Wen, Patrick Y.

Abstract Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood–brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0–like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.

Abstract Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40–50 ms at 1.5 T, 20–35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.

Abstract Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

2046 Background: Vorinostat (VOR) is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single-agent activity in recurrent disease (Galanis,et al, 2009) and radiosensitizing properties, this phase I/II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts): the phase I portion of the trial is the focus of this report. Methods: A standard cohorts of three design was used to assess the safety of VOR in combination with RT and concomitant TMZ and establish the phase II dose of the combination. VOR was given orally days 1 - 5 every wk beginning with the first dose of RT (total dose 60 Gy) and (75mg/m²/day). Following a 4 - 6 week rest, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR on days 1-7 and 15 – 21 of each cycle; dose was based on NABTT trial 04-03 (Lee, et al, 2012). Results: The phase I component is complete with 15 pts, 12 pts at dose level 0 (VOR 300 mg/day days 1 - 5, weekly x 6 wks), and 3 pts at dose level 1 (VOR 400 mg/day, days 1 – 5 weekly x 6 wks) in combination with RT/TMZ. Dose limiting toxicity (DLT) in dose level 1 included grade 3 fatigue in 2 pts, grade 3 wound dehiscence in 1 pt, and grade 4 neutropenia and thrombocytopenia in 1 pt. In dose level 0, 1/6 pts had DLT (gr 3 dyspnea). An MTD expansion cohort of 6 additional patients was added to dose level 0; one patient experienced grade 4 thrombocytopenia and grade 3 fatigue, and 1 patient experienced grade 3 febrile neutropenia. In the 12 pts treated in the phase II dose, most common toxicities were hematologic, including lymphopenia (gr 3/4 in 66.7%), thrombocytopenia (gr 3 in 16.7%, gr 4 in 16.7%) and neutropenia (gr 3 in 16.7%, gr 4 in 8.3%). Grade 3 fatigue was observed in 8.3% of the pts. Conclusions: MTD for VOR in combination with TMZ/RT in newly diagnosed GBM patients is 300 mg/d, days 1 - 5 weekly during RT. Toxicity was primarily hematologic. This dose was used in the recently completed phase II trial of the combination (110 pts). RNA expression profiling in patient samples is in process to assess vorinostat responsive signatures observed in preclinical models. Clinical trial information: NCT00731731.

2039 Background: Vorinostat (V) is an oral inhibitor of histone deacetylase. In preclinical studies it inhibits growth of glioblastoma (GBM) cell lines and has supra-additive activity when combined with TMZ. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I study of V in combination with TMZ in patients with malignant gliomas (MG). Eligibility criteria are histologically proven GBM and anaplastic gliomas (AG) who have received radiotherapy and have not progressed on temozolomide, > 18 yrs old, life expectancy > 8 weeks, KPS > 60, adequate bone marrow reserve and organ function. There was no limitation to the type of antiepileptic drugs that could be used. All patients received TMZ at a dose of 150 mg/m2/day on days 1–5 days every 28 days. Variable doses of V were administered with food on days 1–14 every 28 days. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade 4 hematologic toxicity except for grade 3 thrombocytopenia, and any grade 3 non-hematologic toxicities. Escalation was performed in standard groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 patients. PKs were determined on cycle 1 for TMZ, V and its metabolites. Results: To date, 19 eligible patients have been enrolled (15 GBM; 4 AG). Patients’ characteristics are 11 male, 8 female; median age 54 yrs (36–78); median KPS 90 (70–100). DLTs were encountered at 300 mg bid of vorinostat (1 grade 3 thrombocytopenia; 1 grade 3 fatigue in 3 patients), 200 mg tid (1 grade 3 nausea, 1 grade 4 thrombocytopenia in 3 patients) and 200 mg twice daily (grade 3 fatigue in 2/6 patients). No DLTs were encountered in 6 patients receiving 300 mg daily. TMZ PKs included [n=16: Cmax 5.2 (± 1.55) μg/ml; AUC 20.1 (±4.66) μg x hr/ml; t1/2 1.9 (±0.32)/hr]. Vorinostat PKs (300mg dose level) were [n=4; Cmax 267 (±174) ng/ml; AUC0–8 603 (±197) ng x hr/ml]. The t1/2 for V and its glucuronide metabolite were identical (1.6 hrs) vs. 5.6 hrs for the acid metabolite. Conclusions: The MTD of vorinostat in combination with TMZ is 300 mg daily on days 1–14 every 28 days. Final PK results, and toxicities from an additional 10 patients enrolled at the MTD will be presented. [Table: see text]

AbstractA recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

AbstractBuilding on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.

Abstract BACKGROUND A major impediment to improving neuro-oncology outcomes is poor clinical trial accrual. METHODS We convened a multi-stakeholder group including Society for Neuro-Oncology, Response Assessment in Neuro-Oncology, patient advocacy groups, clinical trial cooperative groups, and other partners to determine how we can improve trial accrual. RESULTS We described selected factors contributing to poor trial accrual and possible solutions. We focused on patient and community factors, disparities, physician and provider factors, clinical trial factors, and site and organizational factors CONCLUSIONS We will implement strategies with the intent to double accrual to neuro-oncology trials over the next 5 years.