Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Challenges in the Treatment of Newly Diagnosed and Recurrent Primary Central Nervous System Lymphoma.

Primary central nervous system lymphomas (PCNSLs) are rare cancers of the central nervous system (CNS) and are predominantly diffuse large B-cell lymphomas of the activated B-cell (ABC) subtype. They typically present in the sixth and seventh decade of life, with the highest incidence among patients aged >75 years. Although many different regimens have demonstrated efficacy in newly diagnosed and relapsed or refractory PCNSL, there have been few randomized prospective trials, and most recommendations and treatment decisions are based on single-arm phase II trials or even retrospective studies. High-dose methotrexate (HD-MTX; 3-8 g/m2) is the backbone of preferred standard induction regimens. Various effective regimens with different toxicity profiles can be considered that combine other chemotherapies and/or rituximab with HD-MTX, but there is currently no consensus for a single preferred regimen. There is controversy about the role of various consolidation therapies for patients who respond to HD-MTX-based induction therapy. For patients with relapsed or refractory PCNSL who previously experienced response to HD-MTX, repeat treatment with HD-MTX-based therapy can be considered depending on the timing of recurrence. Other more novel and less toxic regimens have been developed that show efficacy in recurrent disease, including ibrutinib, or lenalidomide ± rituximab. There is uniform agreement to delay or avoid whole-brain radiation therapy due to concerns for significant neurotoxicity if a reasonable systemic treatment option exists. This article aims to provide a clinically practical approach to PCNSL, including special considerations for older patients and those with impaired renal function. The benefits and risks of HD-MTX or high-dose chemotherapy with autologous stem cell transplantation versus other, better tolerated strategies are also discussed. In all settings, the preferred treatment is always enrollment in a clinical trial if one is available.

Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma.

PURPOSE: Perifosine (PRF) is an oral alkylphospholipid with antineoplastic effects and reasonable tolerability. It inhibits signaling through the PI3/AKT axis and other cascades of biologic importance in glioblastoma, and has promising pre-clinical activity in vitro and in vivo. Therefore, we conducted a phase II open-label single-arm clinical trial of perifosine for patients with recurrent glioblastoma (GBM). METHODS: We planned to accrue up to 30 adults with recurrent GBM with a minimum Karnofsky Performance Status of 50 following radiotherapy but without other restrictions on the number or types of prior therapy. Concurrent p450 stimulating hepatic enzyme inducing anticonvulsants were prohibited. Patients were treated with a loading dose of 600 mg PRF (in 4 divided doses on day 1) followed by 100 mg daily until either disease progression or intolerable toxicity. The primary endpoint was the 6-month progression free survival (PFS6) rate, with at least 20% considered promising. Accrual was continuous but if 0 of the first 12 patients with GBM reached PFS6, then further accrual would terminate for futility. Patients with other high grade gliomas were accrued concurrently to an exploratory cohort. RESULTS: Treatment was generally well tolerated; gastrointestinal toxicities were the most common side effects, although none resulted in treatment discontinuation. However, there was limited to no efficacy in GBM (n = 16): the PFS6 rate was 0%, median PFS was 1.58 months [95% CI (1.08, 1.84)], median overall survival was 3.68 months [95% CI (2.50, 7.79)], with no radiographic responses. There was a confirmed partial response in one patient with anaplastic astrocytoma (n = 14). CONCLUSIONS: PRF is tolerable but ineffective as monotherapy for GBM. Preclinical data suggests synergistic effects of PRF in combination with other approaches, and further study is ongoing.

R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma.

High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154.

Phase I study of RO4929097 with bevacizumab in patients with recurrent malignant glioma.

Antiangiogenic therapies for malignant gliomas often result in transient response, and recurrent disease is characterized by adoption of invasive and hypoxic phenotype. The notch signaling pathway is activated in gliomas, and augments cell migration and hypoxic response. Here we report a clinical study of the combination of bevacizumab and RO4929097, an inhibitor of the notch signaling cascade. A phase I clinical trial was conducted through the Adult Brain Tumor Consortium in subjects with recurrent malignant glioma. Primary objectives were to assess safety and to define the maximum tolerated dose of RO4929097 in combination with bevacizumab. Secondary objectives were to determine overall survival, progression free survival, radiographic response, pharmacokinetic evaluation, and tissue biomarker analysis. Thirteen subjects were enrolled. Of the three subjects treated with the highest dose of RO4929097, one grade 3 toxicity and one grade 2 toxicity were observed. Definitive maximum tolerated dose of RO4929097 in combination with bevacizumab was not identified due to manufacturer's decision to halt drug production. 2 of 12 evaluable subjects demonstrated radiographic response; one subject experienced CR and the second PR. The median overall survival was 10.9 months with a median progression-free survival of 3.7 months. Two subjects remained free of disease progression at 6 months from treatment initiation. PK evaluation did not identify clinically significant drug-drug interactions. All analyzed tissue specimens revealed activation of notch signaling. Combination of RO4929097 and bevacizumab was well-tolerated. Given the compelling scientific rationale, additional studies of antiangiogenic and notch signaling inhibitors should be considered.

Durable complete response in a patient with leptomeningeal melanoma after treatment with dabrafenib, trametinib, and nivolumab.

Leptomeningeal disease (LMD) is a devastating complication of melanoma with a dismal prognosis. We present the case of a young man with stage IV BRAF V600E mutant melanoma with lung, lymph node, and brain metastases initially treated with ipilimumab and nivolumab, who subsequently developed LMD. Upon change to BRAF/MEK targeted therapy with nivolumab, a durable complete response was achieved and remains ongoing, off treatment, 7 years from diagnosis. Management of symptomatic LMD remains a critical unmet clinical challenge, with limited clinical trial data. This exceptional case is instructive, as the first published case of the use of the triplet, and the first durable response with therapy discontinuation, in melanoma LMD. The triple-drug regimen may be considered a viable option in fit patients. This case highlights the potential for long-term disease control and the critical and urgent need to develop clinical trials inclusive of patients with LMD to define the best treatment strategies.

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization.

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

Temozolomide or bevacizumab for spinal cord high-grade gliomas.

High-grade gliomas of the spinal cord are rare tumors, traditionally managed with surgery and radiotherapy. Once patients fail standard treatment, many receive some chemotherapy, although the data supporting such is limited. We reviewed our experience treating high-grade gliomas of the spinal cord with standard intracranial regimens including temozolomide and bevacizumab. Outcomes investigated include radiographic response, clinical response, progression-free survival, and overall survival. We identified eight patients who were treated with temozolomide and six who were treated with bevacizumab. Temozolomide was administered to three patients at initial diagnosis and five patients at recurrence after failing prior radiotherapy. For the recurrent patients, the median time-to-progression was 6.6 months (range 1-40 months) and the median overall survival from initiation of temozolomide was 16.6 months (range 1.2-64.5 months). We identified six patients who received bevacizumab at the time of recurrence. MRI demonstrated a partial response in five patients which also correlated with clinical improvement. The median time to progression was 20.7 months (range 3.3-29.9 months) and median overall survival was 22.8 months (range 3.3-31.8 months). This retrospective review suggests that temozolomide and bevacizumab may be beneficial in spinal cord high-grade gliomas. The compact architecture of the spinal cord makes bevacizumab a particularly appealing agent due to the drug's effect on peritumoral edema and mass effect.

Atypical and anaplastic meningiomas treated with bevacizumab.

Atypical and anaplastic (WHO Grades II and III) meningiomas are aggressive tumors, and patients often progress despite surgery and radiation. There is no known effective chemotherapeutic option for these patients. Meningiomas have a high expression of vascular endothelial growth factor receptor (VEGFR). We sought to retrospectively study the activity of bevacizumab, which is an anti-angiogenic agent targeting the VEGF pathway in these tumors. This is a retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab. We analyzed radiographic response according to standard RANO criteria, progression-free survival (PFS) and overall survival from the initiation of bevacizumab therapy using Kaplan-Meier statistics. We identified 15 patients across four institutions who carried a diagnosis of atypical or anaplastic meningioma and were treated with bevacizumab. Best radiographic response was stable disease. MR perfusion studies showed decreased tumor blood volume in one patient. Three patients developed non-fatal intratumoral hemorrhage. Median PFS was 26 weeks (95 % CI, 10-29 weeks). Six month PFS rate was 43.8 % (95 % CI, 15.7-69.1 %). Bevacizumab was well-tolerated in our patients, and may be considered in patients who have exhausted radiation and surgical options. Prospective studies are required to define the safety and efficacy of bevacizumab in atypical and anaplastic meningiomas.

Biology and Treatment of Meningiomas: A Reappraisal.

Meningiomas are largely indolent tumors with a benign clinical course, but a minority exhibit aggressive behavior characterized by rapid growth, neurologic deficits, and increased mortality. Identifying high-risk patients requiring intervention is challenging, but recent insights into meningioma biology provide a useful guide for decision making. Standard of care for recurrent or biologically aggressive tumors consists of surgery and radiation therapy. Systemic therapies targeting vascular endothelial growth factor signaling and somatostatin analogues are potential options for those with refractory disease but display only modest activity. New paradigms in meningioma clinical trial design provide hope for improved options in the future.

Combination Olaparib and Temozolomide for the Treatment of Glioma: A Retrospective Case Series.

OBJECTIVES: To report on the tolerability and efficacy of olaparib with temozolomide (TMZ) for glioma METHODS: Single-center retrospective series of glioma patients treated with olaparib/TMZ September 2018-December 2021 RESULTS: Twenty patients (median age: 42, median Karnofsky Performance Status: 90) received olaparib/TMZ for diagnoses of IDH-mutant oligodendroglioma (n=5), IDH-mutant astrocytoma grade 2-3 (n=4), IDH-mutant astrocytoma grade 4 (n=7), or IDH-wildtype glioma (n=4). One patient was treated upfront and 19 at recurrence (median=3). Olaparib 150mg was administered three times/week concurrent with TMZ 50-75mg/m2 daily. Fatigue, gastrointestinal symptoms, and hematologic toxicity were common. 6/20 patients required dose reduction (n=4) or discontinuation (n=2) due to toxicity. Radiographic response was evaluable in 16 and observed (complete + partial) in 4/8 with IDH-mutant grade 2-3 glioma. No responses were seen in patients with grade 4 IDH-mutant astrocytomas (0/5) or IDH-wildtype gliomas (0/3). Progression-free survival was 7.8, 1.3, and 2.0 months, respectively. DISCUSSION: Olaparib/TMZ resulted in objective radiographic response in 50% of evaluable patients with recurrent IDH-mutant grade 2-3 gliomas with encouraging PFS and manageable toxicity. This supports a prospective trial of olaparib/TMZ for this population. CLASSIFICATION OF EVIDENCE: This case series provides Class IV evidence that treatment with olaparib/TMZ may result in radiographic response in patients with glioma.

EANO - EURACAN - SNO Guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors.

In the new WHO 2021 Classification of CNS Tumors the chapter "Circumscribed astrocytic gliomas, glioneuronal and neuronal tumors" encompasses several different rare tumor entities, which occur more frequently in children, adolescents, and young adults. The Task Force has reviewed the evidence of diagnostic and therapeutic interventions, which is low particularly for adult patients, and draw recommendations accordingly. Tumor diagnosis, based on WHO 2021, is primarily performed using conventional histological techniques; however, a molecular workup is important for differential diagnosis, in particular, DNA methylation profiling for the definitive classification of histologically unresolved cases. Molecular factors are increasing of prognostic and predictive importance. MRI finding are non-specific, but for some tumors are characteristic and suggestive. Gross total resection, when feasible, is the most important treatment in terms of prolonging survival and achieving long-term seizure control. Conformal radiotherapy should be considered in grade 3 and incompletely resected grade 2 tumors. In recurrent tumors reoperation and radiotherapy, including stereotactic radiotherapy, can be useful. Targeted therapies may be used in selected patients: BRAF and MEK inhibitors in pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas when BRAF altered, and mTOR inhibitor everolimus in subependymal giant cells astrocytomas. Sequencing to identify molecular targets is advocated for diagnostic clarification and to direct potential targeted therapies.

Phase I clinical trial of temsirolimus and perifosine for recurrent glioblastoma.

PURPOSE: Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. METHODS: Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. RESULTS: We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). CONCLUSION: Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

Therapy of chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is still a common and disabling side effect of many chemotherapy agents in use today. Unfortunately, neither prophylactic strategies nor symptomatic treatments have proven useful yet. This review will discuss the diagnosis and evaluation of neuropathy in cancer patients, as well as reviewing the various prophylactic and symptomatic treatments that have been proposed or tried. However, sufficient evidence is lacking to recommend any of these treatments to patients suffering with CIPN. Therefore, the best approach is to treat symptomatically, and to start with broad-spectrum analgesic medications such as non-steroidal anti-inflammatory drugs (NSAIDs). If NSAIDs fail, a reasonable second-line agent in properly selected patients may be an opioid. Unfortunately, even when effective in other types of neuropathic pain, anti-depressants and anticonvulsants have not yet proven effective for treating the symptoms of CIPN.

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

Genomic Correlates of Disease Progression and Treatment Response in Prospectively Characterized Gliomas.

PURPOSE: The genomic landscape of gliomas has been characterized and now contributes to disease classification, yet the relationship between molecular profile and disease progression and treatment response remain poorly understood.Experimental Design: We integrated prospective clinical sequencing of 1,004 primary and recurrent tumors from 923 glioma patients with clinical and treatment phenotypes. RESULTS: Thirteen percent of glioma patients harbored a pathogenic germline variant, including a subset associated with heritable genetic syndromes and variants mediating DNA repair dysfunctions (29% of the total) that were associated with somatic biallelic inactivation and mechanism-specific somatic phenotypes. In astrocytomas, genomic alterations in effectors of cell-cycle progression correlated with aggressive disease independent of IDH mutation status, arose preferentially in enhancing tumors (44% vs. 8%, P < 0.001), were associated with rapid disease progression following tumor recurrence (HR = 2.6, P = 0.02), and likely preceded the acquisition of alkylating therapy-associated somatic hypermutation. Thirty-two percent of patients harbored a potentially therapeutically actionable lesion, of whom 11% received targeted therapies. In BRAF-mutant gliomas, response to agents targeting the RAF/MEK/ERK signaling axis was influenced by the type of mutation, its clonality, and its cellular and genomic context. CONCLUSIONS: These data reveal genomic correlates of disease progression and treatment response in diverse types of glioma and highlight the potential utility of incorporating genomic information into the clinical decision-making for patients with glioma.

Tumor mutational load predicts survival after immunotherapy across multiple cancer types.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

Radiographic patterns of recurrence and pathologic correlation in malignant gliomas treated with bevacizumab.

Interpretation of MRI abnormalities in patients with malignant gliomas (MG) treated with bevacizumab is challenging. Recent reports describe quantitative analyses of diffusion-weighted imaging abnormalities not available in standard clinical settings, to differentiate tumor recurrence from treatment necrosis. We retrospectively reviewed bevacizumab treated MG patients who underwent surgery or autopsy to correlate radiographic recurrence patterns with pathologic findings. 32 patients with MG (26 glioblastoma, three anaplastic astrocytoma and three anaplastic oligodendroglioma) were identified. Recurrence patterns: local enhancing (n = 23), distant enhancing (n = 1), nonenhancing (n = 7) and leptomeningeal (n = 1). HISTOLOGY: tumor (n = 25), mixed tumor/necrosis (n = 5) and all necrosis (n = 2). On diffusion-weighted imaging, 5/32 had restricted diffusion (three mixed and two necrosis). Irrespective of radiographic recurrence pattern, tumor was found in 94% of cases. Restricted diffusion correlated with necrosis.

Multicenter Phase IB Trial of Carboxyamidotriazole Orotate and Temozolomide for Recurrent and Newly Diagnosed Glioblastoma and Other Anaplastic Gliomas.

Purpose Carboxyamidotriazole orotate (CTO) is a novel oral inhibitor of non-voltage-dependent calcium channels with modulatory effects in multiple cell-signaling pathways and synergistic effects with temozolomide (TMZ) in glioblastoma (GBM) models. We conducted a phase IB study combining CTO with two standard TMZ schedules in GBM. Methods In cohort 1, patients with recurrent anaplastic gliomas or GBM received escalating doses of CTO (219 to 812.5 mg/m2 once daily or 600 mg fixed once-daily dose) combined with TMZ (150 mg/m2 5 days during each 28-day cycle). In cohort 2, patients with newly diagnosed GBM received escalating doses of CTO (219 to 481 mg/m2/d once daily) with radiotherapy and TMZ 75 mg/m2/d, followed by TMZ 150 mg to 200 mg/m2 5 days during each 28-day cycle. Results Forty-seven patients were enrolled. Treatment was well tolerated; toxicities included fatigue, constipation, nausea, and hypophosphatemia. Pharmacokinetics showed that CTO did not alter TMZ levels; therapeutic concentrations were achieved in tumor and brain. No dose-limiting toxicities were observed; the recommended phase II dose was 600 mg/d flat dose. Signals of activity in cohort 1 (n = 27) included partial (n = 6) and complete (n = 1) response, including in O6-methylguanine-DNA methyltransferase unmethylated and bevacizumab-refractory tumors. In cohort 2 (n = 15), median progression-free survival was 15 months and median overall survival was not reached (median follow-up, 28 months; 2-year overall survival, 62%). Gene sequencing disclosed a high rate of responses among EGFR-amplified tumors ( P = .005), with mechanisms of acquired resistance possibly involving mutations in mismatch-repair genes and/or downstream components TSC2, NF1, NF2, PTEN, and PIK3CA. Conclusion CTO can be combined safely with TMZ or chemoradiation in GBM and anaplastic gliomas, displaying favorable brain penetration and promising signals of activity in this difficult-to-treat population.

Bevacizumab in high-grade glioma patients following intraparenchymal hemorrhage.

BACKGROUND: Intraparenchymal hemorrhage (IPH) is a relative contraindication to bevacizumab therapy, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody approved for the treatment of recurrent glioblastoma. However, in patients with symptomatic enhancing tumors and poor functional status, bevacizumab may be the only beneficial therapeutic option. METHODS: We retrospectively reviewed all patients with high-grade glioma who were treated between January 1, 2005 and December 31, 2014 with bevacizumab despite prior IPH. RESULTS: Eighteen patients met our study criteria. There were 12 women and 6 men with a median age of 56 years. Tumor types were glioblastoma (n = 15), anaplastic astrocytoma (n = 2), and anaplastic oligodendroglioma (n = 1). Seventeen patients had prior spontaneous intratumoral bleed (13 grade 1-2; 4 grade 3-4); the 1 remaining patient had a grade 3 bleed due to cerebral venous thrombosis. Among them, identifiable risk factors for hemorrhage were anti-VEGF therapy, anticoagulation use, thrombocytopenia, and hypertension; seven had no identifiable risk factors. The median duration from IPH to (re-)initiation of bevacizumab was 113 days (range 13-1367). Brain imaging performed prior to bevacizumab treatment showed persistent or evolving hemorrhage in 8 patients and complete resolution in 10 patients. With a median follow-up duration of 137 days after bevacizumab re-initiation, only 1 (6%) of the 18 patients re-bled; this patient had an anaplastic oligodendroglioma and developed a grade 2 intratumoral bleed after 3 doses of bevacizumab. CONCLUSIONS: The incidence of re-bleed is rare. Bevacizumab use was safe in patients with recurrent high-grade glioma following IPH for whom no other meaningful treatment options existed.