Publications by authors named "Annick Desjardins"

110 Publications

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy.

Nat Commun 2021 01 13;12(1):352. Epub 2021 Jan 13.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, 27710, USA.

Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
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http://dx.doi.org/10.1038/s41467-020-20469-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806846PMC
January 2021

A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma.

Invest New Drugs 2020 12 20;38(6):1784-1795. Epub 2020 May 20.

Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.

Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF-06840002 was 1.5-3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (< 1%). At 500 mg BID, maximum mean percentage inhibition of C10 kynurenine vs endogenous kynurenine was 75% vs 24%. PF-06840002 CSF-to-plasma ratio was 1.00. Disease control occurred in eight patients (47%). Mean duration of stable disease (SD) was 32.1 (12.1-72.3) weeks. Two patients with SD discontinued the study at 450 and 561 days and continued PF-06840003 on compassionate use. Conclusion PF‑06840003 up to 500 mg BID was generally well tolerated with evidence of a pharmacodynamic effect and durable clinical benefit in a subset of patients with recurrent malignant glioma. ClinicalTrials.gov, NCT02764151, registered April 2016.
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http://dx.doi.org/10.1007/s10637-020-00950-1DOI Listing
December 2020

Patterns of relapse after successful completion of initial therapy in primary central nervous system lymphoma: a case series.

J Neurooncol 2020 Apr 5;147(2):477-483. Epub 2020 Mar 5.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Purpose: Primary central nervous system lymphoma (PCNSL) is a subtype of non-Hodgkin's lymphoma that involves the brain, spinal cord, or leptomeninges, without evidence of systemic disease. This rare disease accounts for ~ 3% of all primary central nervous system (CNS) tumors. Methotrexate-based regimens are the standard of care for this disease with overall survival rates ranging from 14 to 55 months. Relapse after apparent complete remission can occur. We sought to understand the outcomes of patients who relapsed.

Methods: This is an IRB-approved investigation of patients treated at our institution between 12/31/2004 and 10/12/2016. We retrospectively identified all cases of PCNSL as part of a database registry and evaluated these cases for demographic information, absence or presence of relapse, location of relapse, treatment regimens, and median relapse-free survival.

Results: This analysis identified 44 patients with a pathologically confirmed diagnosis of PCNSL. Mean age at diagnosis was 63.1 years (range 20-86, SD = 13.2 years). Of the 44 patients, 28 patients successfully completed an initial treatment regimen without recurrence or toxicity that required a change in therapy. Relapse occurred in 11 patients with the location of relapse being in the CNS only (n = 5), vitreous fluid only (n = 1), outside CNS only (n = 3), or a combination of CNS and outside of the CNS (n = 2). Sites of relapse outside of the CNS included testes (n = 1), lung (n = 1), adrenal gland (n = 1), kidney/adrenal gland (n = 1), and retroperitoneum (n = 1). Median relapse-free survival after successful completion of therapy was 6.7 years (95% CI 1.1, 12.6).

Conclusion: After successful initial treatment, PCNSL has a propensity to relapse, and this relapse can occur both inside and outside of the CNS. Vigilant monitoring of off-treatment patients with a history of PCNSL is necessary to guide early diagnosis of relapse and to initiate aggressive treatment.
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http://dx.doi.org/10.1007/s11060-020-03446-3DOI Listing
April 2020

Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma.

Invest New Drugs 2020 10 5;38(5):1570-1579. Epub 2020 Mar 5.

Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain.

Purpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.
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http://dx.doi.org/10.1007/s10637-020-00910-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497674PMC
October 2020

Rindopepimut with Bevacizumab for Patients with Relapsed EGFRvIII-Expressing Glioblastoma (ReACT): Results of a Double-Blind Randomized Phase II Trial.

Clin Cancer Res 2020 04 7;26(7):1586-1594. Epub 2020 Feb 7.

Celldex Therapeutics, Inc., Hampton, New Jersey.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma.

Patients And Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2.

Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control ( = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; < 0.0001).

Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1140DOI Listing
April 2020

The role of chemotherapy in the treatment of central neurocytoma.

CNS Oncol 2019 11 5;8(3):CNS41. Epub 2019 Nov 5.

Department of Neurosurgery, Duke University Hospital, Durham, NC 27710, USA.

Central neurocytoma (CN) is a rare WHO grade II central nervous system (CNS) tumor. This is an update on chemotherapeutic agents used in its treatment. An institutional review board-approved, chart review of patients seen at our institution resulted in a single case treated with chemotherapy and is herein included. We proceeded with a comprehensive literature review. We identified 18 citations, representing 39 cases of adult and pediatric CN treated with chemotherapy. With the addition of our single case, the total number of recurrent CN patients treated with temozolomide (TMZ) is nine. There exists marked heterogeneity in chemotherapy used to treat CN. TMZ is incorporated into treatment regimens in the setting of tumor recurrence: its role merits further study.
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http://dx.doi.org/10.2217/cns-2019-0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880304PMC
November 2019

Second primary cancers in long-term survivors of glioblastoma.

Neurooncol Pract 2019 Sep 4;6(5):386-391. Epub 2019 Feb 4.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Background: Overall survival (OS) in glioblastoma (GBM) is poor at an average of 14 to 18 months, and long-term survivors (LTS) of GBM are rare. LTS of GBM, defined as surviving >5 years postdiagnosis, represent only 2% to 10% of all GBM patients. LTS of cancer are at high risk of developing second primary neoplasms. This study looks at occurrences of second primary neoplasms in LTS of GBM.

Methods: Records from adult patients newly diagnosed with GBM between January 1, 1998 and February 8, 2010, were retrospectively reviewed to identify LTS, defined as patients who survived ≥5 years. We focused on the identification of a new diagnosis of cancer occurring at least 2 years after the initial GBM diagnosis.

Results: We identified 155 LTS of GBM, with a median OS of 11.0 years (95% CI: 9.0 to 13.1 years) and a median follow-up of 9.6 years (95% CI: 8.7 to 10.7 years). In this cohort of patients, 13 (8.4%) LTS of GBM developed 17 secondary cancers. Eight could potentially be attributed to previous radiation and chemotherapy (skin cancer in radiation field [n = 4], leukemia [n = 2], low-grade glioma [n = 1], and sarcoma of the scalp [n = 1]). The other 9 cases included melanoma (n = 2), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1).

Conclusions: Although second primary cancers are rare in GBM LTS, providers should continue close monitoring with appropriate oncologic care. Moreover, this highlights the need for survivorship care of patients with GBM.
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http://dx.doi.org/10.1093/nop/npz001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753354PMC
September 2019

Randomized open-label phase II trial of 5-day aprepitant plus ondansetron compared to ondansetron alone in the prevention of chemotherapy-induced nausea-vomiting (CINV) in glioma patients receiving adjuvant temozolomide.

Support Care Cancer 2020 May 22;28(5):2229-2238. Epub 2019 Aug 22.

Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.

Purpose: CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated.

Methods: One hundred thirty-six glioma patients receiving their first cycle of adjuvant temozolomide (150-200 mg/m/day × 5 days every 28 days) were randomized to Arm-A (ondansetron 8 mg days 1-5 with aprepitant day 1: 125 mg, days 2-5: 80 mg) or Arm-B (ondansetron). Randomization was stratified by tumor grade and number of prior chemotherapy regimens. The primary endpoint was the percentage of patients achieving complete control (CC), defined as no emetic episode or antiemetic rescue medication over the 7-day study period. Secondary endpoints included CINV efficacy in the acute phase (≤ 24 h) and delayed phase (days 2-7), as well as safety and quality of life (QoL).

Results: Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity.

Conclusions: Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV's effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.
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http://dx.doi.org/10.1007/s00520-019-05039-xDOI Listing
May 2020

Complementary and integrative health interventions and their association with health-related quality of life in the primary brain tumor population.

Complement Ther Clin Pract 2019 Aug 18;36:43-48. Epub 2019 May 18.

Department of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, DUMC Box 3624, Durham, NC, 27710, USA. Electronic address:

Background And Purpose: Little is known about complementary and integrative health intervention usage in the primary brain tumor population. We aimed to identify the percentage of patients using these practices and explore the impact on quality of life.

Materials And Methods: Clinical records from patients seen in clinic between December 16, 2013 and February 28, 2014 were reviewed retrospectively. The questionnaires used were a modified version of the International Complementary and Alternative Medicine Questionnaire, the Functional Assessment of Cancer Therapy- Brain Cancer and the Functional Assessment of Chronic Illness Therapy- Fatigue.

Results: 76% of patients utilized a complementary and integrative health modality. The most frequently reported modalities used were vitamins, massage, and spiritual healing, prayer, diet and meditation.

Conclusion: These results confirm the usage of complementary and integrative health practices within the primary brain tumor population; however, there was no evidence of association between use and quality of life.
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http://dx.doi.org/10.1016/j.ctcp.2019.05.002DOI Listing
August 2019

Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.

J Immunother Cancer 2019 05 29;7(1):142. Epub 2019 May 29.

Department of Neurosurgery and the Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Medical Sciences Research Building, Rm 181c, Box 3156, Durham, NC, 27710, USA.

Background: D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma.

Methods: To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test.

Results: D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge.

Conclusions: These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.
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http://dx.doi.org/10.1186/s40425-019-0614-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542114PMC
May 2019

Single-institution retrospective review of patients with recurrent glioblastoma treated with bevacizumab in clinical practice.

Health Sci Rep 2019 Apr 13;2(4):e114. Epub 2019 Feb 13.

The Preston Robert Tisch Brain Tumor Center Duke University Medical Center Durham North Carolina.

Background And Aims: This retrospective review of patients with recurrent glioblastoma treated at the Preston Robert Tisch Brain Tumor Center investigated treatment patterns, survival, and safety with bevacizumab in a real-world setting.

Methods: Adult patients with glioblastoma who initiated bevacizumab at disease progression between January 1, 2009, and May 14, 2012, were included. A Kaplan-Meier estimator was used to describe overall survival (OS), progression-free survival (PFS), and time to greater than or equal to 20% reduction in Karnofsky Performance Status (KPS). The effect of baseline demographic and clinical factors on survival was examined using a Cox proportional hazards model. Adverse event (AE) data were collected.

Results: Seventy-four patients, with a median age of 59 years, were included in this cohort. Between bevacizumab initiation and first failure, defined as the first disease progression after bevacizumab initiation, biweekly bevacizumab and bevacizumab/irinotecan were the most frequently prescribed regimens. Median duration of bevacizumab treatment until failure was 6.4 months (range, 0.5-58.7). Median OS and PFS from bevacizumab initiation were 11.1 months (95% confidence interval [CI], 7.3-13.4) and 6.4 months (95% CI, 3.9-8.5), respectively. Median time to greater than or equal to 20% reduction in KPS was 29.3 months (95% CI, 13.8-∞). Lack of corticosteroid usage at the start of bevacizumab therapy was associated with both longer OS and PFS, with a median OS of 13.2 months (95% CI, 8.6-16.6) in patients who did not initially require corticosteroids versus 7.2 months (95% CI, 4.8-12.5) in those who did ( = 0.0382, log-rank), while median PFS values were 8.6 months (95% CI, 4.6-9.7) and 3.7 months (95% CI, 2.7-6.6), respectively ( = 0.0243, log-rank). Treatment failure occurred in 70 patients; 47 of whom received salvage therapy, and most frequently bevacizumab/carboplatin (7/47; 14.9%). Thirteen patients (18%) experienced a grade 3 AE of special interest for bevacizumab.

Conclusions: Treatment patterns and outcomes for patients with recurrent glioblastoma receiving bevacizumab in a real-world setting were comparable with those reported in prospective clinical trials.
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http://dx.doi.org/10.1002/hsr2.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482327PMC
April 2019

Adjunctive perampanel for glioma-associated epilepsy.

Epilepsy Behav Case Rep 2018 9;10:114-117. Epub 2018 Oct 9.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States of America.

Glioma-associated epilepsy is associated with excessive glutamate signaling. We hypothesized that perampanel, an amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor antagonist, would treat glioma-related epilepsy. We conducted a single-arm study of adjunctive perampanel for patients with focal-onset glioma-associated seizures. The most common related adverse events were fatigue and dizziness. Three out of 8 participants had self-reported seizure reduction and an additional 3 reported improved control. Of these 6, 5 had isocitrate dehydrogenase 1 mutant gliomas. We conclude that perampanel is safe for patients with glioma-related focal-onset epilepsy. Further study into the association between AMPA signaling, IDH1 status and seizures is warranted.
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http://dx.doi.org/10.1016/j.ebcr.2018.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202665PMC
October 2018

Recurrent Glioblastoma Treated with Recombinant Poliovirus.

N Engl J Med 2018 07 26;379(2):150-161. Epub 2018 Jun 26.

From the Departments of Neurosurgery (A.D., M.G., A.H.F., H.S.F., K.B.P., D.R., J.H.S., G.V., D.A., D.D.B.), Biostatistics (J.E.H., F.M.), Surgery (D.P.B., S.N.), and Pathology (W.T.H., R.E.M.) and the Preston Robert Tisch Brain Tumor Center (A.D., M.G., J.E.H., D.P.B., A.H.F., H.S.F., F.M., S.N., K.B.P., D.R., J.H.S., G.V., W.T.H., R.E.M., D.A., D.D.B.), Duke University Medical Center, and Istari Oncology (D.P.B.) - all in Durham, NC; Tempus Labs, Chicago (N.B.); and the School of Medicine, Deakin University, Geelong, VIC, Australia (A.M.M.).

Background: The prognosis of patients with recurrent World Health Organization (WHO) grade IV malignant glioma is dismal, and there is currently no effective therapy. We conducted a dose-finding and toxicity study in this population of patients, evaluating convection-enhanced, intratumoral delivery of the recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO). PVSRIPO recognizes the poliovirus receptor CD155, which is widely expressed in neoplastic cells of solid tumors and in major components of the tumor microenvironment.

Methods: We enrolled consecutive adult patients who had recurrent supratentorial WHO grade IV malignant glioma, confirmed on histopathological testing, with measurable disease (contrast-enhancing tumor of ≥1 cm and ≤5.5 cm in the greatest dimension). The study evaluated seven doses, ranging between 10 and 10 50% tissue-culture infectious doses (TCID), first in a dose-escalation phase and then in a dose-expansion phase.

Results: From May 2012 through May 2017, a total of 61 patients were enrolled and received a dose of PVSRIPO. Dose level -1 (5.0×10 TCID) was identified as the phase 2 dose. One dose-limiting toxic effect was observed; a patient in whom dose level 5 (10 TCID) was administered had a grade 4 intracranial hemorrhage immediately after the catheter was removed. To mitigate locoregional inflammation of the infused tumor with prolonged glucocorticoid use, dose level 5 was deescalated to reach the phase 2 dose. In the dose-expansion phase, 19% of the patients had a PVSRIPO-related adverse event of grade 3 or higher. Overall survival among the patients who received PVSRIPO reached a plateau of 21% (95% confidence interval, 11 to 33) at 24 months that was sustained at 36 months.

Conclusions: Intratumoral infusion of PVSRIPO in patients with recurrent WHO grade IV malignant glioma confirmed the absence of neurovirulent potential. The survival rate among patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among historical controls. (Funded by the Brain Tumor Research Charity and others; ClinicalTrials.gov number, NCT01491893 .).
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http://dx.doi.org/10.1056/NEJMoa1716435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065102PMC
July 2018

Phase II Study to Evaluate the Efficacy and Safety of Rilotumumab and Bevacizumab in Subjects with Recurrent Malignant Glioma.

Oncologist 2018 08 17;23(8):889-e98. Epub 2018 Apr 17.

Duke University Medical Center, Durham, North Carolina, USA

Lessons Learned: Due to evolving imaging criteria in brain tumors and variation in magnetic resonance imaging evaluation, it is not ideal to use response rate as a primary objective. Future studies involving antiangiogenic agents should use overall survival.Disease-expected toxicities should be considered when defining the clinical significance of an adverse event. For example, vascular thromboembolic events are common in brain tumor patients and should not be attributed to the study drug in the safety analysis.

Background: Recurrent malignant glioma (rMG) prognosis is poor, with a median patient survival of 3-11 months with bevacizumab (BEV)-containing regimens. BEV in rMG has 6-month progression free survival (PFS-6) of ∼40% and an objective response rate of 21.2%. BEV-containing regimens improve PFS-6 to 42.6%-50.3%, indicating that BEV combination therapies may be superior to single agent. Rilotumumab, a hepatocyte growth factor (HGF) antibody, inhibits angiogenesis and expression of angiogenic autocrine factors (e.g., vascular endothelial growth factor [VEGF]) by c-Met inhibition. Combination of rilotumumab with BEV to block vascular invasion and tumor proliferation may synergistically inhibit tumor growth.

Methods: Thirty-six BEV-naïve rMG subjects received rilotumumab (20 mg/kg and BEV (10 mg/kg) every 2 weeks. Endpoints included objective response rate (using Response Assessment in Neuro-Oncology [RANO] criteria), PFS-6, overall survival (OS), and toxicity.

Results: Median patient follow-up was 65.0 months. Objective response rate was 27.8% (95% confidence interval [CI]: 15.7%-44.1%). Median OS was 11.2 months (95% CI: 7-17.5). PFS-6 was 41.7% (95% CI: 25.6%-57.0%). Most frequent treatment-related grade ≤2 events included weight gain, fatigue, allergic rhinitis, and voice alteration; grade ≥3 events included venous thromboembolism (four patients), including one death from pulmonary embolism.

Conclusion: Rilotumumab with BEV did not significantly improve objective response compared with BEV alone, and toxicity may preclude the use of rilotumumab in combination BEV regimens.
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http://dx.doi.org/10.1634/theoncologist.2018-0149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156179PMC
August 2018

Volumetric response quantified using T1 subtraction predicts long-term survival benefit from cabozantinib monotherapy in recurrent glioblastoma.

Neuro Oncol 2018 09;20(10):1411-1418

UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.

Background: To overcome challenges with traditional response assessment in anti-angiogenic agents, the current study uses T1 subtraction maps to quantify volumetric radiographic response in monotherapy with cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and AXL, in an open-label, phase II trial in patients with recurrent glioblastoma (GBM) (NCT00704288).

Methods: A total of 108 patients with adequate imaging data and confirmed recurrent GBM were included in this retrospective study from a phase II multicenter trial of cabozantinib monotherapy (XL184-201) at either 100 mg (N = 87) or 140 mg (N = 21) per day. Contrast enhanced T1-weighted digital subtraction maps were used to define volume of contrast-enhancing tumor at baseline and subsequent follow-up time points. Volumetric radiographic response (>65% reduction in contrast-enhancing tumor volume from pretreatment baseline tumor volume sustained for more than 4 wk) was tested as an independent predictor of overall survival (OS).

Results: Volumetric response rate for all therapeutic doses was 38.9% (41.4% and 28.6% for 100 mg and 140 mg doses, respectively). A log-linear association between baseline tumor volume and OS (P = 0.0006) and a linear correlation between initial change in tumor volume and OS (P = 0.0256) were observed. A significant difference in OS was observed between responders (median OS = 20.6 mo) and nonresponders (median OS = 8.0 mo) (hazard ratio [HR] = 0.3050, P < 0.0001). Multivariable analyses showed that continuous measures of baseline tumor volume (HR = 1.0233, P < 0.0001) and volumetric response (HR = 0.2240, P < 0.0001) were independent predictors of OS.

Conclusions: T1 subtraction maps provide value in determining response in recurrent GBM treated with cabozantinib and correlated with survival benefit.
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http://dx.doi.org/10.1093/neuonc/noy054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120362PMC
September 2018

Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models.

J Neurooncol 2018 Jul 21;138(3):489-498. Epub 2018 Mar 21.

Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, 3624 DUMC, Baker House, Durham, NC, 27710, USA.

Background: Sym004 is a mixture of two monoclonal antibodies (mAbs), futuximab and modotuximab, targeting non-overlapping epitopes on the epidermal growth factor receptor (EGFR). Previous studies have shown that Sym004 is more efficient at inducing internalization and degradation of EGFR than individual components, which translates into superior cancer cell inhibition. We investigated whether Sym004 induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII).

Methods: To address this question, we tested the effect of Sym004 versus cetuximab in eight patient-derived GBM xenograft models expressing either wild-type EGFR (EGFRwt) and/or mutant EGFRvIII. All models were tested as both subcutaneous and orthotopic intracranial xenograft models.

Results: In vitro studies demonstrated that Sym004 internalized and removed EGFRvIII more efficiently than mAbs, futuximab, modotuximab, and cetuximab. Removal of EGFRvIII by Sym004 translated into significant in vivo anti-tumor activity in all six EGFRvIII xenograft models. Furthermore, the anti-tumor activity of Sym004 in vivo was superior to that of its individual components, futuximab and modotuximab, suggesting a clear synergistic effect of the mAbs in the mixture.

Conclusion: These results demonstrate the broad activity of Sym004 in patient-derived EGFRvIII-expressing GBM xenograft models and provide a clear rationale for clinical evaluation of Sym004 in EGFRvIII-positive adult GBM patients.
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http://dx.doi.org/10.1007/s11060-018-2832-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999169PMC
July 2018

Phase I/II trial of vorinostat, bevacizumab, and daily temozolomide for recurrent malignant gliomas.

J Neurooncol 2018 Apr 21;137(2):349-356. Epub 2017 Dec 21.

Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.

Prognosis of recurrent glioblastoma (GBM) is poor with 6-month progression-free survival (PFS6) ranging from 9 to 48% depending on the treatment regimen and use of anti-angiogenic therapies. We sought to study vorinostat (VOR), a histone deacetylase inhibitor, in combination with bevacizumab (BEV) and daily metronomic temozolomide (TMZ) in a Phase I/II trial in recurrent high-grade gliomas (HGGs). This was a Phase I/II open-label, single-arm study in recurrent HGG patients. Phase I primary endpoint was to determine the maximum tolerated dose (MTD) of VOR with BEV and daily TMZ. Phase II primary endpoint was PFS6. Regimen was BEV 10 mg/kg iv every 2 weeks, TMZ 50 mg/m po daily, and VOR 200 or 400 mg po alternating 7 days on then 7 days off throughout a 28-day cycle. Phase I portion enrolled nine subjects with three receiving VOR 200 mg and 6 receiving VOR 400 mg. With no dose-limiting toxicities (DLTs) at 200 mg and one DLT (thrombocytopenia, Grade 3) at 400 mg, the MTD was 400 mg. Phase II portion enrolled 39 GBM subjects, and PFS6 was 53.8% (95% CI 37.2-67.9%). Of note, 14 subjects had received prior BEV and all had received prior 5-day TMZ. Combination therapy with VOR, BEV, and daily TMZ was well tolerated and safe. While PFS6 was not statistically improved beyond historical controls, it is important to note that this was a heavily pretreated GBM population and further consideration is warranted in a less pretreated group.
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http://dx.doi.org/10.1007/s11060-017-2724-1DOI Listing
April 2018

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma.

Oncologist 2018 02 13;23(2):157-e21. Epub 2017 Nov 13.

Duke University Medical Center, Durham, North Carolina, USA

Lessons Learned: Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens.

Background: Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression-free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM.

Materials And Methods: In this phase II, single-center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28-day cycle. The primary endpoint was 6-month PFS (PFS6).

Results: Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%-44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6-12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment-related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified.

Conclusion: Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy.
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http://dx.doi.org/10.1634/theoncologist.2017-0501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813746PMC
February 2018

Dendritic Cells Enhance Polyfunctionality of Adoptively Transferred T Cells That Target Cytomegalovirus in Glioblastoma.

Cancer Res 2018 01 1;78(1):256-264. Epub 2017 Nov 1.

Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Median survival for glioblastoma (GBM) remains <15 months. Human cytomegalovirus (CMV) antigens have been identified in GBM but not normal brain, providing an unparalleled opportunity to subvert CMV antigens as tumor-specific immunotherapy targets. A recent trial in recurrent GBM patients demonstrated the potential clinical benefit of adoptive T-cell therapy (ATCT) of CMV phosphoprotein 65 (pp65)-specific T cells. However, analyses from this study found no change in the capacity of CMV pp65-specific T cells to gain multiple effector functions or polyfunctionality, which has been associated with superior antitumor efficacy. Previous studies have shown that dendritic cells (DC) could further enhance tumor-specific CD8 T-cell polyfunctionality when administered as a vaccine. Therefore, we hypothesized that vaccination with CMV pp65 RNA-loaded DCs would enhance the frequency of polyfunctional CMV pp65-specific CD8 T cells after ATCT. Here, we report prospective results of a pilot trial in which 22 patients with newly diagnosed GBM were initially enrolled, of which 17 patients were randomized to receive CMV pp65-specific T cells with CMV-DC vaccination (CMV-ATCT-DC) or saline (CMV-ATCT-saline). Patients who received CMV-ATCT-DC vaccination experienced a significant increase in the overall frequencies of IFNγ, TNFα, and CCL3 polyfunctional, CMV-specific CD8 T cells. These increases in polyfunctional CMV-specific CD8 T cells correlated ( = 0.7371, = 0.0369) with overall survival, although we cannot conclude this was causally related. Our data implicate polyfunctional T-cell responses as a potential biomarker for effective antitumor immunotherapy and support a formal assessment of this combination approach in a larger randomized study. A randomized pilot trial in patients with GBM implicates polyfunctional T-cell responses as a biomarker for effective antitumor immunotherapy. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754236PMC
January 2018

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients with prior antiangiogenic therapy.

Neuro Oncol 2018 01;20(2):259-267

The Ronald Reagan UCLA Medical Center, Los Angeles, California (T.F.C.); Center for Neuro-Oncology, Dana-Farber/Brigham & Women's Cancer Center, Boston, Massachusetts (P.Y.W., J.D.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.dG.); University of California San Francisco, San Francisco, California (M.D.P.); Duke University, Durham, North Carolina (D.A.R., A.D.); Neuro-Oncology Center, University of Virginia Health System, Charlottesville, Virginia (D.S.); University of Washington, Department of Neurology, Fred Hutchinson Cancer Research Center, Seattle, Washington (M.C.); Henry Ford Health System, Detroit, Michigan (T.M.); Exelixis, South San Francisco, California (J.P., J.H., R.W.).

Background: Cabozantinib is a potent, multitarget inhibitor of MET and vascular endothelial growth factor receptor 2 (VEGFR2). This open-label, phase II trial evaluated cabozantinib in patients with recurrent or progressive glioblastoma (GBM).

Methods: Patients were initially enrolled to a starting cabozantinib dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of safety concerns. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate, assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, glucocorticoid use, and safety.

Results: Among 222 patients enrolled, 70 had received prior antiangiogenic therapy. Herein, we report results in this subset of 70 patients. The objective response rate was 4.3%, and the median duration of response was 4.2 months. The proportion of patients alive and progression free at 6 months was 8.5%. Median progression-free survival was 2.3 months, and median overall survival was 4.6 months. The most common adverse events reported in all patients, regardless of dose group, included fatigue (74.3%), diarrhea (47.1%), increased alanine aminotransferase (37.1%), headache (35.7%), hypertension (35.7%), and nausea (35.7%); overall, 34 (48.6%) patients experienced adverse events that resulted in dose reductions.

Conclusions: Cabozantinib treatment appeared to have modest clinical activity with a 4.3% response rate in patients who had received prior antiangiogenic therapy for GBM.

Clinical Trials Registration Number: NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).
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http://dx.doi.org/10.1093/neuonc/nox151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777491PMC
January 2018

Phase II study of cabozantinib in patients with progressive glioblastoma: subset analysis of patients naive to antiangiogenic therapy.

Neuro Oncol 2018 01;20(2):249-258

Center for Neuro-Oncology, Dana-Farber/Brigham & Women's Cancer Center, Boston, Massachusetts (P.Y.W, J.D.); The University of Texas MD Anderson Cancer Center, Houston, Texas (J.dG.); University of California, San Francisco, Helen Diller Cancer Center Building, San Francisco, California (M.D.P.); Duke University, Durham, North Carolina (D.A.R., A.D.); Neuro-Oncology Center, University of Virginia Health System, Charlottesville, Virginia (D.S.); University of Washington, Department of Neurology, Fred Hutchinson Cancer Research Center, Seattle, Washington (M.C.); Henry Ford Health System, Detroit, Michigan (T.M.); Exelixis, South San Francisco, California (J.H., J.P., R.W.); The Ronald Reagan UCLA Medical Center, Los Angeles, California (T.F.C.).

Background: Cabozantinib is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET that has demonstrated clinical activity in advanced solid tumors. This open-label, phase II trial evaluated cabozantinib in patients with recurrent or refractory glioblastoma (GBM).

Methods: Patients were initially enrolled at a starting dose of 140 mg/day, but the starting dose was amended to 100 mg/day because of toxicity. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by an independent radiology facility using modified Response Assessment in Neuro-Oncology criteria. Additional endpoints included duration of response, 6-month and median progression-free survival, overall survival, and safety.

Results: Among 152 patients naive to prior antiangiogenic therapy, the objective response rate was 17.6% and 14.5% in the 140 mg/day and 100 mg/day groups, respectively, which did not meet the predefined statistical target for success. The proportions of patients alive and progression free at 6 months were 22.3% and 27.8%, respectively. Median progression-free survival was 3.7 months in both groups, and median overall survival was 7.7 months and 10.4 months, respectively. The incidence of grade 3/4 adverse events (AEs) was 79.4% and 84.7% in the 140 mg/day and 100 mg/day groups, respectively, and dose reductions due to AEs were experienced by 61.8% and 72.0%, respectively. Common grade 3/4 AEs included fatigue, diarrhea, and palmar-plantar erythrodysesthesia syndrome.

Conclusions: Cabozantinib showed evidence of clinical activity in patients with recurrent GBM naive to antiangiogenic therapy, although the predefined statistical target for success was not met. At the starting doses assessed, AEs were frequently managed with dose reductions.

Clinical Trials Registration Number: NCT00704288 (https://www.clinicaltrials.gov/ct2/show/NCT00704288).
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http://dx.doi.org/10.1093/neuonc/nox154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777496PMC
January 2018

A cross sectional analysis from a single institution's experience of psychosocial distress and health-related quality of life in the primary brain tumor population.

J Neurooncol 2017 Sep 1;134(2):363-369. Epub 2017 Jul 1.

Department of Neurology, Duke University Medical Center, Durham, NC, 27710, USA.

Primary brain tumor patients experience high levels of distress. The purpose of this cross-sectional, retrospective study is to evaluate the level and different sources of psychosocial distress and how these pertain to health-related quality of life (HRQoL). The Primary and Recurrent Glioma registry at Duke's The Preston Robert Tisch Brain Tumor Center was queried retrospectively for demographic and clinical information on patients seen between December 2013 and February 2014. Data also included the National Comprehensive Cancer Network's Distress Thermometer (NCCN-DT), Functional Assessment of Cancer Therapy-Brain Cancer (FACT-Br), and Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F). 829 subjects completed questionnaires. 54% were male; 96% completed the NCCN-DT; 33.3% had a DT score ≥4 (moderate/severe distress). Women reported DT ≥ 4 more often than men (38.6 vs 29.0%; p = 0.005). Patients within 1 year of diagnosis reported DT ≥ 4 more often than those 1+ years after diagnosis (38.8 vs 30.9%; p = 0.034). 73.0% reported physical problems; the most frequent being fatigue (43.2%) and memory/concentration (40.9%). 42.0% complained of emotional problems with worry (29.4%) and nervousness (22.4%) being the most common. Patients who reported at least one practical, family, emotional or physical problem had significantly lower HRQoL scores (p < 0.001). Primary brain tumor patients experience memory dysfunction, fatigue, nervousness, worry, and financial concerns, which have a negative effect on the patient's HRQoL. By identifying and addressing these stressors, it may be possible to improve patient HRQoL.
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http://dx.doi.org/10.1007/s11060-017-2535-4DOI Listing
September 2017

A Phase II single-arm trial of palonosetron for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in malignant glioma patients receiving multidose irinotecan in combination with bevacizumab.

Ther Clin Risk Manag 2017 23;13:33-40. Epub 2016 Dec 23.

The Preston Robert Tisch Brain Tumor Center at Duke, South Hospital, Duke University Medical Center; Department of Neurosurgery, Duke University Health System.

Purpose: Given that the prognosis of recurrent malignant glioma (MG) remains poor, improving quality of life (QoL) through symptom management is important. Meta-analyses establishing antiemetic guidelines have demonstrated the superiority of palonosetron (PAL) over older 5-hydroxytryptamine 3-receptor antagonists in chemotherapy-induced nausea and vomiting (CINV) prevention, but excluded patients with gliomas. Irinotecan plus bevacizumab is a treatment frequently used in MG, but is associated with low (55%) CINV complete response (CR; no emesis or use of rescue antiemetic) with commonly prescribed ondansetron. A single-arm Phase II trial was conducted in MG patients to determine the efficacy of intravenous PAL (0.25 mg) and dexamethasone (DEX; 10 mg) received in conjunction with biweekly irinotecan-bevacizumab treatment. The primary end point was the proportion of subjects achieving acute CINV CR (no emesis or antiemetic ≤24 hours postchemotherapy). Secondary end points included delayed CINV CR (days 2-5), overall CINV CR (days 1-5), and QoL, fatigue, and toxicity.

Materials And Methods: A two-stage design of 160 patients was planned to differentiate between CINV CR of 55% and 65% after each dose of PAL-DEX. Validated surveys assessed fatigue and QoL.

Results: A total of 63 patients were enrolled, after which enrollment was terminated due to slow accrual; 52 patients were evaluable for the primary outcome of acute CINV CR. Following PAL-DEX dose administrations 1-3, acute CINV CR rates were 62%, 68%, and 70%; delayed CINV CR rates were 62%, 66%, and 70%, and overall CINV CR rates were 47%, 57%, and 62%, respectively. Compared to baseline, there was a clinically meaningful increase in fatigue during acute and overall phases, but not in the delayed phase. There were no grade ≥3 PAL-DEX treatment-related toxicities.

Conclusion: Data suggest that PAL-DEX is effective in preventing CINV in MG patients, which ultimately maintains the QoL of patients with glioma.
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http://dx.doi.org/10.2147/TCRM.S122480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207433PMC
December 2016

Phase II study to evaluate the safety and efficacy of intravenous palonosetron (PAL) in primary malignant glioma (MG) patients receiving standard radiotherapy (RT) and concomitant temozolomide (TMZ).

Support Care Cancer 2016 10 6;24(10):4365-75. Epub 2016 Jun 6.

Department of Neurosurgery, Duke University Health System, Durham, NC, 27710, USA.

Background: In malignant glioma (MG) patients undergoing radiation therapy (RT) with concomitant temozolomide, chemoradiation-induced nausea and vomiting (cRINV) degrades quality of life (QoL) and reduces treatment adherence, which thereby potentially compromises cancer control.

Methods: We conducted a 6-week phase II single-arm trial of PAL, a second-generation 5-HT3RA antiemetic, for cRINV prevention in MG patients receiving radiation therapy (RT; 54-60 Gy) and concomitant daily temozolomide (TMZ; 75 mg/m(2)/dX42d). Each week before radiation, patients received single-dose palonosetron (PAL) 0.25 mg IV (total = 6 doses). With safety/tolerability as the primary endpoint, the study was designed to differentiate between toxicity rates of 25 % (unacceptable) and 10 % (acceptable) toxicity rates. Secondary endpoints included the percentage of patients achieving cRINV complete response (CR: no emesis or rescue antiemetic) and QoL. Patients reported adverse effects in Common Toxicity Criteria for Adverse Events diaries; recorded vomiting, nausea, and rescue medication use in diaries (which were used to assess cRINV-CR); and reported QoL 4 days/week using the Modified Functional Living Index-Emesis (M-FLIE) and Osoba nausea and vomiting/retching modules.

Results: We enrolled 38 patients (mean age 59 years, 55 % female, 95 % white, 68 % used oral corticosteroids, 76 % reported low alcohol use). Four patients (10.5 %) experienced unacceptable treatment-related toxicity, defined as any grade 3, 4, or 5 non-hematologic toxicity. M-FLIE and Osoba scores showed no evidence of treatment impact on QoL. Overall, cRINV-CR rates for 6 weeks ranged from 67-79 %.

Conclusion: Single-dose weekly PAL is a safe and tolerable antiemetic for cRINV prevention in MG patients receiving standard RT and concomitant TMZ.
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http://dx.doi.org/10.1007/s00520-016-3276-1DOI Listing
October 2016

Vaccine Therapy, Oncolytic Viruses, and Gliomas.

Oncology (Williston Park) 2016 Mar;30(3):211-8

After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary.
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March 2016

Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier.

Neuro Oncol 2016 06 17;18(6):840-8. Epub 2015 Dec 17.

University of California, Irvine, California (K.D., V.A., D.A.B.); Triphase Accelerator Corporation, San Diego, California (G.K.L., A.M., F.J.B, M.T.); The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina (A.D.).

Background: The proteasome plays a vital role in the physiology of glioblastoma (GBM), and proteasome inhibition can be used as a strategy for treating GBM. Marizomib is a second-generation, irreversible proteasome inhibitor with a more lipophilic structure that suggests the potential for penetrating the blood-brain barrier. While bortezomib and carfilzomib, the 2 proteasome inhibitors approved for treatment of multiple myeloma, have little activity against malignant gliomas in vivo, marizomib could be a novel therapeutic strategy for primary brain tumors.

Methods: The in-vitro antitumor activity of marizomib was studied in glioma cell lines U-251 and D-54. The ability of marizomib to cross the blood-brain barrier and regulate proteasome activities was evaluated in cynomolgus monkeys and rats. The antitumor effect of marizomib in vivo was tested in an orthotopic xenograft model of human GBM.

Results: Marizomib inhibited the proteasome activity, proliferation, and invasion of glioma cells. Meanwhile, free radical production and apoptosis induced by marizomib could be blocked by antioxidant N-acetyl cysteine. In animal studies, marizomib distributed into the brain at 30% of blood levels in rats and significantly inhibited (>30%) baseline chymotrypsin-like proteasome activity in brain tissue of monkeys. Encouragingly, the immunocompromised mice, intracranially implanted with glioma xenografts, survived significantly longer than the control animals (P < .05) when treated with marizomib.

Conclusions: These preclinical studies demonstrated that marizomib can cross the blood-brain barrier and inhibit proteasome activity in rodent and nonhuman primate brain and elicit a significant antitumor effect in a rodent intracranial model of malignant glioma.
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http://dx.doi.org/10.1093/neuonc/nov299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864261PMC
June 2016

Phase 1 dose escalation trial of the safety and pharmacokinetics of cabozantinib concurrent with temozolomide and radiotherapy or temozolomide after radiotherapy in newly diagnosed patients with high-grade gliomas.

Cancer 2016 Feb 20;122(4):582-7. Epub 2015 Nov 20.

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Background: Cabozantinib inhibits mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2) and has demonstrated activity in patients with recurrent glioblastoma, warranting evaluation of the addition of cabozantinib to radiotherapy (RT) and temozolomide (TMZ) for patients with newly diagnosed high-grade glioma.

Methods: Cabozantinib doses of 40 mg and 60 mg were explored. Patients on the concurrent treatment arm received cabozantinib daily with standard TMZ and after RT continued cabozantinib daily with adjuvant TMZ. In the maintenance arm, patients who completed RT and ≥1 adjuvant cycle of TMZ continued adjuvant TMZ with added cabozantinib (3 schedules: days 1-28, days 1-14, or days 8-21).

Results: A total of 26 patients (25 with recurrent glioblastoma and 1 patient with anaplastic astrocytoma) aged 30 to 72 years were enrolled (10 to the concurrent arm and 16 to the maintenance arm). The median number of post-RT TMZ cycles was 4.5 (range, 0-14 cycles) in the concurrent arm and 5.5 (range, 1-12 cycles) in the maintenance arm. Cabozantinib at a dose of 60 mg daily was the maximum administered dose and a dose of 40 mg daily was determined to be the maximum tolerated dose for both treatment arms (schedule of days 1-28). The most frequent grade 3/4 adverse events were thrombocytopenia (31% of patients), leukopenia (27% of patients, including 5 patients with neutropenia), and deep vein thrombosis and/or pulmonary embolism (23% of patients) (adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]).

Conclusions: Cabozantinib at a dose of 40 mg daily with RT plus TMZ and post-RT TMZ for patients with newly diagnosed high-grade glioma was generally well tolerated, and demonstrated no pharmacokinetic interactions with concurrent TMZ. Given the strong theoretical rationale for combining anti-VEGF and anti-MET activity with standard therapy, cabozantinib at a dose of 40 mg daily warrants evaluation in combination with standard therapy for patients with newly diagnosed glioblastoma.
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http://dx.doi.org/10.1002/cncr.29798DOI Listing
February 2016

CCR 20th Anniversary Commentary: Bevacizumab in the Treatment of Glioblastoma--The Progress and the Limitations.

Clin Cancer Res 2015 Oct;21(19):4248-50

Department of Hematology/Oncology, Saint Francis Hospital, Hartford, Connecticut.

Vredenburgh and colleagues conducted the first phase II study of bevacizumab plus irinotecan in recurrent malignant glioma, confirming the safety and efficacy of bevacizumab. This study, which was published in the February 15, 2007, issue of Clinical Cancer Research, was a stepping stone for subsequent research, leading to regulatory approval of bevacizumab for recurrent glioblastoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-1381DOI Listing
October 2015

Neuro-oncology: What is the optimal use of bevacizumab in glioblastoma?

Nat Rev Neurol 2015 Aug 21;11(8):429-30. Epub 2015 Jul 21.

The Preston Robert Tisch Brain Tumour Centre at Duke University Medical Centre, Department of Neurosurgery, DUMC Box 3624, Durham, NC 27710, USA.

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http://dx.doi.org/10.1038/nrneurol.2015.127DOI Listing
August 2015