2,526 results on '"Wen, Patrick Y."'
Search Results
2. Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma.
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Ellingson, Benjamin M, Hagiwara, Akifumi, Morris, Connor J, Cho, Nicholas S, Oshima, Sonoko, Sanvito, Francesco, Oughourlian, Talia C, Telesca, Donatello, Raymond, Catalina, Abrey, Lauren E, Garcia, Josep, Aftab, Dana T, Hessel, Colin, Rachmilewitz Minei, Tamar, Harats, Dror, Nathanson, David A, Wen, Patrick Y, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biomedical Imaging ,Rare Diseases ,Cancer ,Brain Cancer ,Brain Disorders ,Humans ,Glioblastoma ,Bevacizumab ,Angiogenesis Inhibitors ,Brain Neoplasms ,Neoplasm Recurrence ,Local ,Irinotecan ,Magnetic Resonance Imaging ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeAntiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy.Experimental designN = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival.ResultsOptimized thresholds occurred at g = 0.07 months-1 (phase II: HR = 0.2579, P = 5 × 10-20; phase III: HR = 0.2197, P = 5 × 10-5); d = 0.11 months-1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10-17; HR = 0.2061, P = 2 × 10-5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth.ConclusionsRecurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.
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- 2023
3. Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults.
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Weller, Michael, Le Rhun, Emilie, Van den Bent, Martin, Chang, Susan M, Cloughesy, Timothy F, Goldbrunner, Roland, Hong, Yong-Kil, Jalali, Rakesh, Jenkinson, Michael D, Minniti, Giuseppe, Nagane, Motoo, Razis, Evangelia, Roth, Patrick, Rudà, Roberta, Tabatabai, Ghazaleh, Wen, Patrick Y, Short, Susan C, and Preusser, Matthias
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Humans ,Lymphoma ,Central Nervous System Neoplasms ,Brain Neoplasms ,Combined Modality Therapy ,Quality of Life ,Adult ,adverse affects ,dose ,interruptions ,prevention ,reexposure ,toxicity ,Patient Safety ,Neurosciences ,Brain Disorders ,Rare Diseases ,Clinical Trials and Supportive Activities ,Brain Cancer ,Cancer ,Clinical Research ,7.3 Management and decision making ,Management of diseases and conditions ,7.1 Individual care needs ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.
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- 2023
4. A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine
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Latzer, Pauline, Zelba, Henning, Battke, Florian, Reinhardt, Annekathrin, Shao, Borong, Bartsch, Oliver, Rabsteyn, Armin, Harter, Johannes, Schulze, Martin, Okech, Thomas, Golf, Alexander, Kyzirakos-Feger, Christina, Kayser, Simone, Pieper, Natalia, Feldhahn, Magdalena, Wünsche, Julian, Seitz, Christian, Hadaschik, Dirk, Garbe, Claus, Hauser, Till-Karsten, la Fougère, Christian, Biskup, Dirk, Brooke, Dawn, Parker, David, Martens, Uwe M., Illerhaus, Gerald, Blumenthal, Deborah T., Merrell, Ryan, Lorenzo, Luisa Sánchez, Hidvégi, Máté, de Robles, Paula, Kebir, Sied, Li, William W., Li, Vincent W., Williams, Matthew, Miller, Alexandra M., Kesari, Santosh, Castro, Michael, Desjardins, Annick, Ashley, David M., Friedman, Henry S., Wen, Patrick Y., Neil, Elisabeth C., Iwamoto, Fabio M., Sipos, Bence, Geletneky, Karsten, Zender, Lars, Glas, Martin, Reardon, David A., and Biskup, Saskia
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- 2024
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5. Phase 1 dose expansion and biomarker study assessing first-in-class tumor microenvironment modulator VT1021 in patients with advanced solid tumors
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Chen, Jian Jenny, Vincent, Melanie Y., Shepard, Dale, Peereboom, David, Mahalingam, Devalingam, Battiste, James, Patel, Manish R., Juric, Dejan, Wen, Patrick Y., Bullock, Andrea, Selfridge, Jennifer Eva, Pant, Shubham, Liu, Joyce, Li, Wendy, Fyfe, Susanne, Wang, Suming, Zota, Victor, Mahoney, James, Watnick, Randolph S., Cieslewicz, Michael, and Watnick, Jing
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- 2024
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6. Updated Response Assessment in Neuro-Oncology (RANO) for Gliomas
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Youssef, Gilbert and Wen, Patrick Y.
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- 2024
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7. Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival
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Ellingson, Benjamin M, Wen, Patrick Y, Chang, Susan M, van den Bent, Martin, Vogelbaum, Michael A, Li, Gang, Li, Shanpeng, Kim, Jiyoon, Youssef, Gilbert, Wick, Wolfgang, Lassman, Andrew B, Gilbert, Mark R, de Groot, John F, Weller, Michael, Galanis, Evanthia, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Clinical Trials and Supportive Activities ,Rare Diseases ,Brain Cancer ,Brain Disorders ,Vaccine Related ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Humans ,Glioblastoma ,Temozolomide ,Brain Neoplasms ,Neoplasm Recurrence ,Local ,Antineoplastic Agents ,Lomustine ,Angiogenesis Inhibitors ,glioblastoma ,objective response rate ,overall survival ,recurrent GBM ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P < .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P < .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.
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- 2023
8. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial.
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Subbiah, Vivek, Kreitman, Robert J, Wainberg, Zev A, Gazzah, Anas, Lassen, Ulrik, Stein, Alexander, Wen, Patrick Y, Dietrich, Sascha, de Jonge, Maja JA, Blay, Jean-Yves, Italiano, Antoine, Yonemori, Kan, Cho, Daniel C, de Vos, Filip YFL, Moreau, Philippe, Fernandez, Elena Elez, Schellens, Jan HM, Zielinski, Christoph C, Redhu, Suman, Boran, Aislyn, Passos, Vanessa Q, Ilankumaran, Palanichamy, and Bang, Yung-Jue
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Humans ,Glioma ,Adenocarcinoma ,Imidazoles ,Pyridones ,Pyrimidinones ,Proto-Oncogene Proteins B-raf ,Antineoplastic Combined Chemotherapy Protocols ,Mutation ,Clinical Research ,Cancer ,Hematology ,Brain Cancer ,Brain Disorders ,Rare Diseases ,Digestive Diseases ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Medical and Health Sciences ,Immunology - Abstract
BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .
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- 2023
9. Artificial intelligence (AI)-based decision support improves reproducibility of tumor response assessment in neuro-oncology: An international multi-reader study
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Vollmuth, Philipp, Foltyn, Martha, Huang, Raymond Y, Galldiks, Norbert, Petersen, Jens, Isensee, Fabian, van den Bent, Martin J, Barkhof, Frederik, Park, Ji Eun, Park, Yae Won, Ahn, Sung Soo, Brugnara, Gianluca, Meredig, Hagen, Jain, Rajan, Smits, Marion, Pope, Whitney B, Maier-Hein, Klaus, Weller, Michael, Wen, Patrick Y, Wick, Wolfgang, and Bendszus, Martin
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Neurosciences ,Brain Cancer ,Clinical Research ,Brain Disorders ,Cancer ,Humans ,Glioblastoma ,Brain Neoplasms ,Artificial Intelligence ,Reproducibility of Results ,Glioma ,Artificial intelligence (AI)-based decision support ,RANO ,tumor response assessment ,tumor volumetry ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundTo assess whether artificial intelligence (AI)-based decision support allows more reproducible and standardized assessment of treatment response on MRI in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden using the Response Assessment in Neuro-Oncology (RANO) criteria.MethodsA series of 30 patients (15 lower-grade gliomas, 15 glioblastoma) with availability of consecutive MRI scans was selected. The time to progression (TTP) on MRI was separately evaluated for each patient by 15 investigators over two rounds. In the first round the TTP was evaluated based on the RANO criteria, whereas in the second round the TTP was evaluated by incorporating additional information from AI-enhanced MRI sequences depicting the longitudinal changes in tumor volumes. The agreement of the TTP measurements between investigators was evaluated using concordance correlation coefficients (CCC) with confidence intervals (CI) and P-values obtained using bootstrap resampling.ResultsThe CCC of TTP-measurements between investigators was 0.77 (95% CI = 0.69,0.88) with RANO alone and increased to 0.91 (95% CI = 0.82,0.95) with AI-based decision support (P = .005). This effect was significantly greater (P = .008) for patients with lower-grade gliomas (CCC = 0.70 [95% CI = 0.56,0.85] without vs. 0.90 [95% CI = 0.76,0.95] with AI-based decision support) as compared to glioblastoma (CCC = 0.83 [95% CI = 0.75,0.92] without vs. 0.86 [95% CI = 0.78,0.93] with AI-based decision support). Investigators with less years of experience judged the AI-based decision as more helpful (P = .02).ConclusionsAI-based decision support has the potential to yield more reproducible and standardized assessment of treatment response in neuro-oncology as compared to manual 2-dimensional measurements of tumor burden, particularly in patients with lower-grade gliomas. A fully-functional version of this AI-based processing pipeline is provided as open-source (https://github.com/NeuroAI-HD/HD-GLIO-XNAT).
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- 2023
10. Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial
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Mellinghoff, Ingo K, Lu, Min, Wen, Patrick Y, Taylor, Jennie W, Maher, Elizabeth A, Arrillaga-Romany, Isabel, Peters, Katherine B, Ellingson, Benjamin M, Rosenblum, Marc K, Chun, Saewon, Le, Kha, Tassinari, Ania, Choe, Sung, Toubouti, Youssef, Schoenfeld, Steven, Pandya, Shuchi S, Hassan, Islam, Steelman, Lori, Clarke, Jennifer L, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Brain Cancer ,Orphan Drug ,Rare Diseases ,Clinical Research ,Genetics ,Cancer ,Brain Disorders ,Neurosciences ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Humans ,Pyridines ,Isocitrate Dehydrogenase ,Glioma ,Mutation ,Pharmaceutical Preparations ,Brain Neoplasms ,Medical and Health Sciences ,Immunology ,Biomedical and clinical sciences ,Health sciences - Abstract
Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
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- 2023
11. Isocitrate dehydrogenase (IDH) mutant gliomas: A Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions
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Miller, Julie J, Castro, L Nicolas Gonzalez, McBrayer, Samuel, Weller, Michael, Cloughesy, Timothy, Portnow, Jana, Andronesi, Ovidiu, Barnholtz-Sloan, Jill S, Baumert, Brigitta G, Berger, Mitchell S, Bi, Wenya Linda, Bindra, Ranjit, Cahill, Daniel P, Chang, Susan M, Costello, Joseph F, Horbinski, Craig, Huang, Raymond Y, Jenkins, Robert B, Ligon, Keith L, Mellinghoff, Ingo K, Nabors, L Burt, Platten, Michael, Reardon, David A, Shi, Diana D, Schiff, David, Wick, Wolfgang, Yan, Hai, von Deimling, Andreas, van den Bent, Martin, Kaelin, William G, and Wen, Patrick Y
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Cancer ,Rare Diseases ,Neurosciences ,Brain Cancer ,Good Health and Well Being ,Adult ,Humans ,Isocitrate Dehydrogenase ,Consensus ,Mutation ,Glioma ,Brain Neoplasms ,D-2HG ,glioma ,Isocitrate dehydrogenase ,D-2HG ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.
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- 2023
12. Clinical trial links oncolytic immunoactivation to survival in glioblastoma
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Ling, Alexander L., Solomon, Isaac H., Landivar, Ana Montalvo, Nakashima, Hiroshi, Woods, Jared K., Santos, Andres, Masud, Nafisa, Fell, Geoffrey, Mo, Xiaokui, Yilmaz, Ayse S., Grant, James, Zhang, Abigail, Bernstock, Joshua D., Torio, Erickson, Ito, Hirotaka, Liu, Junfeng, Shono, Naoyuki, Nowicki, Michal O., Triggs, Daniel, Halloran, Patrick, Piranlioglu, Raziye, Soni, Himanshu, Stopa, Brittany, Bi, Wenya Linda, Peruzzi, Pierpaolo, Chen, Ethan, Malinowski, Seth W., Prabhu, Michael C., Zeng, Yu, Carlisle, Anne, Rodig, Scott J., Wen, Patrick Y., Lee, Eudocia Quant, Nayak, Lakshmi, Chukwueke, Ugonma, Gonzalez Castro, L. Nicolas, Dumont, Sydney D., Batchelor, Tracy, Kittelberger, Kara, Tikhonova, Ekaterina, Miheecheva, Natalia, Tabakov, Dmitry, Shin, Nara, Gorbacheva, Alisa, Shumskiy, Artemy, Frenkel, Felix, Aguilar-Cordova, Estuardo, Aguilar, Laura K., Krisky, David, Wechuck, James, Manzanera, Andrea, Matheny, Chris, Tak, Paul P., Barone, Francesca, Kovarsky, Daniel, Tirosh, Itay, Suvà, Mario L., Wucherpfennig, Kai W., Ligon, Keith, Reardon, David A., and Chiocca, E. Antonio
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- 2023
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13. Liquid biopsy epigenomic profiling for cancer subtyping
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Baca, Sylvan C., Seo, Ji-Heui, Davidsohn, Matthew P., Fortunato, Brad, Semaan, Karl, Sotudian, Shahabbedin, Lakshminarayanan, Gitanjali, Diossy, Miklos, Qiu, Xintao, El Zarif, Talal, Savignano, Hunter, Canniff, John, Madueke, Ikenna, Saliby, Renee Maria, Zhang, Ziwei, Li, Rong, Jiang, Yijia, Taing, Len, Awad, Mark, Chau, Cindy H., DeCaprio, James A., Figg, William D., Greten, Tim F., Hata, Aaron N., Hodi, F. Stephen, Hughes, Melissa E., Ligon, Keith L., Lin, Nancy, Ng, Kimmie, Oser, Matthew G., Meador, Catherine, Parsons, Heather A., Pomerantz, Mark M., Rajan, Arun, Ritz, Jerome, Thakuria, Manisha, Tolaney, Sara M., Wen, Patrick Y., Long, Henry, Berchuck, Jacob E., Szallasi, Zoltan, Choueiri, Toni K., and Freedman, Matthew L.
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- 2023
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14. Molecular Profiling and Targeted Therapies in Gliomas
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Felistia, Yuli and Wen, Patrick Y.
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- 2023
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15. Activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrence of glioblastoma
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Strowd, Roy, Ellingson, Benjamin, Raymond, Catalina, Yao, Jingwen, Wen, Patrick Y., Ahluwalia, Manmeet, Piotrowski, Anna, Desai, Arati, Clarke, Jennifer L., Lieberman, Frank S., Desideri, Serena, Nabors, L. Burt, Ye, Xiaobu, and Grossman, Stuart
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- 2023
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16. Correcting the drug development paradigm for glioblastoma requires serial tissue sampling
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Singh, Kirit, Hotchkiss, Kelly M., Parney, Ian F., De Groot, John, Sahebjam, Solmaz, Sanai, Nader, Platten, Michael, Galanis, Evanthia, Lim, Michael, Wen, Patrick Y., Minniti, Giuseppe, Colman, Howard, Cloughesy, Timothy F., Mehta, Minesh P., Geurts, Marjolein, Arrillaga-Romany, Isabel, Desjardins, Annick, Tanner, Kirk, Short, Susan, Arons, David, Duke, Elizabeth, Wick, Wolfgang, Bagley, Stephen J., Ashley, David M., Kumthekar, Priya, Verhaak, Roel, Chalmers, Anthony J., Patel, Anoop P., Watts, Colin, Fecci, Peter E., Batchelor, Tracy T., Weller, Michael, Vogelbaum, Michael A., Preusser, Matthias, Berger, Mitchel S., and Khasraw, Mustafa
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- 2023
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17. Investigational PET tracers in neuro-oncology-What's on the horizon? A report of the PET/RANO group.
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Galldiks, Norbert, Langen, Karl-Josef, Albert, Nathalie L, Law, Ian, Kim, Michelle M, Villanueva-Meyer, Javier E, Soffietti, Riccardo, Wen, Patrick Y, Weller, Michael, and Tonn, Joerg C
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Cancer ,Neurosciences ,Rare Diseases ,Brain Disorders ,Brain Cancer ,Bioengineering ,Biomedical Imaging ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Neurological ,Humans ,Radiopharmaceuticals ,Positron-Emission Tomography ,Brain Neoplasms ,fluciclovine ,Immuno-PET ,PSMA ,somatostatin ,TSPO ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Many studies in patients with brain tumors evaluating innovative PET tracers have been published in recent years, and the initial results are promising. Here, the Response Assessment in Neuro-Oncology (RANO) PET working group provides an overview of the literature on novel investigational PET tracers for brain tumor patients. Furthermore, newer indications of more established PET tracers for the evaluation of glucose metabolism, amino acid transport, hypoxia, cell proliferation, and others are also discussed. Based on the preliminary findings, these novel investigational PET tracers should be further evaluated considering their promising potential. In particular, novel PET probes for imaging of translocator protein and somatostatin receptor overexpression as well as for immune system reactions appear to be of additional clinical value for tumor delineation and therapy monitoring. Progress in developing these radiotracers may contribute to improving brain tumor diagnostics and advancing clinical translational research.
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- 2022
18. Spatial immune profiling of glioblastoma identifies an inflammatory, perivascular phenotype associated with longer survival
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Wirsching, Hans-Georg, Felsberg, Jörg, Prummer, Michael, Moisoiu, Vlad, Lourman, Roxanne, Hertler, Caroline, Antonios, Michelle, Cimino, Patrick J., Roth, Patrick, Gorlia, Thierry, Prins, Robert M., Cloughesy, Timothy, Wen, Patrick Y., Holland, Eric C., Reifenberger, Guido, and Weller, Michael
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- 2023
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19. Hypothetical generalized framework for a new imaging endpoint of therapeutic activity in early phase clinical trials in brain tumors
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Ellingson, Benjamin M, Gerstner, Elizabeth R, Lassman, Andrew B, Chung, Caroline, Colman, Howard, Cole, Patricia E, Leung, David, Allen, Joshua E, Ahluwalia, Manmeet S, Boxerman, Jerrold, Brown, Matthew, Goldin, Jonathan, Nduom, Edjah, Hassan, Islam, Gilbert, Mark R, Mellinghoff, Ingo K, Weller, Michael, Chang, Susan, Arons, David, Meehan, Clair, Selig, Wendy, Tanner, Kirk, Yung, WK Alfred, van den Bent, Martin, Wen, Patrick Y, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Clinical Research ,Neurosciences ,Rare Diseases ,Brain Cancer ,Brain Disorders ,Cancer ,Biomedical Imaging ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Neurological ,Brain Neoplasms ,Clinical Trials as Topic ,Diagnostic Imaging ,Humans ,Treatment Outcome ,response assessment ,brain tumors ,clinical trials ,growth rates ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Imaging response assessment is a cornerstone of patient care and drug development in oncology. Clinicians/clinical researchers rely on tumor imaging to estimate the impact of new treatments and guide decision making for patients and candidate therapies. This is important in brain cancer, where associations between tumor size/growth and emerging neurological deficits are strong. Accurately measuring the impact of a new therapy on tumor growth early in clinical development, where patient numbers are small, would be valuable for decision making regarding late-stage development activation. Current attempts to measure the impact of a new therapy have limited influence on clinical development, as determination of progression, stability or response does not currently account for individual tumor growth kinetics prior to the initiation of experimental therapies. Therefore, we posit that imaging-based response assessment, often used as a tool for estimating clinical effect, is incomplete as it does not adequately account for growth trajectories or biological characteristics of tumors prior to the introduction of an investigational agent. Here, we propose modifications to the existing framework for evaluating imaging assessment in primary brain tumors that will provide a more reliable understanding of treatment effects. Measuring tumor growth trajectories prior to a given intervention may allow us to more confidently conclude whether there is an anti-tumor effect. This updated approach to imaging-based tumor response assessment is intended to improve our ability to select candidate therapies for later-stage development, including those that may not meet currently sought thresholds for "response" and ultimately lead to identification of effective treatments.
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- 2022
20. Cavitation monitoring, treatment strategy, and acoustic simulations of focused ultrasound blood-brain barrier disruption in patients with glioblastoma
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McDannold, Nathan, Wen, Patrick Y., Reardon, David A., Fletcher, Stecia-Marie, and Golby, Alexandra J.
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- 2024
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21. Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results
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Brastianos, Priscilla K., Kim, Albert E., Giobbie-Hurder, Anita, Lee, Eudocia Q., Lin, Nancy U., Overmoyer, Beth, Wen, Patrick Y., Nayak, Lakshmi, Cohen, Justine V., Dietrich, Jorg, Eichler, April, Heist, Rebecca S., Krop, Ian, Lawrence, Donald, Ligibel, Jennifer, Tolaney, Sara, Mayer, Erica, Winer, Eric, Bent, Brittany, de Sauvage, Magali A., Ijad, Nazanin, Larson, Juliana M., Marion, Braxton, Nason, Sally, Murthy, Naina, Ratcliff, Sherry, Summers, Elizabeth J., Mahar, Maura, Shih, Helen A., Oh, Kevin, Cahill, Daniel P., Gerstner, Elizabeth R., and Sullivan, Ryan J.
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- 2023
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22. Circulating Immune Cell and Outcome Analysis from the Phase 2 Study of PD-L1 Blockade with Durvalumab for Newly Diagnosed and Recurrent GlioblastomaPD-L1 blockade with durvalumab for glioblastoma
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Nayak, Lakshmi, Standifer, Nathan, Dietrich, Jorg, Clarke, Jennifer L, Dunn, Gavin P, Lim, Michael, Cloughesy, Timothy, Gan, Hui K, Flagg, Elizabeth, George, Elizabeth, Gaffey, Sarah, Hayden, Julia, Holcroft, Christina, Wen, Patrick Y, Macri, Mary, Park, Andrew J, Ricciardi, Toni, Ryan, Aileen, Schwarzenberger, Paul, Venhaus, Ralph, de los Reyes, Melissa, Durham, Nicholas M, Creasy, Todd, Huang, Raymond Y, Kaley, Thomas, and Reardon, David A
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Brain Disorders ,Brain Cancer ,Clinical Research ,Rare Diseases ,Cancer ,Antibodies ,Monoclonal ,B7-H1 Antigen ,Bevacizumab ,Biomarkers ,Tumor ,Dexamethasone ,Glioblastoma ,Humans ,Ki-67 Antigen ,Neoplasm Recurrence ,Local ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposePD-L1 is upregulated in glioblastoma and supports immunosuppression. We evaluated PD-L1 blockade with durvalumab among glioblastoma cohorts and investigated potential biomarkers.Patients and methodsMGMT unmethylated newly diagnosed patients received radiotherapy plus durvalumab (cohort A; n = 40). Bevacizumab-naïve, recurrent patients received durvalumab alone (cohort B; n = 31) or in combination with standard bevacizumab (cohort B2; n = 33) or low-dose bevacizumab (cohort B3; n = 33). Bevacizumab-refractory patients received durvalumab plus bevacizumab (cohort C; n = 22). Primary endpoints were: OS-12 (A), PFS-6 (B, B2, B3), and OS-6 (C). Exploratory biomarkers included: a systematic, quantitative, and phenotypic evaluation of circulating immune cells; tumor mutational burden (TMB); and tumor immune activation signature (IAS).ResultsNo cohort achieved the primary efficacy endpoint. Outcome was comparable among recurrent, bevacizumab-naïve cohorts. No unexpected toxicities were observed. A widespread reduction of effector immune cell subsets was noted among recurrent patients compared with newly diagnosed patients that was partially due to dexamethasone use. A trend of increased CD8+Ki67+ T cells at day 15 was noted among patients who achieved the primary endpoint and were not on dexamethasone. Neither TMB nor IAS predicted outcome.ConclusionsPatients with recurrent glioblastoma have markedly lower baseline levels of multiple circulating immune cell subsets compared with newly diagnosed patients. An early increase in systemic Ki67+CD8+ cells may warrant further evaluation as a potential biomarker of therapeutic benefit among patients with glioblastoma undergoing checkpoint therapy. Dexamethasone decreased immune cell subsets. PD-L1 blockade and combination with standard or reduced dose bevacizumab was ineffective.
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- 2022
23. Liquid biopsy in gliomas: A RANO review and proposals for clinical applications.
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Soffietti, Riccardo, Bettegowda, Chetan, Mellinghoff, Ingo K, Warren, Katherine E, Ahluwalia, Manmeet S, De Groot, John F, Galanis, Evanthia, Gilbert, Mark R, Jaeckle, Kurt A, Le Rhun, Emilie, Rudà, Roberta, Seoane, Joan, Thon, Niklas, Umemura, Yoshie, Weller, Michael, van den Bent, Martin J, Vogelbaum, Michael A, Chang, Susan M, and Wen, Patrick Y
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Humans ,Glioma ,DNA ,Neoplasm ,Neoplastic Cells ,Circulating ,Biomarkers ,Tumor ,Liquid Biopsy ,Circulating Tumor DNA ,CSF ,circulating tumor cells ,ctDNA ,extracellular vesicles ,gliomas ,Neurosciences ,Brain Cancer ,Cancer ,Clinical Research ,Rare Diseases ,Brain Disorders ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Good Health and Well Being ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
BackgroundThere is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring.MethodsThe RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF.ResultsctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome.ConclusionsThere is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.
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- 2022
24. Volumetric measurements are preferred in the evaluation of mutant IDH inhibition in non-enhancing diffuse gliomas: Evidence from a phase I trial of ivosidenib
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Ellingson, Benjamin M, Kim, Grace Hyun J, Brown, Matt, Lee, Jihey, Salamon, Noriko, Steelman, Lori, Hassan, Islam, Pandya, Shuchi S, Chun, Saewon, Linetsky, Michael, Yoo, Bryan, Wen, Patrick Y, Mellinghoff, Ingo K, Goldin, Jonathan, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Neurosciences ,Bioengineering ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Brain Neoplasms ,Glioma ,Glycine ,Humans ,Isocitrate Dehydrogenase ,Magnetic Resonance Imaging ,Pyridines ,IDH-mutant gliomas ,ivosidenib ,LGG RANO ,low-grade gliomas ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundSince IDH-mutant (mIDH) low-grade gliomas (LGGs) progress slowly and have a relatively long survival, there is a significant need for earlier measurements of clinical benefit. Guidance using the LGG RANO criteria recommends serial bidirectional (2D) measurements on a single slice; however, questions remain as to whether volumetric (3D) measurements are better, since they would allow for more accurate measurements in irregular shaped lesions and allow readers to better assess areas of subtle change.MethodsTwenty-one (out of 24) non-enhancing, recurrent mIDH1 LGGs were enrolled in a phase I, multicenter, open-label study of oral ivosidenib (NCT02073994), and with imaging pre- and post-treatment as part of this exploratory ad hoc analysis. 2D and 3D measurements on T2-weighted FLAIR images were centrally evaluated at an imaging contract research organization using a paired read and forced adjudication paradigm. The effects of 2D vs 3D measurements on progression-free survival (PFS), growth rate measurement variability, and reader concordance and adjudication rates were quantified.Results3D volumetric measurements showed significantly longer estimated PFS (P = .0181), more stable (P = .0063) and considerably slower measures of tumor growth rate (P = .0037), the highest inter-reader agreement (weighted kappa = 0.7057), and significantly lower reader discordance rates (P = .0002) with 2D LGG RANO.Conclusion3D volumetric measurements are better for determining response assessment in LGGs due to more stable measures of tumor growth rates (ie, less "yo-yo-ing" of measurements over time), highest inter-reader agreement, and lowest reader discordance rates. Continued evaluation in future studies is warranted to determine whether these measurements reflect clinical benefit.
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- 2022
25. A Molecularly Integrated Grade for Meningioma
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Driver, Joseph, Hoffman, Samantha E, Tavakol, Sherwin, Woodward, Eleanor, Maury, Eduardo A, Bhave, Varun, Greenwald, Noah F, Nassiri, Farshad, Aldape, Kenneth, Zadeh, Gelareh, Choudhury, Abrar, Vasudevan, Harish N, Magill, Stephen T, Raleigh, David R, Abedalthagafi, Malak, Aizer, Ayal A, Alexander, Brian M, Ligon, Keith L, Reardon, David A, Wen, Patrick Y, Al-Mefty, Ossama, Ligon, Azra H, Dubuc, Adrian M, Beroukhim, Rameen, Claus, Elizabeth B, Dunn, Ian F, Santagata, Sandro, and Bi, Wenya Linda
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Brain Disorders ,Brain Cancer ,Rare Diseases ,Human Genome ,Cancer ,Genetics ,Good Health and Well Being ,Adult ,Cohort Studies ,Humans ,Meningeal Neoplasms ,Meningioma ,Neoplasm Grading ,Neoplasm Recurrence ,Local ,Prognosis ,Retrospective Studies ,World Health Organization ,meningioma ,copy-number alterations ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundMeningiomas are the most common primary intracranial tumor in adults. Clinical care is currently guided by the World Health Organization (WHO) grade assigned to meningiomas, a 3-tiered grading system based on histopathology features, as well as extent of surgical resection. Clinical behavior, however, often fails to conform to the WHO grade. Additional prognostic information is needed to optimize patient management.MethodsWe evaluated whether chromosomal copy-number data improved prediction of time-to-recurrence for patients with meningioma who were treated with surgery, relative to the WHO schema. The models were developed using Cox proportional hazards, random survival forest, and gradient boosting in a discovery cohort of 527 meningioma patients and validated in 2 independent cohorts of 172 meningioma patients characterized by orthogonal genomic platforms.ResultsWe developed a 3-tiered grading scheme (Integrated Grades 1-3), which incorporated mitotic count and loss of chromosome 1p, 3p, 4, 6, 10, 14q, 18, 19, or CDKN2A. 32% of meningiomas reclassified to either a lower-risk or higher-risk Integrated Grade compared to their assigned WHO grade. The Integrated Grade more accurately identified meningioma patients at risk for recurrence, relative to the WHO grade, as determined by time-dependent area under the curve, average precision, and the Brier score.ConclusionWe propose a molecularly integrated grading scheme for meningiomas that significantly improves upon the current WHO grading system in prediction of progression-free survival. This framework can be broadly adopted by clinicians with relative ease using widely available genomic technologies and presents an advance in the care of meningioma patients.
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- 2022
26. Designing Clinical Trials for Combination Immunotherapy: A Framework for GlioblastomaCombining Immunotherapy for Glioblastoma
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Singh, Kirit, Batich, Kristen A, Wen, Patrick Y, Tan, Aaron C, Bagley, Stephen J, Lim, Michael, Platten, Michael, Colman, Howard, Ashley, David M, Chang, Susan M, Rahman, Rifaquat, Galanis, Evanthia, Mansouri, Alireza, Puduvalli, Vinay K, Reardon, David A, Sahebjam, Solmaz, Sampson, John H, Simes, John, Berry, Donald A, Zadeh, Gelareh, Cloughesy, Tim F, Mehta, Minesh P, Piantadosi, Steven, Weller, Michael, Heimberger, Amy B, and Khasraw, Mustafa
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Cancer ,Immunization ,Clinical Research ,Rare Diseases ,Brain Disorders ,Vaccine Related ,Clinical Trials and Supportive Activities ,Brain Cancer ,5.1 Pharmaceuticals ,Health and social care services research ,8.4 Research design and methodologies (health services) ,Development of treatments and therapeutic interventions ,Brain Neoplasms ,Glioblastoma ,Humans ,Immune Tolerance ,Immunosuppression Therapy ,Immunotherapy ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.
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- 2022
27. Glioblastoma Clinical Trials: Current Landscape and Opportunities for ImprovementCurrent Glioblastoma Clinical Trial Landscape
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Bagley, Stephen J, Kothari, Shawn, Rahman, Rifaquat, Lee, Eudocia Q, Dunn, Gavin P, Galanis, Evanthia, Chang, Susan M, Nabors, Louis Burt, Ahluwalia, Manmeet S, Stupp, Roger, Mehta, Minesh P, Reardon, David A, Grossman, Stuart A, Sulman, Erik P, Sampson, John H, Khagi, Simon, Weller, Michael, Cloughesy, Timothy F, Wen, Patrick Y, and Khasraw, Mustafa
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Brain Disorders ,Neurosciences ,Rare Diseases ,Brain Cancer ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Adult ,Brain Neoplasms ,Glioblastoma ,Humans ,Research Design ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as "recruiting" or "not yet recruiting" as of February 2021.
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- 2022
28. Understanding the activity of antibody–drug conjugates in primary and secondary brain tumours
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Mair, Maximilian J., Bartsch, Rupert, Le Rhun, Emilie, Berghoff, Anna S., Brastianos, Priscilla K., Cortes, Javier, Gan, Hui K., Lin, Nancy U., Lassman, Andrew B., Wen, Patrick Y., Weller, Michael, van den Bent, Martin, and Preusser, Matthias
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- 2023
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29. PET-based response assessment criteria for diffuse gliomas (PET RANO 1.0): a report of the RANO group
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Albert, Nathalie L, Galldiks, Norbert, Ellingson, Benjamin M, van den Bent, Martin J, Chang, Susan M, Cicone, Francesco, de Groot, John, Koh, Eng-Siew, Law, Ian, Le Rhun, Emilie, Mair, Maximilian J, Minniti, Giuseppe, Rudà, Roberta, Scott, Andrew M, Short, Susan C, Smits, Marion, Suchorska, Bogdana, Tolboom, Nelleke, Traub-Weidinger, Tatjana, Tonn, Joerg-Christian, Verger, Antoine, Weller, Michael, Wen, Patrick Y, and Preusser, Matthias
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- 2024
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30. Re-irradiation of recurrent IDH-wildtype glioblastoma in the bevacizumab and immunotherapy era: Target delineation, outcomes and patterns of recurrence
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Christ, Sebastian M., Youssef, Gilbert, Tanguturi, Shyam K., Cagney, Daniel, Shi, Diana, McFaline-Figueroa, J. Ricardo, Chukwueke, Ugonma, Lee, Eudocia Q., Hertler, Caroline, Andratschke, Nicolaus, Weller, Michael, Reardon, David A., Haas-Kogan, Daphne, Guckenberger, Matthias, Wen, Patrick Y., and Rahman, Rifaquat
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- 2024
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31. Author Correction: Liquid biopsy epigenomic profiling for cancer subtyping
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Baca, Sylvan C., Seo, Ji-Heui, Davidsohn, Matthew P., Fortunato, Brad, Semaan, Karl, Sotudian, Shahabbedin, Lakshminarayanan, Gitanjali, Diossy, Miklos, Qiu, Xintao, El Zarif, Talal, Savignano, Hunter, Canniff, John, Madueke, Ikenna, Saliby, Renee Maria, Zhang, Ziwei, Li, Rong, Jiang, Yijia, Taing, Len, Awad, Mark, Chau, Cindy H., DeCaprio, James A., Figg, William D., Greten, Tim F., Hata, Aaron N., Hodi, F. Stephen, Hughes, Melissa E., Ligon, Keith L., Lin, Nancy, Ng, Kimmie, Oser, Matthew G., Meador, Catherine, Parsons, Heather A., Pomerantz, Mark M., Rajan, Arun, Ritz, Jerome, Thakuria, Manisha, Tolaney, Sara M., Wen, Patrick Y., Long, Henry, Berchuck, Jacob E., Szallasi, Zoltan, Choueiri, Toni K., and Freedman, Matthew L.
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- 2024
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32. Author Correction: Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial
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Mellinghoff, Ingo K., Lu, Min, Wen, Patrick Y., Taylor, Jennie W., Maher, Elizabeth A., Arrillaga-Romany, Isabel, Peters, Katherine B., Ellingson, Benjamin M., Rosenblum, Marc K., Chun, Saewon, Le, Kha, Tassinari, Ania, Choe, Sung, Toubouti, Youssef, Schoenfeld, Steven, Pandya, Shuchi S., Hassan, Islam, Steelman, Lori, Clarke, Jennifer L., and Cloughesy, Timothy F.
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- 2024
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33. Therapeutic Response Assessment of High-Grade Gliomas During Early-Phase Drug Development in the Era of Molecular and Immunotherapies
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Ellingson, Benjamin M, Wen, Patrick Y, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Brain Cancer ,Cancer ,Biotechnology ,Brain Disorders ,Neurosciences ,Vaccine Related ,Immunization ,Rare Diseases ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Antineoplastic Agents ,Brain Neoplasms ,Drug Development ,Glioma ,Humans ,Immunotherapy ,Early-phase clinical trials ,high-grade gliomas ,molecular imaging ,RANO ,response assessment ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
AbstractSeveral new therapeutic strategies have emerged over the past decades to address unmet clinical needs in high-grade gliomas, including targeted molecular agents and various forms of immunotherapy. Each of these strategies requires addressing fundamental questions, depending on the stage of drug development, including ensuring drug penetration into the brain, engagement of the drug with the desired target, biologic effects downstream from the target including metabolic and/or physiologic changes, and identifying evidence of clinical activity that could be expanded upon to increase the likelihood of a meaningful survival benefit. The current review article highlights these strategies and outlines how imaging technology can be used for therapeutic response evaluation in both targeted and immunotherapies in early phases of drug development in high-grade gliomas.
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- 2021
34. Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I TrialVorasidenib in Recurrent or Progressive Glioma
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Mellinghoff, Ingo K, Penas-Prado, Marta, Peters, Katherine B, Burris, Howard A, Maher, Elizabeth A, Janku, Filip, Cote, Gregory M, de la Fuente, Macarena I, Clarke, Jennifer L, Ellingson, Benjamin M, Chun, Saewon, Young, Robert J, Liu, Hua, Choe, Sung, Lu, Min, Le, Kha, Hassan, Islam, Steelman, Lori, Pandya, Shuchi S, Cloughesy, Timothy F, and Wen, Patrick Y
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Neurosciences ,Orphan Drug ,Cancer ,Brain Cancer ,Brain Disorders ,Clinical Research ,Clinical Trials and Supportive Activities ,Rare Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Brain Neoplasms ,Diamines ,Disease Progression ,Female ,Glioma ,Humans ,Isocitrate Dehydrogenase ,Male ,Middle Aged ,Mutation ,Neoplasm Recurrence ,Local ,Pyridines ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeLower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.Patients and methodsWe conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.ResultsVorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.ConclusionsVorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.
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- 2021
35. Systematic review on the use of patient-reported outcome measures in brain tumor studies: part of the Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) initiative.
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Dirven, Linda, Vos, Maartje E, Walbert, Tobias, Armstrong, Terri S, Arons, David, van den Bent, Martin J, Blakeley, Jaishri, Brown, Paul D, Bulbeck, Helen, Chang, Susan M, Coens, Corneel, Gilbert, Mark R, Grant, Robin, Jalali, Rakesh, Leach, Danielle, Leeper, Heather, Mendoza, Tito, Nayak, Lakshmi, Oliver, Kathy, Reijneveld, Jaap C, Le Rhun, Emilie, Rubinstein, Larry, Weller, Michael, Wen, Patrick Y, and Taphoorn, Martin JB
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Neurosciences ,Clinical Research ,Brain Cancer ,Cancer ,Rare Diseases ,Brain Disorders ,activities of daily living ,brain tumor ,health-related quality of life ,patient-reported outcome ,symptoms ,Oncology and carcinogenesis - Abstract
BackgroundThe Response Assessment in Neuro-Oncology Patient-Reported Outcome (RANO-PRO) working group aims to provide guidance on the use of PROs in brain tumor patients. PRO measures should be of high quality, both in terms of relevance and other measurement properties. This systematic review aimed to identify PRO measures that have been used in brain tumor studies to date.MethodsA systematic literature search for articles published up to June 25, 2020 was conducted in several electronic databases. Pre-specified inclusion criteria were used to identify studies using PRO measures assessing symptoms, (instrumental) activities of daily living [(I)ADL] or health-related quality of life (HRQoL) in adult patients with glioma, meningioma, primary central nervous system lymphoma, or brain metastasis.ResultsA total of 215 different PRO measures were identified in 571 published and 194 unpublished studies. The identified PRO measures include brain tumor-specific, cancer-specific, and generic instruments, as well as instruments designed for other indications or multi- or single-item study-specific questionnaires. The most frequently used instruments were the EORTC QLQ-C30 and QLQ-BN20 (n = 286 and n = 247), and the FACT-Br (n = 167), however, the majority of the instruments were used only once or twice (150/215).ConclusionMany different PRO measures assessing symptoms, (I)ADL or HRQoL have been used in brain tumor studies to date. Future research should clarify whether these instruments or their scales/items exhibit good content validity and other measurement properties for use in brain tumor patients.
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- 2021
36. Systematic review of combinations of targeted or immunotherapy in advanced solid tumors
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Tan, Aaron C, Bagley, Stephen J, Wen, Patrick Y, Lim, Michael, Platten, Michael, Colman, Howard, Ashley, David M, Wick, Wolfgang, Chang, Susan M, Galanis, Evanthia, Mansouri, Alireza, Khagi, Simon, Mehta, Minesh P, Heimberger, Amy B, Puduvalli, Vinay K, Reardon, David A, Sahebjam, Solmaz, Simes, John, Antonia, Scott J, Berry, Don, and Khasraw, Mustafa
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Research ,Cancer ,Clinical Trials and Supportive Activities ,Good Health and Well Being ,Combined Modality Therapy ,Humans ,Immunotherapy ,Neoplasms ,immunotherapy ,drug therapy ,combination ,clinical trials as topic ,Oncology and carcinogenesis - Abstract
With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel-novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel-novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel-novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel-novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.
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- 2021
37. Unique challenges for glioblastoma immunotherapy—discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank
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Chuntova, Pavlina, Chow, Frances, Watchmaker, Payal B, Galvez, Mildred, Heimberger, Amy B, Newell, Evan W, Diaz, Aaron, DePinho, Ronald A, Li, Ming O, Wherry, E John, Mitchell, Duane, Terabe, Masaki, Wainwright, Derek A, Berzofsky, Jay A, Herold-Mende, Christel, Heath, James R, Lim, Michael, Margolin, Kim A, Chiocca, E Antonio, Kasahara, Noriyuki, Ellingson, Benjamin M, Brown, Christine E, Chen, Yvonne, Fecci, Peter E, Reardon, David A, Dunn, Gavin P, Liau, Linda M, Costello, Joseph F, Wick, Wolfgang, Cloughesy, Timothy, Timmer, William C, Wen, Patrick Y, Prins, Robert M, Platten, Michael, and Okada, Hideho
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Vaccine Related ,Brain Cancer ,Brain Disorders ,Orphan Drug ,Cancer ,Immunization ,Rare Diseases ,Neurosciences ,Good Health and Well Being ,Brain Neoplasms ,Glioblastoma ,Humans ,Immunotherapy ,Medical Oncology ,Neoplasms ,Tumor Microenvironment ,clinical trial ,conference report ,glioblastoma ,immunosuppression ,immunotherapy ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner.
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- 2021
38. Radiographic read paradigms and the roles of the central imaging laboratory in neuro-oncology clinical trials
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Ellingson, Benjamin M, Brown, Matthew S, Boxerman, Jerrold L, Gerstner, Elizabeth R, Kaufmann, Timothy J, Cole, Patricia E, Bacha, Jeffrey A, Leung, David, Barone, Amy, Colman, Howard, van den Bent, Martin J, Wen, Patrick Y, Yung, WK Alfred, Cloughesy, Timothy F, and Goldin, Jonathan G
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Clinical Trials and Supportive Activities ,Cancer ,Biomedical Imaging ,Brain Disorders ,Clinical Research ,Brain Neoplasms ,Diagnostic Imaging ,Humans ,Laboratories ,clinical trials ,Imaging Charter ,imaging endpoints ,neuro-oncology ,RANO ,Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter (referred to as the Charter for the remainder of this article), a document that describes the clinical trial imaging methodology and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.
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- 2021
39. Randomized Phase II and Biomarker Study of Pembrolizumab plus Bevacizumab versus Pembrolizumab Alone for Patients with Recurrent Glioblastoma
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Nayak, Lakshmi, Molinaro, Annette M, Peters, Katherine, Clarke, Jennifer L, Jordan, Justin T, de Groot, John, Nghiemphu, Leia, Kaley, Thomas, Colman, Howard, McCluskey, Christine, Gaffey, Sarah, Smith, Timothy R, Cote, David J, Severgnini, Mariano, Yearley, Jennifer H, Zhao, Qing, Blumenschein, Wendy M, Duda, Dan G, Muzikansky, Alona, Jain, Rakesh K, Wen, Patrick Y, and Reardon, David A
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Brain Disorders ,Brain Cancer ,Rare Diseases ,Clinical Research ,Cancer ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Antibodies ,Monoclonal ,Humanized ,Antineoplastic Combined Chemotherapy Protocols ,Bevacizumab ,Biomarkers ,Tumor ,Brain Neoplasms ,Drug Monitoring ,Female ,Glioblastoma ,Humans ,Male ,Middle Aged ,Neoplasm Recurrence ,Local ,Prognosis ,Progression-Free Survival ,Prospective Studies ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeVEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma.Patients and methodsEighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function.ResultsPembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3-41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7-14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7-25.4), median OS was 10.3 months (95% CI, 8.5-12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment.ConclusionsPembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.
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- 2021
40. Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma
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Ellingson, Benjamin M, Patel, Kunal, Wang, Chencai, Raymond, Catalina, Brenner, Andrew, de Groot, John F, Butowski, Nicholas A, Zach, Leor, Campian, Jian L, Schlossman, Jacob, Rizvi, Shan, Cohen, Yael C, Lowenton-Spier, Noa, Minei, Tamar Rachmilewitz, Shmueli, Shifra Fain, Wen, Patrick Y, and Cloughesy, Timothy F
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Cancer ,Biomedical Imaging ,Clinical Research ,Clinical Trials and Supportive Activities ,Genetics ,Rare Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,anti-VEGF therapy ,bevacizumab ,diffusion MRI ,imaging biomarker ,recurrent GBM ,VB-111 - Abstract
BackgroundEvidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial.MethodsPatients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm2/ms) or low (
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- 2021
41. Novel trial designs in neuro-oncology
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Song, Kun-Wei and Wen, Patrick Y.
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- 2023
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42. Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders’ Collaborative Consortium (EORTC 1419)
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Hertler, Caroline, Felsberg, Jörg, Gramatzki, Dorothee, Le Rhun, Emilie, Clarke, Jennifer, Soffietti, Riccardo, Wick, Wolfgang, Chinot, Olivier, Ducray, François, Roth, Patrick, McDonald, Kerrie, Hau, Peter, Hottinger, Andreas F., Reijneveld, Jaap, Schnell, Oliver, Marosi, Christine, Glantz, Michael, Darlix, Amélie, Lombardi, Giuseppe, Krex, Dietmar, Glas, Martin, Reardon, David A., van den Bent, Martin, Lefranc, Florence, Herrlinger, Ulrich, Razis, Evangelia, Carpentier, Antoine F., Phillips, Samuel, Rudà, Roberta, Wick, Antje, Tabouret, Emeline, Meyronet, David, Maurage, Claude-Alain, Rushing, Elisabeth, Rapkins, Robert, Bumes, Elisabeth, Hegi, Monika, Weyerbrock, Astrid, Aregawi, Dawit, Gonzalez-Gomez, Christian, Pellerino, Alessia, Klein, Martin, Preusser, Matthias, Bendszus, Martin, Golfinopoulos, Vassilis, von Deimling, Andreas, Gorlia, Thierry, Wen, Patrick Y., Reifenberger, Guido, and Weller, Michael
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- 2023
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43. Phase 0 and window of opportunity clinical trial design in neuro-oncology: a RANO review
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Vogelbaum, Michael A, Krivosheya, Daria, Borghei-Razavi, Hamid, Sanai, Nader, Weller, Michael, Wick, Wolfgang, Soffietti, Riccardo, Reardon, David A, Aghi, Manish K, Galanis, Evanthia, Wen, Patrick Y, van den Bent, Martin, and Chang, Susan
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Rare Diseases ,Brain Cancer ,Neurosciences ,Cancer ,Clinical Trials and Supportive Activities ,Orphan Drug ,Brain Disorders ,Patient Safety ,Clinical Research ,Central Nervous System Neoplasms ,Clinical Trials as Topic ,Glioblastoma ,Humans ,Treatment Outcome ,clinical trial ,glioblastoma ,pharmacodynamics ,pharmacokinetics ,phase 0 ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood-brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0-like ("window of opportunity") studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.
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- 2020
44. Baseline requirements for novel agents being considered for phase II/III brain cancer efficacy trials: conclusions from the Adult Brain Tumor Consortium’s first workshop on CNS drug delivery
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Grossman, Stuart A, Romo, Carlos G, Rudek, Michelle A, Supko, Jeffrey, Fisher, Joy, Nabors, L Burt, Wen, Patrick Y, Peereboom, David M, Ellingson, Benjamin M, Elmquist, William, Barker, Fred G, Kamson, David, Sarkaria, Jann N, Timmer, William, Bindra, Ranjit S, and Ye, Xiaobu
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Adult ,Brain Neoplasms ,Clinical Trials ,Phase II as Topic ,Clinical Trials ,Phase III as Topic ,Drug Delivery Systems ,Humans ,Pharmaceutical Preparations ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Published
- 2020
45. Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma
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Mellinghoff, Ingo K, Ellingson, Benjamin M, Touat, Mehdi, Maher, Elizabeth, De La Fuente, Macarena I, Holdhoff, Matthias, Cote, Gregory M, Burris, Howard, Janku, Filip, Young, Robert J, Huang, Raymond, Jiang, Liewen, Choe, Sung, Fan, Bin, Yen, Katharine, Lu, Min, Bowden, Chris, Steelman, Lori, Pandya, Shuchi S, Cloughesy, Timothy F, and Wen, Patrick Y
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Brain Cancer ,Neurosciences ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Genetics ,Rare Diseases ,Orphan Drug ,Brain Disorders ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Aged ,Antineoplastic Agents ,Brain Neoplasms ,Dose-Response Relationship ,Drug ,Enzyme Inhibitors ,Female ,Glioma ,Glycine ,Humans ,Isocitrate Dehydrogenase ,Male ,Middle Aged ,Mutation ,Pyridines ,Young Adult ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeDiffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors.MethodsWe conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with mIDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles.ResultsIn 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors.ConclusionIn patients with mIDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
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- 2020
46. Current drug development and trial designs in neuro-oncology: report from the first American Society of Clinical Oncology and Society for Neuro-Oncology Clinical Trials Conference
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Rahman, Rifaquat, Polley, Mei-Yin C, Alder, Laura, Brastianos, Priscilla K, Anders, Carey K, Tawbi, Hussein A, Mehta, Minesh, Wen, Patrick Y, Geyer, Susan, de Groot, John, Zadeh, Gelareh, Piantadosi, Steven, Galanis, Evanthia, and Khasraw, Mustafa
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- 2023
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47. Consensus recommendations for a dynamic susceptibility contrast MRI protocol for use in high-grade gliomas
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Boxerman, Jerrold L, Quarles, Chad C, Hu, Leland S, Erickson, Bradley J, Gerstner, Elizabeth R, Smits, Marion, Kaufmann, Timothy J, Barboriak, Daniel P, Huang, Raymond H, Wick, Wolfgang, Weller, Michael, Galanis, Evanthia, Kalpathy-Cramer, Jayashree, Shankar, Lalitha, Jacobs, Paula, Chung, Caroline, van den Bent, Martin J, Chang, Susan, Al Yung, WK, Cloughesy, Timothy F, Wen, Patrick Y, Gilbert, Mark R, Rosen, Bruce R, Ellingson, Benjamin M, Schmainda, Kathleen M, Arons, David F, Kingston, Ann, Sandak, David, Wallace, Max, Musella, Al, and Haynes, Chas
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Biomedical Imaging ,Neurosciences ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Rare Diseases ,Minority Health ,Brain Cancer ,Algorithms ,Brain Neoplasms ,Consensus ,Contrast Media ,Glioma ,Humans ,Magnetic Resonance Imaging ,cerebral blood volume ,clinical trial ,consensus protocol ,DSC-MRI ,high-grade glioma ,Jumpstarting Brain Tumor Drug Development Coalition Imaging Standardization Steering Committee ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Despite the widespread clinical use of dynamic susceptibility contrast (DSC) MRI, DSC-MRI methodology has not been standardized, hindering its utilization for response assessment in multicenter trials. Recently, the DSC-MRI Standardization Subcommittee of the Jumpstarting Brain Tumor Drug Development Coalition issued an updated consensus DSC-MRI protocol compatible with the standardized brain tumor imaging protocol (BTIP) for high-grade gliomas that is increasingly used in the clinical setting and is the default MRI protocol for the National Clinical Trials Network. After reviewing the basis for controversy over DSC-MRI protocols, this paper provides evidence-based best practices for clinical DSC-MRI as determined by the Committee, including pulse sequence (gradient echo vs spin echo), BTIP-compliant contrast agent dosing (preload and bolus), flip angle (FA), echo time (TE), and post-processing leakage correction. In summary, full-dose preload, full-dose bolus dosing using intermediate (60°) FA and field strength-dependent TE (40-50 ms at 1.5 T, 20-35 ms at 3 T) provides overall best accuracy and precision for cerebral blood volume estimates. When single-dose contrast agent usage is desired, no-preload, full-dose bolus dosing using low FA (30°) and field strength-dependent TE provides excellent performance, with reduced contrast agent usage and elimination of potential systematic errors introduced by variations in preload dose and incubation time.
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- 2020
48. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions
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Wen, Patrick Y, Weller, Michael, Lee, Eudocia Quant, Alexander, Brian M, Barnholtz-Sloan, Jill S, Barthel, Floris P, Batchelor, Tracy T, Bindra, Ranjit S, Chang, Susan M, Chiocca, E Antonio, Cloughesy, Timothy F, DeGroot, John F, Galanis, Evanthia, Gilbert, Mark R, Hegi, Monika E, Horbinski, Craig, Huang, Raymond Y, Lassman, Andrew B, Le Rhun, Emilie, Lim, Michael, Mehta, Minesh P, Mellinghoff, Ingo K, Minniti, Giuseppe, Nathanson, David, Platten, Michael, Preusser, Matthias, Roth, Patrick, Sanson, Marc, Schiff, David, Short, Susan C, Taphoorn, Martin JB, Tonn, Joerg-Christian, Tsang, Jonathan, Verhaak, Roel GW, von Deimling, Andreas, Wick, Wolfgang, Zadeh, Gelareh, Reardon, David A, Aldape, Kenneth D, and van den Bent, Martin J
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Neurosciences ,Rare Diseases ,Cancer ,Brain Disorders ,Brain Cancer ,Good Health and Well Being ,Brain Neoplasms ,Chemoradiotherapy ,Clinical Trials ,Phase III as Topic ,Consensus ,Glioblastoma ,Humans ,Isocitrate Dehydrogenase ,Randomized Controlled Trials as Topic ,glioblastoma ,diagnosis ,therapy ,clinical trials ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.
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- 2020
49. Consensus recommendations for a standardized brain tumor imaging protocol for clinical trials in brain metastases
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Kaufmann, Timothy J, Smits, Marion, Boxerman, Jerrold, Huang, Raymond, Barboriak, Daniel P, Weller, Michael, Chung, Caroline, Tsien, Christina, Brown, Paul D, Shankar, Lalitha, Galanis, Evanthia, Gerstner, Elizabeth, van den Bent, Martin J, Burns, Terry C, Parney, Ian F, Dunn, Gavin, Brastianos, Priscilla K, Lin, Nancy U, Wen, Patrick Y, and Ellingson, Benjamin M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Cancer ,Neurosciences ,Brain Cancer ,Clinical Research ,Biomedical Imaging ,Brain Disorders ,Brain Neoplasms ,Consensus ,Contrast Media ,Gadolinium ,Humans ,Magnetic Resonance Imaging ,brain metastases ,imaging ,MRI ,protocol ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
A recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The "minimum standard" recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)-prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An "ideal" protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.
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- 2020
50. Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study
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Brenner, Andrew J, Peters, Katherine B, Vredenburgh, James, Bokstein, Felix, Blumenthal, Deborah T, Yust-Katz, Shlomit, Peretz, Idit, Oberman, Bernice, Freedman, Laurence S, Ellingson, Benjamin M, Cloughesy, Timothy F, Sher, Naamit, Cohen, Yael C, Lowenton-Spier, Noa, Minei, Tamar Rachmilewitz, Yakov, Niva, Mendel, Itzhak, Breitbart, Eyal, and Wen, Patrick Y
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Brain Disorders ,Orphan Drug ,Cancer ,Rare Diseases ,Clinical Research ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,Evaluation of treatments and therapeutic interventions ,Antineoplastic Combined Chemotherapy Protocols ,Bevacizumab ,Brain Neoplasms ,Genetic Therapy ,Glioblastoma ,Humans ,Progression-Free Survival ,anti-angiogenesis ,gene therapy ,glioblastoma ,VB-111 ,viral immuno-oncology ,VB-111 ,glioblastoma ,Neurosciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundVB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM).MethodsPatients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS).ResultsVB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease.ConclusionsPatients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.
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- 2020
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