeningeal response has been a partial response in 4 patients (44%) and stable disease in 5 patients (56%). Six patients continue study therapy currently.

CONCLUSIONS

Study therapy was well tolerated with a pertuzumab RP2D of 80 mg. Preliminary efficacy appears encouraging and continues to be assessed in the phase II portion.
CTNI-07. PHASE I STUDY OF PAXALISIB AND RADIOTHERAPY FOR CNS DISEASE HARBORING PI3K PATHWAY MUTATIONS: PILOT ANALYSIS OF CIRCULATING TUMOR DNA FOR PATIENT ELIGIBILITY CONFIRMATION AND POST-TREATMENT RESPONSE
Authors: Imber Brandon , Ravichandran Vignesh , Rao Pavitra , Casanova Hilary , Friend John , Simpson Jeremy , Pike Luke , Zinovoy Melissa , Mitchell Ryan , Chacko Christina , Kotecha Rupesh , Somai Somica , Boire Adrienne , Gavrilovic Igor , Piotrowski Anna , Wilcox Jessica , Malani Rachna , Young Robert , Offin Michael , Diamond Eli , Yang Jonathan
Published: November 2023

INTRODUCTION

Radiotherapy (RT) is effective for brain metastases (BM) or leptomeningeal disease (LMD), but disease control is poor for tumors harboring PI3K pathway alterations (PI3Kalt). We hypothesized that combining RT with paxalisib, a CNS-penetrant PI3K/mTOR inhibitor, offers therapeutic synergy. The role of plasma circulating tumor DNA (ctDNA) to confirm study eligibility and response monitoring is unclear.

METHODS

This is a multi-institutional, phase I trial of concurrent paxalisib and whole brain RT (30 Gy in 10 fractions, NCT04192981) for CNS disease. To establish eligibility, patients had documented PI3Kalt performed using institutional tumor targeted sequencing (MSK-IMPACT) of primary or metastatic tumors (eligibility sequencing). Plasma ctDNA was collected at baseline and 3-, 6- and 9-months post-treatment and sequenced using institutional plasma ctDNA targeted sequencing platform (MSK-ACCESS). Our objectives were to a) determine PI3Kalt concordance between eligibility sequencing and baseline ctDNA and b) analyze quantitative post-treatment plasma ctDNA dynamics.

RESULTS

Between 3/2020-5/2023, 15 patients were enrolled to receive daily paxalisib (45mg, n = 11 or 60mg, n = 4) and WBRT. Twelve were treated for BM and 3 for LMD. Eligibility sequencing was determined a median of 8.1months (range: 2.4-38.6) pre-study enrollment and the most common PI3Kalt were PIK3CA (n = 7), INPP4B (n = 2), INPPL1 (n = 1) and PIK3CG (n = 1), and PTEN copy number alterations (homdel n = 2). Baseline ctDNA was sequenced from 13/15 patients (18 samples: baseline = 13, 3-months = 4 and 6-months = 1). We confirmed 100% of PIK3CA mutations using baseline ctDNA. One breast cancer BM patient demonstrated significant variant allele frequency reduction from 50% (baseline) to 0.1% (3-months post-treatment) for two tracked PIK3CA mutations (p.E545K and p.A1066V), which correlated with a partial response per RANO-BM.

CONCLUSIONS

For patients on genomically-driven targeted therapy and RT combination trials, alterations detected using plasma ctDNA, especially PIK3CA, may be used to rapidly assess eligibility. Serial ctDNA collection may serve as a potential response biomarker with further validation.
CTNI-09. DOSE ESCALATION FOR NEOADJUVANT STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: PHASE I RESULTS
Authors: Murphy Erin , Yang Kailin , Suh John , Yu Jennifer , Stevens Glen , Angelov Lilyana , Vogelbaum Michael A , Barnett Gene , Ahluwalia Manmeet , Neyman Gennady , Mohammadi Alireza , Chao Samuel
Published: November 2023

BACKGROUND

Surgical resection may be required for large and symptomatic brain metastases. Adjuvant radiotherapy or stereotactic radiosurgery (SRS) is needed to reduce local recurrence. Adjuvant radiosurgery has been associated with higher rates of leptomeningeal failure and radionecrosis. We conducted a phase I trial for brain metastases greater than 2 cm in size to determine the safety of preoperative SRS at escalating doses.

METHODS

Radiosurgery dose was escalated at 3 Gy increments starting with RTOG 90-05 dosing for 3 cohorts based on maximum tumor diameter: 18 Gy for >2-3 cm, 15 Gy for >3-4 cm, and 12 Gy >4-6 cm. Dose limiting toxicity (DLT) was defined as grade III or greater acute toxicity. Patients underwent surgical resection within 2 weeks and were followed with imaging and physical evaluations every 3 months.

RESULTS

For tumor size >2-3 cm, patients were enrolled up to the second dose level (21 Gy); for >3-4 cm and >4-6 cm cohorts the third dose level (21 Gy and 18 Gy, respectively) was reached. 35 patients were enrolled with 36 brain metastases treated with preoperative radiosurgery. There were 2 DLT (wound issues) in the >3-4 cm arm at the third dose level and 1 DLT (hemorrhage) in the >4-6 cm arm at the third dose level. The maximal tolerated SRS dose (MTD) for >-2-3 cm arm was not reached, for >3-4 cm arm was 18 Gy and for >4-6 cm arm was 18 Gy. With a median follow-up of 64 months, the 6- and 12-month local control rates were 88.8% and 79.1%, respectively. The 2-year rate of LMD was 0%.

CONCLUSION

This Phase I preoperative SRS dose escalation trial found a MTD for brain metastases greater than 3 and up to 6 cm in size. The phase II trial will be conducted at the maximum tolerated SRS doses.
CTNI-17. APPLICATION OF THE GBM-X DATA PLATFORM TO ESTIMATE TREATMENT EFFECTS OF THE EXPERIMENTAL THERAPIES OF THE RANDOMIZED PHASE 2 INDIVIDUALIZED SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPIES
Authors: Rahman Rifaquat , Trippa Lorenzo , Fell Geoffrey , Lee Eudocia , Arrillaga-Romany Isabel , Touat Mehdi , Drappatz Jan , Welch Mary , Galanis Evanthia , Ahluwalia Manmeet , Colman Howard , Nabors Burt , Hepel Jaroslaw , Elinzano Heinrich , Schiff David , Chukwueke Ugonma , Beroukhim Rameen , Nayak Lakshmi , McFaline-Figueroa Jose Ricardo , Batchelor Tracy , Rinne Mikael , Kaley Thomas , Lu-Emerson Christine , Mellinghoff Ingo , Bi Wenya Linda , Arnaout Omar , Peruzzi Pier Paolo , Haas-Kogan Daphne , Tanguturi Shyam , Cagney Daniel , Aizer Ayal , Doherty Lisa , Santagata Sandro , Meredith David , Antonio Chiocca E , Reardon David , Alexander Brian , Ligon Keith , Wen Patrick
Published: November 2023

BACKGROUND

Leveraging external data has the potential to increase efficiency and precision of drug development in glioblastoma by complementing or replacing data from in-trial controls. We used an external control arm (ECA) to re-analyze data of the abemaciclib, neratinib and CC-115 arms of the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial.

METHODS

INSIGhT (NCT02977780) is an ongoing phase 2 adaptive platform trial in newly diagnosed MGMT unmethylated glioblastoma with a shared control arm of patients receiving radiation therapy with concurrent and maintenance temozolomide. The initial experimental arms (abemaciclib, neratinib, CC-115) have not shown a survival benefit relative to the shared control arm. We re-analyzed the experimental arm data and replaced the shared control arm with an ECA. The ECA was developed from a collection of trial datasets and real-world data available through the Glioblastoma External (GBM-X) Data Platform (). Propensity score matching was used to adjust for possible differences between pretreatment covariates (age, sex, resection, KPS) in the ECA and shared control arm. Cox proportional hazards models were used to estimate treatment effects.

RESULTS

On INSIGhT, patients were randomized to abemaciclib (n = 74), neratinib (n = 80), and CC-115 (n = 12). There were 687 unmethylated MGMT patients in the GBM-X ECA. After propensity score matching, there was no significant treatment effect associated with abemaciclib (HR 1.091, 95%CI:0.834-1.433, p = 0.536), neratinib (HR = 1.043, 95%CI:0.787-1.383, p = 0.770), or CC-115 (HR 1.088, 95%CI:0.834-1.433, p = 0.794) compared to the ECA.

CONCLUSION

In comparison to an ECA, there was no significant survival benefit with abemaciclib, neratinib and CC-115. Treatment effects estimates were similar to the primary analyses based on the original shared control arm of INSIGhT. The use of external control arms in early phase testing of new therapies is supported by our findings and could significantly reduce costs and time to conduct trials in newly diagnosed glioblastoma.
CTNI-21. PHASE I STUDY OF BTK INHIBITOR IBRUTINIB WITH TEMOZOLOMIDE AND RADIATION IN NEWLY-DIAGNOSED GLIOBLASTOMA (EQUILIBRIUM): FINAL TRIAL REPORT
Authors: Ahluwalia Manmeet , Ozair Ahmad , Khosla Atulya , Patel Neha , Elson Paul , Murphy Erin , Chao Samuel , Suh John , Stevens Glen , Peereboom David
Published: November 2023

BACKGROUND

Glioblastoma carries dismal prognosis for which novel therapeutics are urgently needed. Ibrutinib, an oral small molecule inhibitor of BTK, has been shown in preclinical models to inhibit cancer stem cells in glioblastoma. We sought to investigate safety and tolerability of ibrutinib for newly-diagnosed glioblastoma (nGBM).

METHODS

EQUILIBRIUM was a prospective, phase I trial conducted in nGBM patients with KPS ≥ 70% and normal organ function. Patients received standard of care chemoradiation plus ibrutinib in a 3 + 3 dose-escalation design (level 1: 420 mg daily, level 2: 560 mg daily, level -1: 280 mg daily). Primary study objective was to determine maximum tolerated dose (MTD) of ibrutinib in combination with radiotherapy (RT) of 60Gy over 6 weeks with/without 75 mg/m2 of temozolomide (TMZ) in MGMT methylated and unmethylated cohorts respectively. Secondary objective was to determine safety, overall survival (OS), and progression-free survival.

RESULTS

26 patients were enrolled, with 12 (46%) females. Median age was 61.5 years (range 76-22). 15 (58%) patients were MGMT methylated and 11 (42%) were unmethylated. Dose-limiting toxicities (DLTs) were observed at all dose levels of ibrutinib+RT arm. MTD of ibrutinib was noted to be 420 mg daily with RT+TMZ in methylated arm. In Ibrutinib+RT+TMZ arm, median cycles of TMZ were 4 (range 0-6) and of ibrutinib were 3 (range 0-26). Median OS for MGMT methylated arm was 26.0 (22.0-NA) months and for MGMT unmethylated cohort was 14.0 (8.54-NA) months. Median OS for EGFR-amplified was 29.5 (21.9-NA) months and for EGFR-non-amplified was 21.8 (16.6-NA) months. 2-year OS for MGMT methylated arm was 56% (34-95%) and for MGMT unmethylated arm was 2% (6-70%).

CONCLUSIONS

420 mg of Ibrutinib daily is safe and feasible with TMZ and RT for nGBM. Ibrutinib appears promising compared to historical outcomes in MGMT methylated patients. EGFR-amplified patients potentially derive significant benefit. Trial information: NCT03535350.
CTNI-26. EFFICACY AND SAFETY OF METFORMIN PLUS LOW-DOSE TEMOZOLOMIDE IN PATIENTS WITH RECURRENT OR REFRACTORY GLIOBLASTOMA: A RANDOMIZED, PROSPECTIVE, MULTICENTER, DOUBLE-BLIND, CONTROLLED, PHASE 2 TRIAL
Authors: Yoon Wan Soo , Chang Jong Hee , Kim Jeong Hoon , Kim Yu Jung , Jung Tae Young , Yoo Heon , Kim Se-Hyuk , Nam Do-Hyun , Kim Tae Min , Kim Se Hoon , Park Sung Hye , Lee Youn Soo , Kim Hyeon Woo , Hong Yong-Kil , Yang Seung Ho
Published: November 2023

Glioblastoma(GBM) has a poor prognosis after standard treatment. Recently, metformin has been shown to have an antitumor effect on glioma cells. We performed the first randomized prospective phase II clinical trial to investigate the clinical efficacy and safety of meformin in patients with recurrent or refractory GBM treated with low-dose temozolomide (TMZ). Included patients were randomly assigned to a control group [placebo plus low-dose TMZ (50mg/m2, daily) or and experimental group [metformin (1,000mg, 1,500mg, and 2,000mg per day during the 1st, 2nd, and 3rd week until disease progression, respectively) plus low-dose TMZ]. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), disease control rate, overall response rate, health-related quality of life, and safety. Among the 92 patients screened, 81 were randomly assigned to the control group (43 patients) or the experimental group (38 patients). Although the control group showed a longer median PFS, the difference between the two groups was not statistically significant (2.66 versus 2.3 months, p = 0.679). The median OS was 17.22 months (95% CI:12.19-21.68 months) in the experimental group and 7.69 months (95% CI: 5.16-22.67 months) in the control group, showing no significant difference by the log-rank test (HR:0.78; 95% CI:0.39-1.58; p = 0.473). The overall response rate and disease control rate were 9.3% and 46.5% in the control group and 5.3% and 47.3% in the experimental group, respectively. Although the metformin plus TMZ regimen was well tolerated, it did not confer a clinical benefit in patients with recurrent or refractory GBM.
CTNI-27. TRIAL IN PROGRESS A PHASE 2 STUDY OF BPM 31510 (AN OXIDIZED COQ10-LIPID CONJUGATE NANODISPERSION) WITH VITAMIN K AND STANDARD CHEMORADIATION IN NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Stocksdale Brian , Bertrand Sophie , Villanueva Eleanor , Naya Lewis , Molaie Donna , Lyng Arianne , Berman Brian , Vishnudas Vivek , Kiebish Michael , Gesta Stephane , Narain Niven , Recht Lawrence , Nagpal Seema
Published: November 2023

INTRODUCTION: BPM 31510 is a novel drug-lipid conjugate nanodispersion that significantly increases the bioavailability of ubidecarenone (oxidized CoQ10). Supraphysiological concentrations of CoQ10 have been shown to have a paradoxical pro-oxidant effect on a variety of malignant cells while not altering the metabolic phenotype in normal cells. Glioblastoma multiforme (GBM) is a metabolically active cancer that is reliant on mechanisms of redox homeostasis to avert reactive oxygen species (ROS)-triggered apoptosis. This trial investigates whether this susceptibility of GBM metabolism may be effectively targeted by the potentially synergistic combination of BPM 31510 and standard-of-care radiotherapy, a known producer of ROS. Early-phase trials of BPM 31510 have shown a favorable safety profile with primarily hepatotoxicity and coagulopathy, the latter of which is mitigated by co-administration of Vitamin K. TRIAL DESIGN: BPM 31510IV-11 (NCT04752813) is a single-arm multicenter phase 2 study of BPM 31510 + Vitamin K1 in combination with standard chemoradiation for newly diagnosed GBM. Eligible patients have GBM with no prior therapy, and those with recent hemorrhage, coagulopathy, or who require anticoagulation are excluded. BPM 31510 starts 2-4 weeks after biopsy or resection initially as monotherapy for 2 weeks followed by an additional 6 weeks in combination with temozolomide-based chemoradiation. To assess safety of BPM 31510 with concomitant chemoradiotherapy, this study begins with a dose confirmation phase and allows for one dose reduction in the event of a DLT. The starting dose of BPM 31510 is 110 mg/kg administered as a continuous infusion over 96-hours weekly. The primary endpoint is 6-month progression-free survival (PFS6) by RANO criteria. Secondary endpoints include overall survival and safety. Approximately 50 patients will be enrolled for 90% power in rejecting the null hypothesis of PFS6 ≤ 30%. The study is enrolling at two US sites with a third opening soon.
CTNI-28. FINAL RESULTS OF A PILOT STUDY TO EVALUATE INFUSION RATE ESCALATION TO MAXIMIZE VOLUME OF DISTRIBUTION DURING CONVECTION ENHANCED DELIVERY TO CONTRAST-ENHANCING GLIOBLASTOMA
Authors: Liu James , Tran Nam , Piteo Cecily , Matzza Sebastian , Forsyth Peter , Vogelbaum Michael A
Published: November 2023

BACKGROUND

Volume of distribution (Vd) during convection enhanced delivery is impacted by the characteristics of the tissue being treated. For Glioblastoma (GBM), Vd is substantially higher in non-contrast enhancing tumor than in contrast enhancing tumor due to higher infusate efflux in enhancing tumor. We hypothesized that increasing the infusion rate could overcome the infusate efflux rate in enhancing tumor to improve the Vd to volume of infusion (Vi) ratio and provide better tumor coverage.

METHODS

A single center, IRB-approved pilot study was conducted under an IND (held by MAV) to perform rate escalated delivery of Topotecan with Gadolinium-DTPA to contrast-enhancing recurrent GBM (rGBM). A single Cleveland Multiport Catheter was surgically placed into enhancing tumor and then a 4-hour infusion was performed with real-time MRI visualization. Intra- and inter-patient rate escalation was performed.

RESULTS

3 patients with rGBM were enrolled and treated. The initial infusion rate for patient 1 was 5 microliters/minute per microcatheter (4 total) and the final infusion rate for the third patient was 20 microliters/minute per microcatheter. We observed partial backflow at this rate and so did not escalate higher. There was coverage of both enhancing and non-enhancing tumor in all cases, and the Vd/Vi ratio ranged from 0.7 to 1.3. Patients tolerated the treatments well; there were no CTCAE Grade 3 or higher treatment related adverse events.

CONCLUSIONS

The higher efflux rate associate with contrast-enhancing tumor tissue can be overcome with sufficient infusion rate escalation.
CTNI-29. A PHASE 2 STUDY TO EVALUATE EFFICACY AND SAFETY OF ACT001 AND TEMOZOLOMIDE COMBINATION TREATMENT IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME
Authors: Li Wenbin , Li Qun , Wang Liang , Cai Dongpo , Yang Xunjun
Published: November 2023

BACKGROUND

Han Chinese patients with rGBM were randomly assigned to one of three cohorts in this phase 2 open label study: Arm A (ACT001, 400mg, BID), B (ACT001 and temozolomide combination) and C (TMZ or CCNU). Study endpoints include 1-year OS rate, PFS (by iRANO) and AE incidence.

RESULTS

7, 6 and 6 patients were enrolled to Arms A, B and C respectively including one patient in Arm C with a mutant IDH1 (R132H). The median age was 52 years (range: 34-68) and male to female ratio 11/8. In addition to 7 SAEs, 189 TEAEs were reported in this interim analysis including 49 and 70 chemo-related AEs in Arm B and Arm C. Post enrollment MRI scans were performed in 6,6 and 4 patients in Arms A, B and C respectively. Despite the lack of objective response and difference in 1-year OS, a prolonged PFS lasting at least 12 months was noted in 3 patients including the patient with mutant IDH1 in Arm C (23 months and ongoing) and two patients in Cohort B (19 and 22 months, both ongoing) who were sensitive to TMZ in first line treatment as shown by at least 12-month interval between TMZ initiation and first relapse. Among 18 patients with wild type IDH, the prolonged stable disease was restricted to combination Arm whereas either the four patients with positive MGMT methylation or two patients with a similar history of sensitivity to first line TMZ treatment didn’t have such prolonged stable disease after being treated with TMZ or ACT001 alone during this study.

CONCLUSIONS

ACT001 restored sensitization of rGBM patients to TMZ treatment in sub-group of patients likely due to reduced DNA repair capacity by ACT001 treatment. Further study is warranted to evaluate the effect of ACT001 and TMZ combination in phase 2b study.
CTNI-32. IMPLEMENTING GENOMIC PROFILING AS STANDARD-OF-CARE FOR GLIOBLASTOMA PATIENTS
Authors: Fougner Vincent , Urup Thomas , Hasselbalch Benedikte , Poulsen Hans , Rohrberg Kristoffer , Spanggard Iben , Højgaard Martin , Belcaid Laila , Yde Christina , Lassen Ulrik , Noeroexe Dorte
Published: November 2023

BACKGROUND

The introduction of targeted therapies (TT) has provided few new options for glioblastoma patients (pts). Implementing genomic profiling as standard-of-care may aid in finding new treatments for glioblastoma pts. Here, we report the impact of genomic profiling in pts with WHO grade 4 CNS tumors at the Department of Oncology, Rigshospitalet, Denmark.

METHODS

Eligible pts were ≥18 years of age, with newly diagnosed glioblastoma; astrocytoma, IDH mutated grade IV or diffuse midline glioma between January 2016 and December 2022. Whole exome sequencing (WES), whole genome sequencing (WGS) or panel sequencing with Trusight Oncology (TSO500) along with SNP-array analyses and RNAseq was performed on DNA/RNA extracted from tumor tissue. Tumor tissue from patients enrolled before 2021 were analyzed by WES, and from January 2021 and forth, WGS was used for frozen tissue and TSO500 for paraffin-embedded tissue. Each genomic profile was presented at a weekly national molecular tumor board meeting for multidisciplinary evaluation, treatment recommendations and matching with clinical trials.

RESULTS

387 pts had tissue samples available for analysis. Tissue from 202 patients (52%) were analyzed using WES, 174 (45%) using WGS, and 11 (3%) using TSO500. As of May 2023, of the 343 sequenced pts that have progressed after standard therapy, 14 patients (4%) have been treated with molecularly matched TTs. The actionable targets were TMB-high ( >10mut/MB) (n = 4), FGFR-mutations/-fusions (n = 4), BRAFv600E (n = 2), NTRK-fusions (n = 2), PDGFRA-fusion (n = 1) and MET-mutation (n = 1). Additionally, germline mutations were reported in 8 patients (2%).

CONCLUSION

Genomic profiling revealed actionable targets and new therapeutic options for glioblastoma pts. A full and updated overview of patient characteristics, actionable targets and survival data will be presented at the meeting.
CTNI-35. A RANDOMIZED, CONTROLLED TRIAL OF BERUBICIN VS. LOMUSTINE AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): INTERIM RESULTS OF A PRE-PLANNED ANALYSIS OF OVERALL SURVIVAL (OS)
Authors: Silberman Sandra , Muzyczenko Zena , Hsu Sigmund
Published: November 2023

Berubicin is an analog of doxorubicin (Dox) that appears to cross the BBB with significant central nervous system (CNS) uptake. RESULTS: of a Phase 1 dose-escalation study with 25 patients evaluable for efficacy showed 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%. Our current, potentially pivotal trial for patients with recurrent GBM after first-line therapy is enrolling in the US and Europe. It is unique in that all patients must be Grade 4 IDH WT, classifying these tumors as a poorer prognostic population than Grade 4 IDH mutated. Patients are randomized in a 2:1 design of Berubicin:Lomustine and stratified by MGMT methylation status. The primary endpoint is OS. Data has been presented showing that Berubicin and Lomustine arms are balanced with respect to MGMT status and demographics, with relatively comparable safety profiles (SNO Annual Meeting 2022 Abstract #383142). A pre-planned non-binding futlity analysis of the primary endpoint, OS, is being evaluated when the trial reaches ~30% of expected events (44 events). The interim analysis will be performed by an independent statistician under the supervision of the Data Safety Monitoring Board (DSMB). The futility analysis will be based on the conditional power that the trial will be positive (e.g., statistically significant difference between treatment groups’ OS). If the conditional power is <10% then the DSMB may recommend to end the study; otherwise the study will continue as it is currently planned. The review will also include safety and secondary efficacy endpoint summaries. RESULTS: of this interim analysis will be available for the SNO annual meeting and an evaluation of its outcome will be performed, with conclusions and recommendations for the further development of Berubicin as a therapeutic option for patients with recurrent GBM.
CTNI-36. SACITUZUMAB GOVITECAN FOR RECURRENT GLIOBLASTOMA
Authors: Kelly William , Balinda Henriette , Ghamasaee Pegah , Gilbert Andrea , Michalek Joel , Surapaneni Prathibha , Floyd John , Brenner Andrew
Published: November 2023

Glioblastoma (GBM) is an aggressive and highly malignant brain tumor characterized by its infiltrative growth, rapid progression, and poor prognosis. Sacituzumab govitecan (SG), an antibody-drug conjugate, has demonstrated antitumor activity and acceptable tolerability in patients with advanced epithelial cancers. It consists of a humanized anti-Trop-2 monoclonal antibody linked to a potent topoisomerase I inhibitor, SN-38. We conducted a prospective, single center, window of opportunity trial (NCT03995706) to examine the intra-tumoral concentrations of SN-38 in patients undergoing craniotomy for recurrent GBM (rGBM; n = 12). We enrolled patients aged ≥18 years diagnosed with rGBM to receive a single intravenous dose of SG at 10 mg/kg one day before surgical resection. Tumor and corresponding serum were collected during surgery to measure their levels of SN-38. Following recovery, patients resumed SG treatment at 10 mg/kg on days 1 and 8 of 21-day cycles and were accessed for responses by MRI every third cycle using response assessment in neuro-oncology (RANO) criteria. Trop-2 and carbonic anhydrase IX (CAIX) expression was investigated by IHC. An average of 2850.6 ng/ml in serum and 128.7 ng/g in tissue of SN-38 was quantified in our patient samples. Trop-2 expression was observed in 50% of patient tumors and 38% of the samples showed high expression of hypoxia marker CAIX. A strong positive correlation between the tissue/serum SN-38 and Trop-2 (r = 0.86, p = 0.01) was observed. Median overall survival of 17.5 months (0.9 - 28.5 months) and progression free survival of 2 months (0.5 - 12 months) were observed. A multicenter, phase II clinical trial has been initiated to further investigate the efficacy of SG in patients with breast brain metastasis. Updated data on response rates and accrual to the multicenter trial for rGBM will be presented
CTNI-38. RACTAC TRIAL: PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS COMBINATION WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS
Authors: Pace Andrea , Lombardi Giuseppe , Villani Veronica , Benincasa Dario , Abruzzese Claudia , Cestonaro Ilaria , Corrà Martina , Cerretti Giulia , Caccese Mario , Silvani Antonio , Gaviani Paola , Giannarelli Diana , Paggi Marco
Published: November 2023

The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for more effective therapies, particularly for GBMs with unmethylated MGMT. Drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use for psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability, induced polyploidy, reduced cloning efficiency as well as neurosphere formation. Moreover, chlorpromazine synergized with temozolomide, in reducing cell viability and cooperated in reducing cloning efficiency and inducing cell death. With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ was administered orally at a dose of 50 mg/day – GG 1-28 – of every cycle of the adjuvant treatment with TMZ. . Efficacy outcomes were evaluated using Kaplan–Meier methodology. OS was measured from diagnosis to death; PFS was determined from radiotherapy to PD or death due to any cause. Between April 2020 and June 2022, 45 patients who met the eligibility requirements were screened. Forty-one patients received at least one cycle of treatment and were included in the analysis. 43 patients have been enrolled, 29 male, 12 female. 20 patients completed 6 cycles of treatment, without relevant toxicity. The results show a median PFS of 8 months (St.Dev. 5,7) and a median OS of 15 months (St.Dev. 6,9). The addition of Chlorpromazine to temozolomide was well tolerated in newly diagnosed Glioblastoma unmethylated patients, with promising impact on outcome measures.
CTNI-48. SURVIVAL, TOXICITY, AND PATIENT REPORTED QOL OUTCOMES FOLLOWING PULSED REDUCED DOSE RATE RE-IRRADIATION WITH CONCURRENT BEVACIZUMAB FOR RECURRENT GRADE 4 GLIOMAS: RESULTS OF A PHASE II STUDY
Authors: Morris Brett , Burr Adam , Weiss Marissa , Anger Nicholas , Harari Colin , Tomé Wolfgang , Bayliss Robert , Bhatia Ankush , Grogan Patrick , Robins Henry , Howard Steven
Published: November 2023

Grade 4 gliomas are aggressive primary brain tumors with dismal prognosis despite maximal treatment. Recurrent disease is typically found within the prior radiation treatment field, complicating reirradiation. Pulsed reduced dose rate (PRDR) radiation is a treatment technique that reduces effective dose rate and increases treatment time allowing for intrafraction repair. Bevacizumab is a systemic VEGF inhibitor with efficacy in treating gliomas. We conducted a phase 2 prospective trial combining PRDR radiation with biweekly bevacizumab (10 mg/kg) in patients with recurrent grade 4 gliomas. Radiation was delivered with reduced dose rate delivered in 20 cGy pulses every 3 minutes in 2 Gy daily fractions to a total dose of 54 Gy. Kaplan Meier analysis was utilized to calculate progression free survival (PFS) and overall survival (OS). Toxicities were evaluated based on Common Terminology Criteria for Adverse Event v5.0 criteria. Mini Mental Status Examination (MMSE), as well as FACT-Brain, and FACIT-Fatigue patient reported quality of life (QoL) surveys were collected at baseline and follow up visits. Minimal important difference scores were calculated using by ½ standard deviation method. A total of 36 patients were enrolled, with 77% having previously received additional therapy for recurrent disease prior to study enrollment. Median PFS was 4.9 months and median OS was 6.9 months. No grade 4+ toxicity was observed. Two patients had grade 3 treatment related toxicity (seizure and radiation necrosis, both PRDR related). Treatment related grade 2 toxicity was seen in 44% of patients, primarily fatigue (30%). Clinically significant decrease in mean MMSE score, and FACT-BR QoL metrics across all sub-domains were noted in follow up. No clinically significant difference in mean FACIT-Fatigue QoL metric was observed. In this prospective phase 2 trial, PRDR with concurrent bevacizumab resulted in encouraging survival outcomes with acceptable toxicity in patients with recurrent grade 4 gliomas.
CTNI-57. PRELIMINARY RESULTS OF A PHASE 1 TRIAL OF ORAL GALLIUM MALTOLATE IN RECURRENT GLIOBLASTOMA
Authors: Connelly Jennifer , Zoss Casey , Schmainda Kathleen , Al-Gizawiy Mona , Pinheiro Fernando Santos , Chitambar Christopher
Published: November 2023

BACKGROUND

Glioblastoma (GBM) is an aggressive brain tumor with a dismal prognosis. New drugs that exploit previously underexplored cancer-related pathways are needed. We and others have shown that GBM stem cells require significantly greater amounts of iron than normal cells to drive critical iron-dependent processes that are altered in malignancy. We showed that oral gallium maltolate (GaM), an iron-targeting metal compound, has significant activity against GBM stem cells in vitro and shrinks GBM tumors and prolongs survival in a rat brain tumor model. GaM’s mechanisms include inhibition of cellular iron homeostasis, ribonucleotide reductase, and mitochondrial complex 1. Further study of GaM’s toxicity and benefit in patients with recurrent GBM is warranted.

METHODS

The Phase 1 trial design follows a 3 + 3 dose escalation scheme. Eligible patients will receive GaM at 3 dose levels: 500, 1,000, or 1,500 mg/day for a minimum of two 28-day cycles. Hepatic, renal, and hematologic functions, iron panel, and gallium levels are monitored every 2 weeks. Toxicity and tumor response are assessed by NCI CTCAE criteria and by RANO criteria, respectively. Patients with responding or stable disease may continue treatment with monitoring.

RESULTS

Ten patients have completed treatment at dose levels 1 and 2 and eight patients are evaluable. Four patients enrolled after first recurrence while the other four patients enrolled after their second, third (2 patients) and fourth recurrence. Median progression-free survival (PFS) on treatment was 118 days. Three patients experienced PFS >180 days and two of those patients remain on treatment. To-date, no dose-limiting toxicities (DLTs) at dose levels 1 and 2 have been encountered.

CONCLUSIONS

Oral GaM is well tolerated without significant DLTs to date. An additional 6 patients are presently enrolled at dose-level 3. Updated toxicity data and clinical outcomes of the study will be presented at the annual SNO meeting.
CTNI-63. A PHASE IIA CLINICAL TRIAL FOR COMBINATION OF NAVIGATION-GUIDE FOCUSED ULTRASOUND AND BEVACIZUMAB FOR PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Wei Kuo-Chen
Published: November 2023

INTRODUCTION

Bevacizumab (BEV), a vascular normalizing therapy that prolongs progression free survival (PFS) for patients with recurrent glioblastoma (rGBM). Focused ultrasound combines with microbubbles (MB-FUS), an emergent technology for targeted blood-brain barrier opening (BBBO), is under investigation for its combinatorial effect with current standard of care for GBM treatment. This study aims to evaluate the safety and efficacy of BEV + MB-FUS for treating patients with rGBM.

METHODS

This is a phase IIa, open-label, single-arm clinical trial (NCT04446416). Eligible patients received BEV (10 mg/kg), then MB-FUS with a MB dosage of 0.1 ml/kg and neuronavigation-guided FUS system (NaviFUS-001, NaviFUS, Taiwan). The MB-FUS is planned to be an add-on modality to the bi-weekly BEV therapy for up to 18 sessions (FUSBEV, 34 weeks).

RESULTS

Six patients underwent total 156 FUS-BEVs (26 times per patients). Three patients (50%) completed the trial protocol, 2 of another 3 patients had disease progression during the treatments, the remaining one patient was in stable disease. The mean progression free survival was 7.5 months. Among the 156 sessions of MB-FUS, there were 3 (1.9%) transient focal scalp pain related to heating. An evaluation of the MB-FUS penetrated regions revealed a significant normalization effect of T2 signal hyperintensity at beam-concentrated areas.

CONCLUSIONS

The PFS-6 was 67% in this study.

RESULTS

have demonstrated the safety, feasibility, and a potential to decrease edema by the mechanism of enhance bevacizumab delivery to the treated site. The preliminary results are encouraging. More data are needed to proof the efficacy of BEV-FUS on rGBM patients.
CTNI-64. EFFICACY AND SAFETY OF ERDAFITINIB IN PATIENTS WITH HIGH-GRADE AND LOW-GRADE GLIOMAS AND PRESPECIFIED FIBROBLAST GROWTH FACTOR RECEPTOR ALTERATIONS (FGFRALT) IN THE RAGNAR TRIAL
Authors: Reardon David , Welsh Liam , Shih Kent , Shimizu Toshio , Goeminne Jean-Charles , Geoerger Birgit , Baldini Capucine , Massard Christophe , Loriot Yohann , Pant Shubham , Sait Sameer Farouk , Thomas Shibu , Hammond Constance , Najmi Saltant , Triantos Spyros , Crow Lauren , Sweiti Hussein , Witt Olaf
Published: November 2023

BACKGROUND

Erda is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat adults with locally advanced/metastatic urothelial carcinoma with susceptible FGFR3/2alt who have progressed during/after ≥1 line of platinum-based chemotherapy. RAGNAR interim results demonstrated tumor-agnostic efficacy in adults/adolescents with previously-treated advanced solid tumors with prespecified FGFRalt. Here we report results for patients with HGG/LGG.

METHODS

Patients with HGG/LGG harboring prespecified FGFR1-4alt (mutations/fusions), disease progression after ≥1 line of systemic therapy, and who exhausted standard therapies received oral erda until disease progression or intolerable toxicity. Primary endpoint: ORR by independent review committee (IRC). Secondary endpoints: DOR, disease control rate (DCR), investigator-assessed efficacy, and safety. Response was based on RANO criteria.

RESULTS

At data cutoff, 37 HGG (n = 30)/LGG (n = 7) patients received erda. In HGG (glioblastoma, n = 25 [83%]; median (m) age 54.5y [range 13-70]), 29 (97%) had FGFR fusions (FGFR3-TACC3, n = 24); all (100%) underwent initial resection (if feasible) and received radiotherapy/chemotherapy per institution (eg, Stupp protocol); patients received median 2 prior therapies (range 1-6; 37% with prior bevacizumab). ORR in HGG was 10% by IRC (95%CI, 2-27) and 20% by Investigator (95%CI, 8-39); mDOR was not reached (m-F/U, 18.0mo); DCR was 57% (95%CI, 37-75). In LGG (m-age 22y; range 12-32), 4 (57%) had FGFR1 mutation (all FGFR1-K656E); 3 (43%) had FGFR fusion. ORR in LGG was 29% by IRC (95%CI, 4-71) and 14% by Investigator (95%CI, 0-58); mDOR was not reached; DCR was 71% (95%CI, 29-96). 17 HGG patients (57%) had TERT co-alterations; 9 (30%) had PTEN deletions. No HGG/LGG patients had IDH1/2 mutations. Most common (≥40%) adverse events (AEs): hyperphosphatemia, diarrhea, dry skin, dry mouth. 43% had serious AEs (treatment-related, 16%). 19% discontinued due to AEs. No treatment-related deaths occurred.

CONCLUSIONS

Erda demonstrated clinically meaningful activity in heavily pre-treated HGG/LGG with FGFRalt. Safety was consistent with known safety profile of erda.
CTNI-68. PHASE I/II STUDY OF MAINTENANCE THERAPY WITH METFORMIN AND TEMOZOLOMIDE FOR TARGETING GLIOBLASTOMA CANCER STEM CELLS
Authors: Narita Yoshitaka , Ohno Makoto , Kitanaka Chifumi , Tanaka Shota , Sonoda Yukihiko , Mishima Kazuhiko , Ishikawa Eiichi , Ohashi Ken , Nagane Motoo
Published: November 2023

BACKGROUND

Glioblastoma (GBM) is an aggressive primary brain tumor with poor prognosis. One strategy for overcoming resistance is developing a new therapy targeting the cancer stem/initiating cells. We have shown that the antidiabetic drug metformin (MF) can induce differentiation of stem-like glioma-initiating cells and suppress tumor formation through AMPK-FOXO3 activation (Stem Cells Transl Med. 2012;1(11)). We conducted a phase I/II study to examine the clinical effect of MF combined with standard maintenance temozolomide (TMZ). Patients and

METHODS

Patients between 20 and 74 years of age with supratentorial GBM were eligible. MF dose-escalation study was performed using a 3 + 3 design as phase I part to determine recommended phase II dose. Dose-limiting toxicities (DLTs) were assessed during the first 6 weeks after MF initiation. After completing phase I study, we proceeded to phase II part.

RESULTS

The first three patients were treated with 1,500 mg/day MF from 2021 and the next four patients were treated with 2,250 mg/day MF, which is the maximum dose approved in Japan. No DLTs were observed. The most common adverse effects were appetite loss, nausea, and diarrhea, which were observed in three patients. All of them were manageable, with grade 1 or 2 (Cancers (Basel). 2022;14(17)). Based on the phase I study, we proceeded to phase II study with 2,250 mg/day MF from April 2022 and finished recruiting patients for phase II part in May 2023. Primary endpoint of phase II trial is progression-free survival rate at 12 months compared to historical data.

CONCLUSION

MF dose of up to 2,250 mg/day combined with maintenance TMZ was well tolerated. We report the safety and efficacy of MF with TMZ for GBM.