PURPOSE:We developed a novel approach to treat newly diagnosed glioblastoma (GBM) using genetically modified gamma-delta (γδ) T cells following the forced upregulation of stress-associated targets on tumor cells. We leveraged the temozolomide (TMZ)-induced activation of the DNA damage response pathway to transiently upregulate the natural killer ligand (NKG2D-L) targets on GBM. Manufactured γδ T cells are engineered to be resistant to alkylating chemotherapies, including TMZ, through insertion of a methylguanine-DNA methyltransferase (MGMT)-expressing lentivector (DeltEx drug-resistant immunotherapy-DRI). METHODS:A total of 23 patients were enrolled, and 13 were treated (62% male; median age 66 years [range, 21-75]; 92% isocitrate dehydrogenase wild type (IDH-WT), 54% MGMT unmethylated, 46% subtotal resection). Cohorts 1, 2, and 3 received 1, 3, or up to 6 doses, respectively (1 × 107 DRI cells/dose), using a Rickham catheter, which was placed into the resection cavity. The DRI cells were dosed in combination with 150 mg/m2 intravenous (IV) TMZ once per day on Day (D) 1 of each maintenance cycle, which was followed by 4 days of oral TMZ. RESULTS:No dose-limiting toxicities were seen nor were any occurrences of cytokine release syndrome (CRS) or neurotoxicity (immune effector cell-associated neurotoxicity syndrome) observed. The median follow-up of patients who received DRI γδ T cells was 15.6 months. For Cohort 1 patients who received a single dose of DRI γδ T cells, the median progression-free survival (mPFS) was 8.0 months; the median PFS was 9.9 months for all patients and 16.1 months for patients who received repeated doses in Cohorts 2 and 3. The median overall survival for all patients was 15.6 months. CONCLUSION:To date, all patients had manageable toxicity with outpatient treatment and a continued encouraging trend in outcomes from repeated investigational treatments with intracranially delivered, longitudinal DRI γδ T cells.

Purpose Adjuvant radiation therapy for atypical meningiomas (AMs) aids in local control following surgery and salvage after recurrence. The role of fractionated stereotactic radiosurgery (FSRT) in this population remains an area of active study with many unanswered clinical questions. This single-institution retrospective study evaluates the local control, marginal control, and toxicity of FSRT in treating AM. Methods Between 2009 and 2022, 39 patients with WHO grade 2 AM underwent FSRT via marginless, frameless volumetric-modulated arc therapy (VMAT) at doses of 27.5-30 Gy in five fractions. Local recurrence was defined as an increase of 20% in the greatest cross-sectional diameter on MRI or CT, following RECIST criteria. Cavity and marginal recurrences were defined as any new lesion outside the prescription volume but within the resection cavity or within 2 cm of the resection cavity, respectively. High-grade toxicity was defined per Common Terminology Criteria for Adverse Events (CTCAE) v5. Resection for radionecrosis with viable residual tumor was considered a local failure. Results Twenty-six AMs were treated post-subtotal resection (STR), 16 post-gross total resection (GTR) with recurrence, and five treated definitively. Patient characteristics included a mean age of 54 years, 20 (51%) male patients, and 31 (79%) patients with ECOG 0-1. The three-year local control rate was 84.0%. Larger tumors were more likely to fail locally (p > 0.001). Two (5%) patients experienced high-grade toxicity necessitating resection. The three-year marginal control rate was 92.3%, and recurrent tumors post-GTR failed marginally more often compared to those treated after STR (p = 0.009). One (4%) tumor treated after STR failed marginally, while four (33%) tumors treated after GTR recurrence failed marginally. The three-year control rate of the unirradiated cavity was 88%. Conclusion The rate of high-grade toxicity in AM patients receiving FSRT was low. Local control appeared comparable to historical rates, which may suggest the potential need for dose escalation with longer-term follow-up. Recurrent tumors were more prone to marginal failures. Further investigation is needed to determine which patients may benefit from whole-cavity treatment, additional CTV margin, or prolonged fractionated dose schedules. Newer imaging studies, including DOTATATE PET, should be explored to assess whether improvements in targeting accuracy can enhance outcomes.

Purpose:Robustness evaluation is critical for proton beam therapy (PBT) planning, but ideal robustness criteria are not clearly defined. Here, we compared robustness of PBT plans to published intensity-modulated radiation therapy (IMRT)-derived clinical target volume (CTV) robustness benchmarks and assessed the dosimetric impact of meeting IMRT-derived benchmarks on adjacent organs at risk. Patients and Methods:Patients receiving PBT to 70 GyE in 28 fractions to the prostate alone from 2021 to 2022 at our institution were evaluated. PBT plan robustness was evaluated in nominal and worst-case data scenarios for CTV V100%, CTV V95%, rectum V70 Gy, and bladder V60 Gy. Clinically delivered ("Clinical") plans were compared to IMRT-derived worst-case CTV benchmarks. If benchmarks were not met, PBT plans were modified to meet both CTV V100% and V95% goals ("Benchmark" plans). Dosimetric comparisons between Clinical and Benchmark plans used a Wilcoxon signed-rank test with alpha set at 0.05. Results:Among 32 patients, median age and PSA at diagnosis were 71 years and 6.84 ng/mL, respectively. Most patients had favorable-intermediate risk disease (56.3%). Only 31% of clinical PBT met both worst-case CTV V100% > 90% and CTV V95% > 99% IMRT benchmarks. Plan renormalization (16 patients) or reoptimization (6 patients) resulted in all Benchmark plans meeting worst-case CTV thresholds. For Benchmark plans, nominal rectum V70 Gy increased from 0.72 to 0.92 cm3, and nominal bladder V60 Gy increased from 5.9% to 6.0% (P < .05 for each). Overall plan hot spot between Clinical and Benchmark plans increased from 104.5 to 105.5% (P < .05). Conclusion:When compared to an IMRT-derived benchmark for robustness coverage, Clinical PBT plans were less robust. However, all PBT plans were successfully modified to meet worst-case CTV benchmark with limited clinically expected impact on organ at risk dosimetry. Consideration should be made to adopt these benchmark criteria for prostate PBT.

Purpose Improved treatments for brain metastases from non-small cell lung cancer (NSCLC BM) are needed to prolong time to intracranial progression (TTIP) without increasing neurotoxicity. Tumor Treating Fields (TTFields), electric fields delivered via skin-based arrays that disrupt cancer cell division, have demonstrated efficacy and safety in glioblastoma, NSCLC, and pancreatic cancer. Methods and Materials In the phase 3 METIS trial (NCT02831959), adults with 1 to 10 newly diagnosed NSCLC BMs suitable for stereotactic radiosurgery (SRS) receiving optimal therapy for extracranial disease were randomized 1:1 to SRS followed by TTFields (150 kHz) or SRS alone. Radiologic progression was assessed by an independent radiology review committee. The primary endpoint was TTIP (Response Assessment in Neuro-Oncology Brain Metastases criteria). Secondary endpoints included overall survival, neurocognitive function, quality of life (QoL), and safety. Results Patients (N = 298) were followed for a median of 8.6 (0.07-85.2) months. TTFields significantly delayed TTIP (hazard ratio [HR], 0.72 [95% CI, 0.53-0.98]; Fine-Gray P = .044). Intracranial progression rates at months 2, 6, 12, and 24 were 13.6% versus 22.1% (P = .034), 33.7% versus 46.4% (P = .018), 46.9% versus 59.4% (P = .023), and 53.6% versus 65.2% (P = .031; post hoc). Time to distant intracranial progression favored TTFields therapy, although not statistically significantly (HR, 0.76 [95% CI, 0.51-1.12]; log-rank P = .165; post hoc). In patients receiving immune checkpoint inhibitors (n = 118), the delays in both TTIP (HR, 0.63 [95% CI, 0.39-1.0]; Cox P = .049; Fine-Gray P = .055) and time to distant intracranial progression (HR, 0.41 [95% CI, 0.21-0.81]; log-rank P = .0087, post hoc) were more pronounced. Device-related adverse events were mainly grade ≤2 skin events. TTFields did not cause QoL deterioration, and improvements in deterioration-free survival and time to deterioration of the global health status, physical functioning and fatigue domains were observed (post hoc). Conclusions By significantly prolonging TTIP, without worsening QoL or cognitive function, TTFields after SRS is a new treatment option for patients with NSCLC BMs, including those receiving immune checkpoint inhibitor.

Purpose:Single isocenter stereotactic radiosurgery (SRS) efficiently delivers radiation to patients with multiple brain metastases. Although several fractionated SRS (fSRS) regimens show acceptable local control and toxicity, few studies directly compare them. This retrospective study evaluates 2 common regimens-6 Gy × 5 fractions and 9 Gy × 3 fractions-for their effects on local control and toxicity. Methods and Materials:A retrospective review was conducted of 1215 brain tumors from 251 patients receiving either 9 Gy × 3 fx or 6 Gy × 5 fx fSRS. All tumors were treated with single isocenter volumetric modulated arc therapy. Recurrent tumors and postoperative cavities were excluded from the analysis. Local tumor failure was defined as 25% increase in maximum tumor diameter (minimum 3 mm) or more than scant tumor cells at time of salvage surgery. Toxicity included CTCAE V5.0 central nervous system (CNS) grade 3 or greater events. Local tumor control and freedom from toxicity were calculated using Kaplan-Meier method and Cox regression models. Results:Overall local control was 93% at 1 year and 88% at 2 years. The 3-fraction regimen had superior 1-year local control compared with the 5-fraction regimen (97% vs. 91%, P = .001). Tumors <2 cm had significantly better control with 3 fractions (99% vs. 95%, P = .004), whereas tumors 2-4 cm showed no significant difference. One-year freedom from grade 3+ toxicity was similar between regimens (99% for 3-fx vs. 96% for 5-fx, P = .097). Conclusions:In this study, 9 Gy × 3 fx for brain metastases had improved tumor control and comparable toxicity to 6 Gy × 5, particularly among tumors <2 cm. 9 Gy × 3 fx may be the preferred regimen when treating multiple tumors with one prescription using single isocenter radiosurgery as it improves efficiency and local control while having similar toxicity.

PURPOSE:The adaption of radiotherapy (RT) plans in response to anatomical and physiological changes during treatment marks a significant shift toward personalized cancer care. However, the complexity of Online Adaptive Radiotherapy (OART) procedures often leads to variability in treatment quality across institutions. The development of planning templates, particularly through the Ethos treatment planning system (TPS) and Intelligent Optimization Engine (IOE) (Varian Medical Systems, Palo Alto, CA), plays a crucial role in standardizing and streamlining OART. To address the challenges of sharing and optimizing treatment templates across diverse clinical environments, we developed the ADaptive rAdiotherapy Planning Template (ADAPT-) Marketplace to facilitate the exchange of XML-based templates and promote collaborative innovation in the OART community. METHODS:ADAPT-Marketplace was developed using the Django web framework, chosen for its security, scalability, and versatility. The platform supports the sharing of XML-based treatment planning templates, compatible with Ethos TPS, and includes features for uploading, downloading, comparing, and editing templates. The development followed a structured process, involving collaborator consultations, prototyping, and both alpha and beta testing. Testing phases included predefined tasks and unscripted evaluations, with feedback collected to refine the platform prior to its official launch. RESULTS:Since its launch in July 2023, ADAPT-Marketplace has registered 65 users from 16 countries and 38 institutions, including academic, non-academic and industrial sectors. Over 50 templates have been uploaded, covering treatment sites such as the pelvis, thorax, head-and-neck, and abdomen. Feedback from alpha and beta testing resulted in key improvements, including enhanced navigation, template validation, and user experience. CONCLUSION:ADAPT-marketplace provides a centralized platform for sharing and collaborating on treatment planning templates, offering the potential to improve research productivity, facilitate knowledge exchange, and standardize OART practices across institutions.

Background/Objectives: Medical research institutions are increasingly leveraging artificial intelligence (AI) to enhance the processing and analysis of medical imaging data. However, scaling AI-driven medical image analysis often requires specialized expertise and infrastructure that individual labs may lack. A centralized solution is to establish a core facility—a shared institutional resource—dedicated to Automated Medical Image Processing and Analysis (AMIPA). Methods: This technical note offers a practical roadmap for institutions to create an AI-based core facility for AMIPA, drawing on our experience in building such a resource. Results: We outline the key components for replicating a successful AMIPA core facility, including high-performance computing resources, robust AI software pipelines, data management strategies, and dedicated support personnel. Emphasis is placed on workflow automation and reproducibility, ensuring researchers can efficiently and consistently process large imaging datasets. Conclusions: By following this roadmap, institutions can accelerate AI adoption in imaging workflows and foster a shared resource that enhances the quality and productivity of medical imaging research.

HyperArc™ (HA) automates both planning and delivery of single-isocenter VMAT radiosurgery (SRS) and was designed for complex multi-metastasis cases. The clinical effectiveness of treating benign intracranial tumors (BIT) with HA is unknown. We collected data on treatment planning, delivery, and clinical outcomes of BIT managed with SRS since HA deployment. Patients received SRS using HA from 2017 to 2021 at a single institution. Prescription dose was normalized to ≥ 99

Purpose:Radiosurgery plan safety is commonly estimated by volumes receiving specific doses (ie, 12 Gy/1 fraction [fx]), which are evaluated postplan generation. However, automated treatment planning can produce highly consistent and thus predictable plans. Thus, we hypothesized that HyperArc (HA) automated stereotactic radiosurgery (SRS) planning enables clinical decision-making prior to plan generation, such as selecting the appropriate SRS fractionation scheme. Methods and Materials:All previously treated single-isocenter HA plans at our institution were queried, totaling 3361 marginless targets without bridging at the 50% isodose level (1495 plans), making this the largest single-institutional SRS dosimetry study to the authors' knowledge. Eight isodose volumes (IDVs; 50.00%-97.60%) were calculated for all HA targets, each corresponding to the ratio of a High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic (HyTEC) brain toxicity dose level and a common prescription dose (eg, 50.00% = 12 Gy/24 Gy). Power law relationships of IDV and target volume ( I D V = a V t a r g e t b ) were generated from a training data set of 361 targets (10.7%) and validated on the remaining 3000 targets (89.3%), allowing grade 1 to 3 brain toxicity rates to be predicted from target volume. Results:Models resulted in high R² values when applied to the validation cohort (≥0.982), allowing targets to be classified as either above or below the HyTEC thresholds (IDV = 5 cm3, 10 cm3, and 20 cm3) with high accuracy (≥97.6%) and precision (≥99.3%). As an example, the 50.0% IDV model predicted that target volumes/diameters of 1.00 cm3/1.24 cm, 2.34 cm3/1.65 cm, and 5.51 cm3/2.19 cm correlate with 3.6%, 4.8%, and 8.6% grade 1 to 3 brain toxicity rates, respectively, when prescribing 24 Gy/1 fx. Conclusion:The resulting models enabled accurate and precise prediction of target volumes/diameters, resulting in 3.6%, 4.8%, and 8.6% brain grade 1 to 3 toxicity rates, according to HyTEC toxicity estimates. Leveraging relative IDVs rather than prescription doses enabled all 3361 targets to be used for modeling 9 common SRS prescriptions (1 fx: 24 Gy, 20 Gy, 18 Gy, 16 Gy, and 15 Gy; 3 fx: 27 Gy and 24 Gy; 5 fx: 30 Gy and 25 Gy), enabling clinicians to estimate brain toxicity a priori via an open-source calculator.

Background:Currently, no definitive method reliably differentiates pseudoprogression from true progression. Misclassification can either halt effective therapy or prolong ineffective treatment. We hypothesized that the diagnostic accuracy could be improved using quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) after error correction via point-of-care portable perfusion phantoms (P4s). This study aimed to develop a P4 for quantitative DCE-MRI of the brain and enhance accuracy in distinguishing between pseudo and true glioblastoma progression. Methods:Twelve patients with potential glioblastoma progression after adjuvant chemoradiation therapy were recruited. Each subject underwent two DCE-MRI exams within a week using a single 3T MRI scanner. Quantitative DCE-MRI parameters were retrieved based on the extended Tofts model (ETM), Tofts model (TM), and shutter speed model (SSM) before and after P4-based error correction. The consistency of the pharmacokinetic (PK) parameter measurements was evaluated based on the within-subject coefficient of variation (wCV) before and after P4-based error correction. Glioblastoma progression status was determined using the Response Assessment in Neuro-Oncology (RANO) criteria about five months after DCE-MRI exams. Results:Among the participants, five had true progression, and seven had pseudoprogression. The wCVs of the Ktrans measurement based on TM, ETM, and SSM were 22%, 22%, and 24%, respectively, before error correction but improved to 7%, 6%, and 8%, respectively, after correction. Similarly, their accuracies in differentiating between pseudo and true progression were 0.88 regardless of the PK models before error correction. However, those after error correction were improved to 100% in TM (or ETM) and 96% in SSM. Conclusions:Following P4-based error correction, a quantitative DCE-MRI parameter, Ktrans , demonstrated 100% accuracy in discriminating between pseudo and true progression when TM or ETM were employed.

Purpose/Objective(s) Radiosurgical thalamotomy is one method to treat medically refractory tremor for patients that are not candidates for deep-brain stimulation. It ablates aberrant cerebello-thalamo-cortical circuitry by targeting the dentato-rubro-thalamic tract (DRTT) within the ventral intermediate nucleus (VIM) of the thalamus. We report on the accuracy of radiosurgical thalamotomy using a linear accelerator equipped with a multileaf collimator (MLC), a thermoplastic mask for immobilization, and surface-imaging for intra-fraction motion monitoring. Materials/Methods Forty patients underwent SRS thalamotomy on a linear accelerator on an IRB-approved clinical trial (ClinicalTrials.gov Identifier: NCT03305588) using our previously described virtual cone technique to deliver 135 Gy to isocenter. Patients were immobilized using a non-invasive thermoplastic Immobilization system and a treatment planning CT was obtained with 0.8 mm slice spacing. MR images were registered to the treatment planning CT and the VIM identified using stereotactic coordinates based on the anterior and posterior commissure locations. Patient position was monitored real-time during treatment using optical surface imaging. At 3, 6, and 12 months after treatment, post Gadolinium-contrast T1 images were acquired on a 3T MRI scanner. For each patient, the first image set for which a lesion was clearly visible was selected and registered to the treatment planning CT using mutual information rigid registration. The lesion was manually segmented by two investigators, a radiation oncologist and a medical physicist. For each lesion, the centroid of the segmented volume was determined. For each patient, the mid-point of the two centroids was compared with the isocenter position. Results Post-treatment imaging data was available for 39/40 patients. The mean distance between the centroids identified by the two observers was 0.3 mm (range = 0.1-0.6 mm, interquartile range = 0.1 mm). The mean distance between the centroid mid-points and the isocenter was 0.7 mm (range = 0.2-1.6 mm, interquartile range = 0.4 mm). The mean difference (standard deviation) in the x, y, and z directions of the treatment planning CT coordinate system was -0.1 (0.3), -0.2 (0.4), and 0.3 (0.4) mm, respectively. Conclusion Our findings demonstrate sub-millimeter accuracy of frameless MLC-based linear accelerator SRS using optical surface imaging for intra-fraction position monitoring. These results are comparable to accuracies reported using other techniques for radiosurgical thalamotomy and to open surgical lesioning/stimulation procedures.

OBJECTIVE Radiation therapy (RT) is used selectively for patients with low-grade glioma (LGG) given the concerns for potential cognitive effects in survivors, but prior cognitive outcome studies among LGG survivors have had inconsistent findings. Translational studies that characterize changes in brain anatomy and physiology after treatment of LGG may help to both contextualize cognitive findings and improve the overall understanding of radiation effects in normal brain tissue. This study aimed to investigate the hypothesis that patients with LGG who are treated with RT will experience greater brain volume loss than those who do not receive RT. METHODS This retrospective longitudinal study included all patients with WHO grade 2 glioma who received posttreatment surveillance MRI at the University of Alabama at Birmingham. Volumetric analysis of contralateral cortical white matter (WM), cortical gray matter (GM), and hippocampus was performed on all posttreatment T1-weighted MRI sequences using the SynthSeg script. The effect of clinical and treatment variables on brain volumes was assessed using two-level hierarchical linear models. RESULTS The final study cohort consisted of 105 patients with 1974 time points analyzed. The median length of imaging follow-up was 4.6 years (range 0.36–18.9 years), and the median number of time points analyzed per patient was 12 (range 2–40). Resection was performed in 79 (75.2%) patients, RT was administered to 61 (58.1%) patients, and chemotherapy was administered to 66 (62.9%) patients. Age at diagnosis (β = −0.06, p < 0.001) and use of RT (β = −1.12, p = 0.002) were associated with the slope of the contralateral cortical GM volume model (i.e., change in GM over time). Age at diagnosis (β = −0.08, p < 0.001), midline involvement (β = 1.31, p = 0.006), and use of RT (β = −1.45, p = 0.001) were associated with slope of the contralateral cortical WM volume model. Age (β = −0.0027, p = 0.001), tumor resection (β = −0.069, p < 0.001), use of chemotherapy (β = −0.0597, p = 0.003), and use of RT (β = −0.0589, p < 0.001) were associated with the slope of the contralateral hippocampus volume model. CONCLUSIONS This study demonstrated volume loss in contralateral brain structures among LGG survivors, and patients who received RT experienced greater volume loss than those who did not. The results of this study may help to provide context for cognitive outcome research in LGG survivors and inform the design of future strategies to preserve cognition.

Purpose/Objective(s) Brain metastases are routinely treated with surgery, radiation, or a combination of these modalities. Leptomeningeal disease (LMD) is a form of metastatic disease that is associated with very poor prognosis for patients with metastasis from solid tumors and can develop as progression of untreated disease or from seeding after surgery. Surgery followed by stereotactic radiosurgery (SRS) has been shown to improve local control, but is associated with relatively high rates of LMD. Preoperative SRS is hypothesized to reduce rates of LMD by rendering tumor cells incapable of reproduction prior to potential surgical seeding. Materials/Methods This retrospective investigation of patients treated at a single institution compared rates of LMD in patients treated preoperatively with SRS to a previously published dataset of patients treated postoperatively. A total of 81 patients treated preoperatively between 2011 and 2023 were identified and received 12-15 Gy in a single fraction using linear accelerator (LINAC) radiosurgery. The postoperative cohort was treated between 2004 and 2015 and included 91 patients with some treated with Gamma Knife radiosurgery and others LINAC radiosurgery. This cohort primarily received single-fraction SRS, but several also received hypofractionated treatment. LMD was defined as diffuse or focal leptomeningeal enhancement and included enhancement within 5 mm of the index lesion. The Kaplan-Meier approach was used to plot survival curve estimates for months from surgery to LMD time-to-event outcomes. Results Of the 81 patients treated preoperatively with radiation, 6 (7.4%) developed LMD. From the postoperative cohort, 35 out of 91 (38%) patients developed LMD. Table 1 shows Kaplan-Meier estimates which demonstrate a significant difference in the time to LMD failure for patients receiving preoperative SRS, with an estimated mean time to LMD of 71 (95% COI, 63-79) months versus 44 (95% COI, 33-55) months (P<0.00002, log-rank test) for those treated postoperatively. The median estimated time to LMD was 17 mo (95% COI, 0-43) months for the postoperative SRS group but not reportable (not reached) for the preoperative SRS group. Conclusion Single-fraction preoperative radiosurgery with 12-15 Gy shows significant improvement in time to LMD failure compared to postoperative radiosurgery for patients being treated with combination therapy of radiation plus resection for brain metastases.

Background Lisavanbulin (BAL101553) is a small, lipophilic, oral microtubule destabilizer with promising antitumoral activity observed in preclinical glioblastoma (GBM) models.Methods This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Dose escalation followed a modified 3 + 3 design. Secondary objectives included estimation of OS and PFS and pharmacokinetic analysis.Results Twenty-six patients with uGBM (median age, 63 years, 42.3% male, 61.5% with gross total resection, median Karnofsky performance status 80) were enrolled; 2 tumors had an IDH1 mutation. Predefined dose levels of Lisavanbulin, administered daily concomitantly with RT, were: 4 mg (5 pts), 6 mg (5 pts), 8 mg (7 pts), 12 mg (5 pts), and 15 mg (4 pts). The initial starting dose was 8 mg. Due to grade 4 aseptic meningoencephalitis in the first patient, the dose was decreased to 4 mg. Dose escalation resumed and continued to 15 mg with dose-limiting toxicities of grade 2 confusion and memory impairment observed at 12 mg. Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15 mg.Conclusions Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily. Lisavanbulin is a new drug that shows promise for treating glioblastoma, a serious type of brain cancer, in early lab studies. The authors of this study wanted to see if the drug was safe for patients with glioblastoma. To do this, they tested the drug at doses from 4 to 15 mg per day in combination with radiation in 26 patients who had been recently diagnosed with glioblastoma. While some patients experienced side effects, most were not severe. The authors considered the drug to be safe in patients up to a dose of 15 mg per day.

PURPOSE:AT-101 is an oral bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, Bcl-W) and potent inducer of proapoptotic proteins. A prior study of the parent compound, racemic gossypol, demonstrated objective and durable responses in patients with malignant glioma. AT-101 has demonstrated synergy with radiation in animal models. The objectives of trial NABTT 0602 were to determine the MTD of AT-101 concurrent with temozolomide (TMZ) and radiation therapy (RT) (Arm I) and to determine the MTD of AT-101 when given with adjuvant TMZ after completion of standard chemoradiation (Arm 2). Separately in trial NABTT 0702, the survival and response rates of single agent AT-101 were evaluated in patients with recurrent glioblastoma. METHODS:In NABTT 0602 Phase I, a 3+3 design was used to define MTDs after maximal safe resection, patients with newly diagnosed glioblastoma received standard concurrent RT (60 Gy) and TMZ 75 mg/m2/day followed by adjuvant TMZ 150-200 mg/m2 days 1-5 in 28-day cycles (Stupp regimen). In Arm I, AT-101 was administered M-F during the six weeks of RT beginning 20 mg qd. In Arm 2, concurrent with each adjuvant cycle of TMZ, AT-101 was administered at a starting dose of 20 mg, days 1-21 followed by 7-day break for a maximum of 6 cycles. The PK blood samples were collected in the first three patients in each cohort of arm 1. In NABTT 0702 patients with recurrent glioblastoma received 20 mg p.o. per day for 21 of 28 days in repeated cycles to assess overall survival (OS). RESULTS:A total of sixteen patients were enrolled on the two study arms of NABTT 0602. In Arm 1 AT-101 was escalated from 20 to 30 mg where one of six patients experienced DLT (grade 3 GI ulcer). On Arm 2 one patient treated at 20 mg experienced DLT (grade 3 ileus, nausea and diarrhea). The cohort was expanded to include seven patients without observation of DLT. PK results were consistent with drug levels from non-CNS studies. At study closure six patients are still alive. The median survival times for Arm I and Arm II are 15.2 months and 18.2 months, respectively. In NABTT 0702 fifty-six patients were enrolled and forty-three were eligible for imaging response. Sixteen patients (29%) had stable disease as best response and one partial response was observed. The median OS with single agent AT-101 was 5.7 months (95%CI: 3.8-7.6 months) for patients with rGBM. CONCLUSIONS:AT-101 can be safely administered with radiation therapy and TMZ in patients with newly diagnosed glioblastoma without toxicity unique to patients with CNS tumors. Because of toxicity observed in non-CNS AT-101 clinical trials, further dose-escalation was not attempted. The recommended dose for future studies that utilize continual AT-101 exposure is 20 mg days M-F concurrent with RT/TMZ and 20 mg days 1-21 for each 28-day cycle of TMZ. AT-101 has limited activity as a single agent in unselected patients with recurrent glioblastoma. Future trials should attempt to better understand resistance mechanisms and consider combination therapy.