A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR).

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

A multi-site phase I trial of Veliparib with standard radiation and temozolomide in patients with newly diagnosed glioblastoma multiforme (GBM).

PURPOSE: A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma. METHODS: Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed. RESULTS: Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%). CONCLUSIONS: Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.

A Multi-Site Phase I Trial of Veliparib with Standard Radiation and Temozolomide in Patients with Newly Diagnosed Glioblastoma Multiforme (GBM).

Purpose: A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma. Methods: Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed. Results: Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%). Conclusions: Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies.

Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma.

INTRODUCTION: Hypoxia inducible factor 2-alpha (HIF2α) mediates cellular responses to hypoxia and is over-expressed in glioblastoma (GBM). PT2385 is an oral HIF2α inhibitor with in vivo activity against GBM. METHODS: A two-stage single-arm open-label phase II study of adults with GBM at first recurrence following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (ORR = complete response + partial response, CR + PR); secondary outcomes were safety, overall survival (OS), and progression free survival (PFS). Exploratory objectives included pharmacokinetics (day 15 Cmin), pharmacodynamics (erythropoietin, vascular endothelial growth factor), and pH-weighted amine- chemical exchange saturation transfer (CEST) MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤ 1 ORR. RESULTS: Of the 24 enrolled patients, median age was 62.1 (38.7-76.7) years, median KPS 80, MGMT promoter was methylated in 46% of tumors. PT2385 was well tolerated. Grade ≥ 3 drug-related adverse events were hypoxia (n = 2), hyponatremia (2), lymphopenia (1), anemia (1), and hyperglycemia (1). No objective radiographic responses were observed; median PFS was 1.8 months (95% CI 1.6-2.5) and OS was 7.7 months (95% CI 4.9-12.6). Drug exposure varied widely and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, p = 0.009). Baseline acidity by pH-weighted CEST MRI correlated significantly with treatment duration (R2 = 0.49, p = 0.017). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. CONCLUSIONS: PT2385 monotherapy had limited activity in first recurrent GBM. Drug exposure was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic lesions on CEST imaging. A second-generation HIF2α inhibitor is being studied.

Immuno-PET Imaging of CD69 Visualizes T-Cell Activation and Predicts Survival Following Immunotherapy in Murine Glioblastoma.

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Immunotherapy may be promising for the treatment of some patients with GBM; however, there is a need for noninvasive neuroimaging techniques to predict immunotherapeutic responses. The effectiveness of most immunotherapeutic strategies requires T-cell activation. Therefore, we aimed to evaluate an early marker of T-cell activation, CD69, for its use as an imaging biomarker of response to immunotherapy for GBM. Herein, we performed CD69 immunostaining on human and mouse T cells following in vitro activation and post immune checkpoint inhibitors (ICI) in an orthotopic syngeneic mouse glioma model. CD69 expression on tumor-infiltrating leukocytes was assessed using single-cell RNA sequencing (scRNA-seq) data from patients with recurrent GBM receiving ICI. Radiolabeled CD69 Ab PET/CT imaging (CD69 immuno-PET) was performed on GBM-bearing mice longitudinally to quantify CD69 and its association with survival following immunotherapy. We show CD69 expression is upregulated upon T-cell activation and on tumor-infiltrating lymphocytes (TIL) in response to immunotherapy. Similarly, scRNA-seq data demonstrated elevated CD69 on TILs from patients with ICI-treated recurrent GBM as compared with TILs from control cohorts. CD69 immuno-PET studies showed a significantly higher tracer uptake in the tumors of ICI-treated mice compared with controls. Importantly, we observed a positive correlation between survival and CD69 immuno-PET signals in immunotherapy-treated animals and established a trajectory of T-cell activation by virtue of CD69-immuno-PET measurements. Our study supports the potential use of CD69 immuno-PET as an immunotherapy response assessment imaging tool for patients with GBM. Significance: Immunotherapy may hold promise for the treatment of some patients with GBM. There is a need to assess therapy responsiveness to allow the continuation of effective treatment in responders and to avoid ineffective treatment with potential adverse effects in the nonresponders. We demonstrate that noninvasive PET/CT imaging of CD69 may allow early detection of immunotherapy responsiveness in patients with GBM.

Phase II study of border zone stereotactic radiosurgery with bevacizumab in patients with recurrent or progressive glioblastoma multiforme.

PURPOSE: Recurrent glioblastoma is universally fatal with limited effective treatment options. The aim of this phase 2 study of Border Zone SRS plus bevacizumab was to evaluate OS in patients with recurrent GBM. METHODS: Patients with histologically confirmed GBM with recurrent disease who had received prior first-line treatment with fractionated radiotherapy and chemotherapy and eligible for SRS were enrolled. Bevacizumab 10 mg/kg was given day -1, day 14, and then every 14 days until disease progression. 1-14 days before BZ-SRS procedure, patients underwent brain MRI /MRS. MRS with measurement of choline-to-N-acetyl aspartate index (CNI) area ≥ 3 was targeted for SRS. RESULTS: From 2015-2017, sixteen of planned 40 patients were enrolled. The median age was 62 (range, 48-74Y). 3/16 (0.188) participants experienced grade 2 toxicity. No AREs were reported. The mOS was 11.73 months compared to 8.74 months (P = 0.324) from date of SRS for the BZ-SRS and institutional historical controls, respectively. PFS-6 and OS-6 were 31.2% (p = 0.00294) and 81.2%(p = 0.058), respectively. Of 13 evaluable for best response: 1 CR (p = 0.077), 4 PR (p = 0.308), 7 SD (p = 0.538), and 1 PD (p = 0.077). 11/16 participants had MRS scans with an estimated probability that MRS changes a treatment plan of 0 (0, 0.285). CONCLUSION: BZ-SRS with bevacizumab was feasible and well tolerated. There is no significant survival benefit using BZ-SRS with bevacizumab compared to institutional historical controls. Secondary analysis revealed a trend toward improved PFS-6, but not OS-6 after BZ-SRS. MRS scans did not result in changes to SRS treatment plans.

Multicenter Phase II Trial of the PARP Inhibitor Olaparib in Recurrent IDH1- and IDH2-mutant Glioma.

Purpose: Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations (IDH1/2mt) are frequent in glioma. Preclinical studies suggest IDH1/2mts confer "BRCAness" phenotype, a vulnerability that can be targeted through PARP inhibition. To test this hypothesis, we conducted a multicenter study of olaparib monotherapy in patients with IDH1/2mt gliomas. Methods: Patients with recurrent, contrast-enhancing IDH1/2mt gliomas were enrolled in a two-step phase II trial; the primary endpoint was overall response rate per Response Assessment in Neuro-Oncology (RANO) criteria. Olaparib 300 mg orally twice daily was given. Results: A total of 15 evaluable patients were enrolled. Histology was astrocytoma (N = 12) and oligodendroglioma (N = 3). Most toxicities were grade 1 or 2. Best response was stable disease (SD) in 9 (60%) patients. Median progression-free survival (PFS) was 3.63 months and median overall survival was 20.7 months. For patients with SD, median PFS was 5.53 months; 4 patients had SD for >6 months. Among patients with best response progressive disease (N = 6), 5 had grade 4 tumor and 4 had known CDKN2A alteration. PFS was 5.23 months for grades 2 or 3 tumors (N = 10) versus 1.8 months for grade 4 (N = 5; P = 0.0013). Conclusion: The study did not meet the prespecified response-based activity threshold for moving to step 2. However, prolonged SD was observed in patients with grades 2 and 3 histologies, suggesting olaparib monotherapy could be of clinical benefit in select populations. Grade 4 tumors per 2021 World Health Organization classification defined by histology or CDKN2A alteration derived no benefit from this drug, highlighting the usefulness of this classification for future patient stratification and trial design. Significance: A single-arm phase II trial of olaparib in IDH-mutant glioma demonstrated clinically significant prolonged SD for select patients with grade 2/3 disease, suggesting potential benefit of olaparib in IDH-mutant gliomas.

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

The Added Value of Family Caregivers' Level of Mastery in Predicting Survival of Glioblastoma Patients: A Validation Study.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive brain tumor. Patients commonly rely on family caregivers for physical and emotional support. We previously demonstrated that caregiver mastery measured shortly after diagnosis was predictive of GBM patient survival, corrected for known predictors of survival (n = 88). OBJECTIVE: The aims of this study were to verify the contribution of caregiver mastery and investigate the added value of mastery over other predictors to predict 15-month survival. METHODS: Data collected for a longitudinal study (NCT02058745) were used. Multivariable Cox regression analyses were performed for models with known clinical predictors (patient age, Karnofsky Performance Status, type of surgery, O6-methylguanine-DNA-methyltransferase promotor methylation status), with and without adding caregiver mastery to predict mortality. The added value of each model in discriminating between patients with the lowest and highest chances of survival at 15 months was investigated through Harrell's concordance index. RESULTS: In total, 41 caregiver-patient dyads were included. When evaluating solely clinical predictors, Karnofsky Performance Status and patient age were significant predictors of mortality (hazard ratio [HR], 0.974; 95% confidence interval [CI], 0.949-1.000; and HR, 1.045; 95% CI, 1.002-1.091, respectively). Adding caregiver mastery, these clinical predictors remained statistically significant, and mastery showed an HR of 0.843 (95% CI, 0.755-0.940). The discriminative value improved from C = 0.641 (model with known clinical predictors) to C = 0.778 (model with mastery), indicating the latter is superior. CONCLUSIONS: We confirm that caregiver mastery is associated with GBM patient survival. IMPLICATIONS FOR PRACTICE: Incorporating support and guidance for caregivers into standard care could lead to benefits for caregiver well-being and patient outcomes.

TIGIT and PD-1 Immune Checkpoint Pathways Are Associated With Patient Outcome and Anti-Tumor Immunity in Glioblastoma.

Glioblastoma (GBM) remains an aggressive brain tumor with a high rate of mortality. Immune checkpoint (IC) molecules are expressed on tumor infiltrating lymphocytes (TILs) and promote T cell exhaustion upon binding to IC ligands expressed by the tumor cells. Interfering with IC pathways with immunotherapy has promoted reactivation of anti-tumor immunity and led to success in several malignancies. However, IC inhibitors have achieved limited success in GBM patients, suggesting that other checkpoint molecules may be involved with suppressing TIL responses. Numerous IC pathways have been described, with current testing of inhibitors underway in multiple clinical trials. Identification of the most promising checkpoint pathways may be useful to guide the future trials for GBM. Here, we analyzed the The Cancer Genome Atlas (TCGA) transcriptomic database and identified PD1 and TIGIT as top putative targets for GBM immunotherapy. Additionally, dual blockade of PD1 and TIGIT improved survival and augmented CD8+ TIL accumulation and functions in a murine GBM model compared with either single agent alone. Furthermore, we demonstrated that this combination immunotherapy affected granulocytic/polymorphonuclear (PMN) myeloid derived suppressor cells (MDSCs) but not monocytic (Mo) MDSCs in in our murine gliomas. Importantly, we showed that suppressive myeloid cells express PD1, PD-L1, and TIGIT-ligands in human GBM tissue, and demonstrated that antigen specific T cell proliferation that is inhibited by immunosuppressive myeloid cells can be restored by TIGIT/PD1 blockade. Our data provide new insights into mechanisms of GBM αPD1/αTIGIT immunotherapy.

A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma.

BACKGROUND: No standard medical treatment exists for adult patients with recurrent ependymoma, and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network conducted a prospective phase II clinical trial of dose-dense temozolomide (TMZ) and lapatinib, targeting the unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter status and increased expression of ErbB2 (human epidermal growth factor receptor 2) and ErbB1 (epidermal growth factor receptor) in ependymomas. METHODS: Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense TMZ and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MD Anderson Symptom Inventory Brain Tumor (MDASI-BT)/MDASI-Spine Tumor modules were collected. RESULTS: The 50 patients enrolled had a median age of 43.5 years, median Karnofsky performance status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI: 5.5,12.2); the 6- and 12-month PFS rates were 55% and 38%, with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. CONCLUSIONS: This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements, is an option as a salvage regimen for adult patients with recurrent ependymoma.

A Phase II and Pharmacodynamic Trial of RO4929097 for Patients With Recurrent/Progressive Glioblastoma.

BACKGROUND: Cancer stem-like cells are a major cause of resistance to therapy in patients with glioblastoma (GBM) as well as other cancers. Tumor cells are maintained in a stem-like proliferative state in large part through the Notch signaling pathway. The function of this pathway in turn depends on gamma secretase activity. Inhibition of this enzyme therefore inhibits the Notch pathway and tumor growth as measured by a reduction in the formation of brain tumor neurospheres in murine models. RO4929097 is an oral gamma secretase inhibitor. OBJECTIVE: To estimate the 6-mo progression-free survival rate (PFS6) in patients with progressive GBM and to inhibit by 50% the generation of neurospheres in fresh tissue resected from patients treated with RO4929097. METHODS: In this phase II and pharmacodynamic study, patients with recurrent GBM received RO4929097 in a study of 2 groups. Group A patients had unresectable disease and received drug in a standard phase II design. Group B patients had resectable disease and received drug before and after surgical resection. Endpoints included PFS6 and the inhibition of neurosphere formation in the resected tumor samples. RESULTS: A total of 47 patients received treatment, 7 of whom had tumor resection. The PFS6 was 4%, and the inhibition of neurosphere formation occurred in 1 of 7 patient samples. CONCLUSION: RO4929097 was inactive in recurrent GBM patients and demonstrated minimal inhibition of neurosphere formation in fresh tissue samples.

Phase I/II study of sorafenib in combination with erlotinib for recurrent glioblastoma as part of a 3-arm sequential accrual clinical trial: NABTC 05-02.

BACKGROUND: Receptor tyrosine kinases such as epidermal growth factor receptors (EGFRs) and their downstream signaling pathways such as the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway play important roles in glioblastoma (GBM). This study investigated the safety, pharmacokinetics, and efficacy of sorafenib (Ras/Raf/MAPK inhibitor) in combination with erlotinib (EGFR inhibitor) for treatment of recurrent GBMs. METHODS: Patients with recurrent GBM were eligible. A novel sequential accrual trial design was used, where patients were sequentially accrued into separate treatment arms in phase I and phase II investigations to optimize recruitment efficiency. In phase I, a standard 3 + 3 format was used to identify dose-limiting toxicities (DLTs), determine maximum tolerated dose (MTD), and investigate pharmacokinetics. Phase II followed a 2-stage design with the primary endpoint being 6-month progression-free survival (PFS6). RESULTS: Sixteen patients were recruited for phase I, and the MTD was determined to be sorafenib 200 mg twice daily and erlotinib 100 mg once daily. DLTs include Grade 3 hypertension, Grade 3 elevated liver transaminases, and Grade 4 elevated lipase. While erlotinib did not affect sorafenib levels, sorafenib reduced erlotinib levels. In phase II, 3 of 19 stage 1 participants were progression free at 6 months. This did not meet the predetermined efficacy endpoint, and the trial was terminated. CONCLUSION: This study identified the MTD and DLTs for sorafenib and erlotinib combination therapy for recurrent GBMs; however, efficacy data did not meet the primary endpoint. This study also demonstrates the feasibility of a novel sequential accrual clinical trial design that optimizes patient recruitment for multiarm studies, which is particularly effective for multicenter clinical trials.

Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients.

Building 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.

The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525.

BACKGROUND: Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m2 may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m2 was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed. METHODS: The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. Obesity was defined as a BMI ≥30. RESULTS: There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, P < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) P = .009 in spite of the lack of association between gender and BSA or BMI. CONCLUSION: TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.

Psychometric Evaluation of the Caregiver Needs Screen in Neuro-Oncology Family Caregivers.

BACKGROUND AND PURPOSE: The informal care demands of primary malignant brain tumor (PMBT) patients include unique issues associated with neurological and cognitive symptoms. Existing caregiver needs questionnaires do not include these disease-specific symptoms, which are particularly distressing. Therefore, we have developed the neuro-oncology Caregiver Needs Screen (CNS) and evaluated its psychometric properties. METHODS: The 32-item instrument was developed based on PMBT caregiver interviews (N = 109) and expert review. The CNS was tested along measures of depression, anxiety, burden, and mastery in 122 PMBT caregivers. Principal components analysis was used to examine item properties and internal structure. Internal consistency reliability and construct validity were assessed. RESULTS: Six subscales were identified with internal consistency ranging between alpha = .653 and .857. Convergent validity was verified by moderate/high correlations between measures of caregiver well-being and CNS scale scores. CONCLUSIONS: Findings provide preliminary evidence of reliability and validity for the CNS. This instrument can be useful when assessing caregivers' needs for supportive care.

Phase 2 Study of Radiation Therapy Plus Low-Dose Temozolomide Followed by Temozolomide and Irinotecan for Glioblastoma: NRG Oncology RTOG Trial 0420.

PURPOSE: To evaluate the toxicity and efficacy of adjuvant temozolomide (TMZ) and irinotecan (CPT-11) for 12 months after concurrent chemoradiation in patients with newly diagnosed glioblastoma (GBM). METHODS AND MATERIALS: Trial RTOG 04-20, a single-arm, multi-institutional phase 2 trial, was designed to determine the efficacy and toxicity of concomitant TMZ and radiation therapy (RT) followed by adjuvant TMZ combined with CPT-11 given for 12 cycles compared with historical controls of adjuvant TMZ alone given for 6 cycles. RESULTS: A total of 170 patients were enrolled, 152 of whom were eligible. Adjuvant CPT-11 combined with TMZ was more toxic than expected. A higher rate of hematologic and gastrointestinal toxicities was more frequently noted with the combination regimen compared with adjuvant TMZ alone. Grade 3/4 hematologic toxicity was 38% compared with 14% reported in the Stupp trial. After an early interim analysis, the adjuvant CPT-11 dose was reduced to 100 mg/m2 on days 1 and 5 for the first cycle. CPT-11 dose escalation proceeded over the first 3 cycles if tolerated. Median overall survival for all eligible patients was 16.9 months compared with 13.7 months of the historical control (P = .03). Post hoc subgroup analysis suggested an improvement in overall survival for patients with Radiation Therapy Oncology Group recursive partitioning analysis class 3, although improvement was limited to 22 patients (14% of eligible patients). CONCLUSIONS: Although irinotecan and TMZ for 12 cycles given after chemoradiation for patients with newly diagnosed glioblastoma significantly improved median survival compared with historical control data at the time the study was conducted, the historical control median survival time of 13.7 months does not represent the current benchmark for this patient population. Treatment intensification does prolong overall survival compared with the current standard.

Complementary Molecular and Metabolic Characterization of Meningiomas With DOTATATE and FDG-PET: Advancing Treatment Planning and Prognostication.

Ga-DOTATATE imaging for meningiomas is gaining clinical use for selecting patients that may benefit from targeted therapy (eg, Lu-DOTATATE). We present an image of a 67-year-old man with an intracranial WHO grade III anaplastic meningioma. He underwent tumor resection followed by intensity-modulated radiation therapy but experienced a recurrence 25 months later. He received an F-(FDG) and Ga-DOTATATE PET/MR to evaluate for the presence of somatostatin receptor expression and guide subsequent treatment. The scans showed both concordant and discordant regions of uptake, indicating that high somatostatin receptor (SSTR2) expression may not coincide with areas of increased metabolic rate.