Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement.

Therapeutic advances for glioblastoma have been minimal over the past two 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.

[1]  Susan M. Chang,et al.  Systematic review of combinations of targeted or immunotherapy in advanced solid tumors , 2021, Journal for ImmunoTherapy of Cancer.

[2]  P. Wen.  Positron emission tomography imaging of drug concentrations in the brain. , 2021, Neuro-Oncology.

[3]  G. Zadeh,et al.  Lessons learned from contemporary glioblastoma randomized clinical trials through systematic review and network meta-analysis: part 1 newly diagnosed disease , 2021, Neuro-oncology advances.

[4]  Edward S. Kim,et al.  Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO–Friends of Cancer Research Joint Research Statement , 2021, Clinical Cancer Research.

[5]  E. Helseth,et al.  Real-world validity of randomized controlled phase III trials in newly diagnosed glioblastoma: to whom do the results of the trials apply? , 2021, Neuro-oncology advances.

[6]  A. Balasubramanian,et al.  Inefficiencies in phase II to phase III transition impeding successful drug development in glioblastoma , 2020, Neuro-oncology advances.

[7]  Duane A. Mitchell,et al.  Adult precision medicine: learning from the past to enhance the future , 2020, Neuro-oncology advances.

[8]  G. Reifenberger,et al.  EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood , 2020, Nature Reviews Clinical Oncology.

[9]  S. Pfister,et al.  DNA Methylation based glioblastoma subclassification is related to tumoral T cell infiltration and patient survival. , 2020, Neuro-oncology.

[10]  Aliz R. Rao,et al.  Effect of Vocimagene Amiretrorepvec in Combination With Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients With Recurrent High-Grade Glioma: A Randomized Clinical Trial. , 2020, JAMA oncology.

[11]  W. Curran,et al.  What happened to the US cancer cooperative groups? A status update ten years after the Institute of Medicine report , 2020, Cancer.

[12]  N. Lipsman,et al.  Blood-Brain Barrier Disruption in Neuro-Oncology: Strategies, Failures, and Challenges to Overcome , 2020, Frontiers in Oncology.

[13]  C. Brennan,et al.  Development of a gene expression-based prognostic signature for IDH wild-type glioblastoma. , 2020, Neuro-oncology.

[14]  Susan M. Chang,et al.  Phase 0 and Window of Opportunity Clinical Trial Design in Neuro-Oncology: A RANO Review. , 2020, Neuro-oncology.

[15]  J. Sarkaria,et al.  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. , 2020, Neuro-oncology.

[16]  M. Weller,et al.  Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma , 2020, JAMA oncology.

[17]  M. Weller,et al.  How did lomustine become standard of care in recurrent glioblastoma? , 2020, Cancer treatment reviews.

[18]  E. Nduom,et al.  Biomarkers for immunotherapy for treatment of glioblastoma , 2020, Journal for immunotherapy of cancer.

[19]  Raymond Y Huang,et al.  Glioblastoma in Adults: A Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) Consensus Review on Current Management and Future Directions. , 2020, Neuro-oncology.

[20]  O. Elemento,et al.  Tumor microenvironment is critical for the maintenance of cellular states found in primary glioblastomas. , 2020, Cancer discovery.

[21]  Susan M. Chang,et al.  Optimizing eligibility criteria and clinical trial conduct to enhance clinical trial participation for primary brain tumor patients. , 2020, Neuro-oncology.

[22]  Zev A. Binder,et al.  A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity , 2019, Cell.

[23]  K. Aldape,et al.  ACTR-21. A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIAL OF DEPATUXIZUMAB MAFODOTIN (ABT-414) IN EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) AMPLIFIED (AMP) NEWLY DIAGNOSED GLIOBLASTOMA (nGBM) , 2019, Neuro-Oncology.

[24]  Shawn M. Gillespie,et al.  Electrical and synaptic integration of glioma into neural circuits , 2019, Nature.

[25]  T. Jaki,et al.  A Review of Perspectives on the Use of Randomization in Phase II Oncology Trials , 2019, Journal of the National Cancer Institute.

[26]  Lorenzo Trippa,et al.  Design and Evaluation of an External Control Arm Using Prior Clinical Trials and Real-World Data , 2019, Clinical Cancer Research.

[27]  P. Wen,et al.  To randomize, or not to randomize, that is the question: using data from prior clinical trials to guide future designs. , 2019, Neuro-oncology.

[28]  Susan M. Chang,et al.  Barriers to Accrual and Enrollment in Brain Tumor Trials. , 2019, Neuro-oncology.

[29]  Jay-Jiguang Zhu,et al.  Assessment of Glioblastoma Response in the Era of Bevacizumab: Longstanding and Emergent Challenges in the Imaging Evaluation of Pseudoresponse , 2019, Front. Neurol..

[30]  P. Wen,et al.  Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma , 2019, JCO precision oncology.

[31]  Giles W. Robinson,et al.  Challenges to curing primary brain tumours , 2019, Nature Reviews Clinical Oncology.

[32]  P. Wen,et al.  Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma , 2018, Nature Medicine.

[33]  F. Yamasaki,et al.  A randomized, double-blind, phase III trial of personalized peptide vaccination for recurrent glioblastoma , 2018, Neuro-oncology.

[34]  David T. W. Jones,et al.  N2M2 (NOA-20) phase I/II trial of molecularly matched targeted therapies plus radiotherapy in patients with newly diagnosed non-MGMT hypermethylated glioblastoma. , 2018, Neuro-oncology.

[35]  Zhongming Zhao,et al.  Subtype-specific signaling pathways and genomic aberrations associated with prognosis of glioblastoma , 2018, Neuro-oncology.

[36]  T. Mikkelsen,et al.  Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with EGFR-amplified, recurrent glioblastoma: results from an international phase I multicenter trial , 2018, Neuro-oncology.

[37]  G. Reifenberger,et al.  cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV” , 2018, Acta Neuropathologica.

[38]  William P. Accomando,et al.  Durable complete responses in some recurrent high-grade glioma patients treated with Toca 511 + Toca FC , 2018, Neuro-oncology.

[39]  Akash J. Patel,et al.  Highlighting the need for reliable clinical trials in glioblastoma , 2018, Expert review of anticancer therapy.

[40]  Lorenzo Trippa,et al.  The clinical trials landscape for glioblastoma: is it adequate to develop new treatments? , 2018, Neuro-oncology.

[41]  B. Nahed,et al.  Sequestration of T-cells in bone marrow in the setting of glioblastoma and other intracranial tumors , 2018, Nature Medicine.

[42]  M. J. van den Bent,et al.  Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma , 2018, Neuro-oncology.

[43]  David T. W. Jones,et al.  Radiomic subtyping improves disease stratification beyond key molecular, clinical, and standard imaging characteristics in patients with glioblastoma , 2018, Neuro-oncology.

[44]  K. Ligon,et al.  Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143 , 2018, Neuro-oncology.

[45]  Till Acker,et al.  DNA methylation-based classification of central nervous system tumours , 2018, Nature.

[46]  Diane D. Liu,et al.  Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma , 2018, Neuro-oncology.

[47]  P. Brown,et al.  The Evolving Role of Tumor Treating Fields in Managing Glioblastoma , 2017, American journal of clinical oncology.

[48]  F. Lieberman,et al.  Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial , 2017, JAMA.

[49]  Edward S. Kim,et al.  Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  Edward S. Kim,et al.  Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research Brain Metastases Working Group. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  Brian M Alexander,et al.  Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE , 2017, Clinical Cancer Research.

[52]  Edward F. Chang,et al.  Tumor Evolution of Glioma-Intrinsic Gene Expression Subtypes Associates with Immunological Changes in the Microenvironment. , 2017, Cancer cell.

[53]  B. Alexander,et al.  Point/counterpoint: randomized versus single-arm phase II clinical trials for patients with newly diagnosed glioblastoma , 2017, Neuro-oncology.

[54]  D. Osoba,et al.  Short‐Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma , 2017, The New England journal of medicine.

[55]  Claus Belka,et al.  Current status and perspectives of interventional clinical trials for glioblastoma – analysis of ClinicalTrials.gov , 2017, Radiation Oncology.

[56]  M. J. van den Bent,et al.  Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma , 2016, Neuro-oncology.

[57]  L. Recht,et al.  Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. , 2017, The Lancet. Oncology.

[58]  T. Mikkelsen,et al.  Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma , 2016, Science Translational Medicine.

[59]  W. Mason,et al.  Phase 1, multicenter, open-label, dose-escalation, study of marizomib (MRZ) and bevacizumab (BEV) in WHO grade IV malignant glioma (G4 MG). , 2016 .

[60]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[61]  L. Recht,et al.  A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. , 2015, Neuro-oncology.

[62]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[63]  R. McLendon,et al.  Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. , 2011, Neuro-oncology.

[64]  K. Kurisu,et al.  Phase I trial of a personalized peptide vaccine for patients positive for human leukocyte antigen--A24 with recurrent or progressive glioblastoma multiforme. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[65]  Raymond Sawaya,et al.  Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[66]  D. Sargent,et al.  Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[67]  Steven Piantadosi,et al.  Survival of Patients with Newly Diagnosed Glioblastoma Treated with Radiation and Temozolomide in Research Studies in the United States , 2010, Clinical Cancer Research.

[68]  G. Fuller,et al.  Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice , 2010, Neuro-oncology.

[69]  P. Wen,et al.  Role of a second chemotherapy in recurrent malignant glioma patients who progress on bevacizumab. , 2009, Neuro-oncology.

[70]  T. Mikkelsen,et al.  Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  Martin Glas,et al.  Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[73]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[74]  W. Mason,et al.  EORTC 1709/CCTG CE.8: A phase III trial of marizomib in combination with temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed glioblastoma. , 2022, Journal of Clinical Oncology.