GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.

TPS2074 Background: GBM AGILE, Glioblastoma Adaptive, Global, Innovative Learning Environment, is an international, multi-arm, seamless phase 2/3 response adaptive randomization platform trial designed to evaluate multiple therapies in newly diagnosed (ND) and recurrent glioblastoma (GBM) with the goal of identifying effective therapies matching them accurately to different patient subtypes in an accelerated manner. It is a collaboration between academic investigators, patient organizations and industry to support new drug applications for newly diagnosed and recurrent GBM. Methods: The primary objective of GBM AGILE is to identify therapies that effectively improve overall survival in patients with ND or recurrent GBM. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different pharmaceutical companies to be evaluated simultaneously and/or over time against a common standard of care control. Based on performance, a drug may graduate and move to a rapid stage 2 (phase 3) within the trial, and the totality of the data can be used for a new drug application. An active pipeline is critical to the ongoing success of GBM AGILE. With the leadership of the trial’s Arm Selection Committee, uniform processes for including new drugs have been established to ensure a consistent review of drugs/drug combinations over the course of the trial. Factors considered include relevant pre-clinical data, preliminary evidence for antitumor activity. pharmacokinetic data to support proposed drug dosing and administration, and potential biomarkers helpful for the development of a drug. GBM AGILE provides an efficient mechanism to screen and develop robust information regarding the efficacy of proposed novel therapeutics and associated biomarkers for GBM and to quickly move therapies and biomarkers into clinic. GBM AGILE received IND approval from the FDA in April 2019, screening its first patient in June 2019. Site activation is ongoing in the US, with over 35 active sites and over 425 patients screened (as of February 2021). Expansion to Canada, Europe and China are under progress. Clinical trial information: NCT03970447.

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RTID-11. GBM AGILE: A GLOBAL, PHASE 2/3 ADAPTIVE PLATFORM TRIAL TO EVALUATE MULTIPLE REGIMENS IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.816 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii195-ii196

Author(s):

Meredith Buxton ◽

Brian Alexander ◽

Donald Berry ◽

Webster Cavenee ◽

Howard Colman ◽

...

Keyword(s):

Clinical Trial ◽

Drug Application ◽

Recurrent Glioblastoma ◽

Phase 2 ◽

Newly Diagnosed ◽

New Drug ◽

Health Authorities ◽

Common Control ◽

Innovative Learning ◽

Multiple Drugs

Abstract Developing new therapies for patients with glioblastoma (GBM) requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase 2/3 development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research, whose mission is to accelerate the development of treatments rare and deadly diseases by serving as sponsor of innovative trials. GBM AGILE is an international platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs from different companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, screening its first patient in June 2019. As of June 2020 over 200 patients have been screened. Expansion to Canada, Europe, China, and Australia is also underway. There is currently one investigational arm under evaluation in the trial, with two additional arms to be added in Q4 2020/ Q1 2021. Clinical trial information: NCT03970447.

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GBM AGILE: A global, phase II/III adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps2579 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS2579-TPS2579 ◽

Cited By ~ 1

Author(s):

Meredith Becker Buxton ◽

Brian Michael Alexander ◽

Donald A. Berry ◽

Webster K. Cavenee ◽

Howard Colman ◽

...

Keyword(s):

Clinical Trial ◽

Phase Ii ◽

Drug Application ◽

Recurrent Glioblastoma ◽

Newly Diagnosed ◽

Non Profit ◽

New Drug ◽

Health Authorities ◽

Innovative Learning ◽

Multiple Drugs

TPS2579 Background: Glioblastoma (GBM) is an aggressive brain tumor with few effective therapies and is invariably fatal. Developing new therapies for patients with GBM requires focused interaction between industry, academia, nonprofits, patient advocacy, and health authorities, and novel approaches to clinical trials. Industry is wary of developing drugs for GBM due to the high failure rate and high cost of drug development. GBM Adaptive Global Innovative Learning Environment (GBM AGILE) Trial was designed by over 130 global key opinion leaders in consultation with health authorities to provide an optimal mechanism for phase II/III development in GBM. The Sponsor of GBM AGILE is the Global Coalition for Adaptive Research (GCAR), a non-profit organization. GCAR’s mission is to speed the discovery and development of treatments for patients with rare and deadly diseases by serving as sponsor of innovative trials. Methods: GBM AGILE is an international, seamless phase II/III platform trial designed to evaluate multiple therapies in newly diagnosed and recurrent GBM. Its goals are to identify effective therapies for GBM and match effective therapies with patient subtypes, with data generated to support regulatory filing for new drug applications. Bayesian response adaptive randomization is used within subtypes of the disease to assign participants to investigational arms based on their performance. The primary endpoint is overall survival. The trial is being conducted under a master Investigational New Drug Application/Clinical Trial Agreement and Master Protocol, allowing multiple drugs/drug combinations from different pharmaceutical companies to be evaluated simultaneously and/or over time. The plan is to add experimental therapies as new information is identified and remove therapies as they complete their individual evaluation against a common control. GBM AGILE received IND approval from the FDA in April 2019, enrolling its first patient in June 2019. Site activation is ongoing in the US, with approximately 40 US planned. The trial received CTA approval from Health Canada in January 2020. Expansion to Europe, China, and Australia is also underway. Clinical trial information: NCT03970447 .

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Utility of Bayesian Single-Arm Design in New Drug Application for Rare Cancers in Japan: A Case Study of Phase 2 Trial for Sarcoma

Therapeutic Innovation & Regulatory Science ◽

10.1177/2168479017728989 ◽

2018 ◽

Vol 52 (3) ◽

pp. 334-338 ◽

Cited By ~ 2

Author(s):

Akihiro Hirakawa ◽

Tadaaki Nishikawa ◽

Kan Yonemori ◽

Taro Shibata ◽

Kenichi Nakamura ◽

...

Keyword(s):

Drug Application ◽

Phase 2 ◽

Rare Cancers ◽

New Drug ◽

Phase 2 Trial ◽

New Drug Application

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CBMT-24. CHARACTERIZATION OF PRIMARY CILIUM IN RECURRENT GLIOBLASTOMA: IMPLICATIONS FOR NEW THERAPEUTIC TARGETS

Neuro-Oncology ◽

10.1093/neuonc/noz175.146 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi38-vi38

Author(s):

Vittorio Stumpo ◽

Aruljothi Marappian ◽

Quintino Giorgio D’Alessandris ◽

Simone Pacioni ◽

Rina Di Bonaventura ◽

...

Keyword(s):

Primary Cilium ◽

Intracellular Signaling ◽

Treatment Resistance ◽

Recurrent Glioblastoma ◽

Newly Diagnosed ◽

Ciliated Cells ◽

Differentiation Markers ◽

Compensatory Response ◽

Who Grade ◽

Recurrent Gbm

Abstract INTRODUCTION Primary cilium is a highly conserved, dynamic cellular organelle which plays several roles in embryonic development, intracellular signaling, and cell cycle. Structural alterations of primary cilium have been described in human gliomas including glioblastoma (GBM), however, its actual role in pathogenesis and treatment resistance of these tumors is largely unknown. METHODS We investigated cilium morphology and expression of cilium-related genes in human glioma of various WHO grade and in couples of patient-derived glioma stem-like cells (GSCs) that were established from the very same GBM at first diagnosis and at recurrence. Immunohistochemistry with anti-Arl13b antibody was used to assess cilium morphology. The expression levels of genes involved in ciliary disassembly complex (CDC) were analyzed by quantitative real-time PCR, using neural progenitor cells (NPCs) as control. Lastly, we assessed 3 GSC cultures that were treated with a drug inhibiting cilia disassembly (CCB-Cil). RESULTS Anaplastic oligodendroglioma and proneural GBM showed the highest percentage of ciliated cells. In GBM, we found the highest percentage of fragmented cilia. GSCs derived from newly diagnosed GBMs displayed lower percentages of ciliated cells than those derived from recurrent GBMs (20% vs 70%). Morphological analysis indicated that GSCs from recurrent GBM show cilia with extremely various morphology compared with GSCs from newly diagnosed GBM and NPCs. Gene analysis showed reduced expression of CDC-related genes in GSCs from newly diagnosed GBM with respect to those from recurrent GBMs. CCB-Cil treatment determined a global reduction of CDC-related genes, increased expression of differentiation markers (GFAP), and reduction of stemness markers (SOX2). CONCLUSIONS The increased percentage of ciliated cells in GSCs from recurrent GBM may be related to a compensatory response of CDC and to an accelerated ciliary turnover. Blocking cilia disassembly reduces stemness features and induces differentiation in GSCs, suggesting that this approach could represent a promising strategy for targeting GBM.

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Clinical trials of VAL-083 in patients with chemo-resistant glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps2082 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS2082-TPS2082

Author(s):

Jeffrey A. Bacha ◽

Anne Steino ◽

Richard Stephen Schwartz ◽

John Langlands ◽

Sarath Kanekal ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Dna Methyltransferase ◽

Drug Application ◽

Phase 2 ◽

Current Standard ◽

Pivotal Phase ◽

Phase 2 Study ◽

Recurrent Gbm

TPS2082 Background: Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard of care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Most GBM tumors have unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT); a validated biomarker for TMZ-resistance. Second-line treatment with anti-angiogenic agent bevacizumab has not improved overall survival (OS) and 5-year survival is less than 3%. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent targeting N7-Guanine and inducing interstrand DNA cross-links, double-strand breaks and cell death in GBM cell lines and GBM cancer stem cells, independent of MGMT status in vitro. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. Our recent phase I/II clinical trial in recurrent GBM patients failing both TMZ and bevacizumab, suggested that VAL-083 offers clinically meaningful survival benefits for patients with recurrent GBM and pinpointed a new dosing regimen (40 mg/m2/d on days 1,2,3 of a 21-day cycle) which was well-tolerated and was selected for study in subsequent GBM trials. Methods: These trials include i) an ongoing single-arm, biomarker driven, Phase 2 study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves overall survival at 9 months, compared to historical control with lomustine (clinicaltrials.gov identifier: NCT02717962). ii) A pivotal Phase 3 study in recurrent GBM after failing both TMZ and bevacizumab. The control arm will consist of a limited number of salvage chemotherapies currently used in bevacizumab-failed GBM. If successful, this study will serve as the basis for a New Drug Application (NDA) submission for VAL-083. iii) A single arm, biomarker driven, Phase 2 study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients whose tumors are known to express high MGMT levels. The results of these studies may support a new treatment paradigm in chemotherapeutic regimens for the treatment of GBM. Clinical trial information: NCT02717962.

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Laser interstitial thermal therapy for newly diagnosed and recurrent glioblastoma

Neurosurgical FOCUS ◽

10.3171/2016.7.focus16234 ◽

2016 ◽

Vol 41 (4) ◽

pp. E12 ◽

Cited By ~ 42

Author(s):

Jonathan G. Thomas ◽

Ganesh Rao ◽

Yvonne Kew ◽

Sujit S. Prabhu

Keyword(s):

Median Survival ◽

Progression Free Survival ◽

Primary Brain Tumor ◽

Recurrent Glioblastoma ◽

Thermal Therapy ◽

Newly Diagnosed ◽

Free Survival ◽

Laser Interstitial Thermal Therapy ◽

Median Progression Free Survival ◽

Recurrent Gbm

OBJECTIVE Glioblastoma (GBM) is the most common and deadly malignant primary brain tumor. Better surgical therapies are needed for newly diagnosed GBMs that are difficult to resect and for GBMs that recur despite standard therapies. The authors reviewed their institutional experience of using laser interstitial thermal therapy (LITT) for the treatment of newly diagnosed or recurrent GBMs. METHODS This study reports on the pre-LITT characteristics and post-LITT outcomes of 8 patients with newly diagnosed GBMs and 13 patients with recurrent GBM who underwent LITT. RESULTS Compared with the group with recurrent GBMs, the patients with newly diagnosed GBMs who underwent LITT tended to be older (60.8 vs 48.9 years), harbored larger tumors (22.4 vs 14.6 cm3), and a greater proportion had IDH wild-type GBMs. In the newly diagnosed GBM group, the median progression-free survival and the median survival after the procedure were 2 months and 8 months, respectively, and no patient demonstrated radiographic shrinkage of the tumor on follow-up imaging. In the 13 patients with recurrent GBM, 5 demonstrated a response to LITT, with radiographic shrinkage of the tumor following ablation. The median progression-free survival was 5 months, and the median survival was greater than 7 months. CONCLUSIONS In carefully selected patients with recurrent GBM, LITT may be an effective alternative to surgery as a salvage treatment. Its role in the treatment of newly diagnosed unresectable GBMs is not established yet and requires further study.

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Multiplex-inhibitor bead mass spectrometry reveals differential kinome signatures in newly diagnosed and recurrent glioblastoma

10.1101/2020.09.21.306910 ◽

2020 ◽

Author(s):

Anna Jermakowicz ◽

Alison M. Kurimchak ◽

Jann Sarkaria ◽

Ricardo Komotar ◽

Michael E. Ivan ◽

...

Keyword(s):

Mass Spectrometry ◽

Clinical Trials ◽

Signaling Pathways ◽

Surgical Resection ◽

Kinase Inhibitors ◽

Resistance Mechanisms ◽

Recurrent Glioblastoma ◽

Adult Brain ◽

Newly Diagnosed ◽

Recurrent Gbm

ABSTRACTGlioblastoma (GBM) is the most common and aggressive adult brain tumor. Despite years of research, clinical trials have not improved the outcome for GBM. Standard of care for newly diagnosed GBM includes surgical resection, followed by radiation and chemotherapy. Tumor recurrence is inevitable and since most patients are not candidates for a second surgical resection, there is an urgent need to identify resistance mechanisms that arise in recurrent GBM. We postulated that examining the differences of activated kinases between newly diagnosed and recurrent GBM may provide insight to resistance mechanisms.To map the kinome landscape of newly diagnosed (nGBM) and recurrent GBM (rGBM) patient derived xenograft tumors, we used Multiplexed Inhibitor Beads and Mass Spectrometry (MIB-MS). We performed pathway analysis of kinases that differed in MIB-binding between nGBM and rGBM to identify kinase-driven signaling pathways. We also analyzed transcriptional profiles to determine the overlap in signaling pathways seen using proteomics or transcriptomics.Using MIB-MS kinome profiling, we found key differences in kinase-driven signaling pathways that may account for the increase in aggressive behavior seen in recurrent GBM. This included a shift in pathways driving cell invasion and proliferation, as well as upregulation of signaling pathways that drive GBM stem-cell like cell differentiation. Analysis of RNA-sequencing showed no statistically significant differences between enriched gene ontologies in nGBM and rGBM, demonstrating the importance of MIB-MS kinome profiling. Collectively, these studies suggest that kinome profiling may inform future clinical trials for kinase inhibitors in GBM.

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Potential factors correlating to the PMDA’s decision to waive Japanese Phase 2 and 3 studies for oncology drugs New Drug Application in Japan

Investigational New Drugs ◽

10.1007/s10637-012-9911-x ◽

2012 ◽

Vol 31 (4) ◽

pp. 1051-1055 ◽

Cited By ~ 1

Author(s):

Keitaro Nakajima ◽

Koji Chiba ◽

Hisao Tsubamoto ◽

Jaimie Walsh ◽

Laurie Strawn ◽

...

Keyword(s):

Drug Application ◽

Phase 2 ◽

New Drug ◽

Potential Factors ◽

New Drug Application

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Phase 3 PhALLCON study: Ponatinib (PON) versus imatinib (IM) with reduced-intensity chemotherapy (CT) in patients (pts) with newly diagnosed Philadelphia chromosome–positive (Ph+) ALL.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.tps7061 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. TPS7061-TPS7061

Author(s):

Elias Jabbour ◽

Giovanni Martinelli ◽

Marco Vignetti ◽

Josep-Maria Ribera ◽

David Gomez-Almaguer ◽

...

Keyword(s):

Active Sites ◽

Residual Disease ◽

Single Agent ◽

Philadelphia Chromosome ◽

Phase 2 ◽

Newly Diagnosed ◽

Resistance Mutations ◽

First Line ◽

Open Label ◽

Reduced Intensity

TPS7061 Background: Therapies for adults with newly diagnosed Ph+ ALL are limited and associated with poor outcomes. PON, a potent TKI, is active against native BCR-ABL1 and all identified single resistance mutations, including T315I, which confers resistance to other TKIs (Zhou. Chem Biol Drug Des 2011;77). In the phase 2 PACE study, PON had a 41% major hematologic response rate in heavily pretreated Ph+ ALL, but responses were not durable mainly due to compound mutations (Cortes. Blood 2018;132; Pritchard. Blood 2016;128). As PON suppresses single BCR-ABL1 resistance mutations, resistance in Ph+ ALL is acquired through compound mutations. Decreased likelihood of compound mutations with first-line PON in Ph+ ALL may lead to more durable responses compared with PON in later lines of therapy. In a phase 2 study of PON with CT in newly diagnosed Ph+ ALL, long-term outcomes were improved vs first/second-generation TKIs (Jabbour. Lancet Haematol 2018;5). The PhALLCON trial compares first-line PON vs IM with reduced-intensity CT. Methods: This open-label trial (NCT03589326) is enrolling 230–320 pts (≥18 y) with newly diagnosed Ph+ or BCR-ABL1–positive ALL (p190/p210) and ECOG status ≤2. Pts are randomized 2:1 to PON 30 mg/d or IM 600 mg/d PO with reduced-intensity CT in induction (cycles [C] 1-3), consolidation (C4-9), and maintenance (C10-20). PON dose is reduced to 15 mg once pt achieves minimal residual disease–negative (MRD−) complete remission (CR). After 20C, pts stay on single-agent PON/IM. CNS prophylaxis: 2x/mo in C1-6. Primary endpoint: MRD− (BCR-ABL/ABL1 ≤0.01%) CR (end of induction). Key secondary endpoint: EFS; others in the Table. Subgroup analysis: pts with/without HSCT. Exploratory endpoints include mutation status. Initiated Aug 2018; to include ~110 sites in ≤35 countries. Currently, 5 active sites (4 US, 1 Spain); accrual ongoing. Clinical trial information: NCT03589326. [Table: see text]

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