Combination chemotherapy versus temozolomide (TMZ) for patients with MGMT methylated (m-MGMT) glioblastoma (GBM): Results of cellworks omics biosimulation—MyCare-015.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Michael Castro ◽  
Nirjhar Mundkur ◽  
Anusha Pampana ◽  
Aftab Alam ◽  
Aktar Alam ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Clinical Decision Making ◽  
Drug Effects ◽  
Standard Of Care ◽  
Clinical Decision ◽  
Phase Iii ◽  
Patient Specific ◽  
Experimental Therapy ◽  
Newly Diagnosed ◽  
Current Standard

e14501 Background: UKT-03 evaluated TMZ plus Lomustine in a single arm phase II trial in newly diagnosed GBM patients. An overall survival of 23 months was a substantial improvement over historical experience. Patients with m-MGMT v. unmethylated tumors had a 2-yr survival of 75% and median survival not reached compared to 20% and 12.5 months, respectively. These data formed the basis for NOA-9, a randomized phase III trial in newly diagnosed, m-MGMT GBM which randomized 141 patients to standard therapy or experimental therapy with Lomustine and TMZ every 6 weeks. A superiority for the combination was observed: 48.1 v. 31.4 months for the standard arm in the ITT analysis. Nevertheless, many neurooncologists are reluctant to adopt this approach. The current standard of care uses single biomarker, m-MGMT, in contrast to comprehensive pathway analysis (CPA). We sought to determine if CPA could discriminate more effectively among each patient’s likelihood of benefiting from combination treatment. Methods: Cellworks Singula employs a novel Cellworks Omics Biology Model (CBM) to predict patient-specific biomarker and phenotype response of personalized GBM avatars to drug agents, radiation, and targeted therapies. The CBM was developed and validated using PubMed to generate protein network maps of patient-specific activated and inactivated disease pathways. CBM was used to simulate the TMZ and TMZ-Lomustine therapies for each patient in a TCGA cohort of 368 GBM patients. Omics data including methylation, whole exome sequencing, and copy number alterations were input into CBM. The Singula Composite Inhibition Score (CIS) was calculated based on the measured quantitative drug effects. Results: Though incremental gain from the combination was seen in all patients, CIS varied across the population with relative scores ranging from 32-82, with best responders have more than twice the benefit. Conclusions: CPA shows that m-MGMT is an excellent biomarker for determining the likelihood of benefit from TMZ and lomustine, with the caveat that CBM identifies 18% could be spared from TMZ exposure and would benefit from Lomustine alone. Otherwise, these data lend support for evolving the standard of care with combination therapy for patients with m-MGMT GBM and should help overcome a reluctance to employing combination therapy. Additionally, CBM has utility to individualize clinical decision making. [Table: see text]

RTID-05. THE MULTI-ARM GLIOBLASTOMA AUSTRALASIA (MAGMA) TRIAL

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi193-vi194
Author(s):  
Benjamin Kong ◽  
Hao-Wen Sim ◽  
Eng-Siew Koh ◽  
Hui Gan ◽  
Elizabeth H Barnes ◽  
...  
Keyword(s):  
Data Collection ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Phase Iii ◽  
Low Grade ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Future Design ◽  
Multiple Treatment ◽  
Newly Diagnosed Glioblastoma

Abstract BACKGROUND Survival outcomes for patients with newly diagnosed glioblastoma have not changed significantly since the introduction of concurrent temozolomide with post-surgical radiation followed by adjuvant temozolomide. METHODS Multi-Arm Glioblastoma Australasia (MAGMA) is a recently initiated phase III multi-arm, multi-centre randomized trial for patients with newly diagnosed glioblastoma, led by the Australian Cooperative Trials Group for Neuro-Oncology (COGNO), that will concurrently test multiple treatment questions. Initially, a partial factorial design will be implemented to compare the current standard of care with either or both of (1) neoadjuvant temozolomide and (2) aduvant temozolomide continued beyond six months until progression. MAGMA will transition to a multi-arm multi-stage (MAMS) design as additional tratment question are introduced. Treatment allocation to each question will be balanced (1:1) using minimisation over several stratification factors, including study site, age, IDH-mutation status, surgical extent and randomization to the prior treatment question(s). The primary outcome is overall survival. Secondary outcomes include progression-free survival (measured by mRANO), time to first non-temozolomide systemic treatment, clinically significant toxicity as measured by Grade 2/4 adverse events, and health-related quality of life measures. Parsimonious data collection and a streamlined assessment schedule have been incorporated to mitigate the burden of data collection (such as low grade toxicity from temozolomide), and to encourage participation in regional and rural settings. A consortium model has been adopted to foster neuro-oncology expertise and infrastructure and share academic credit and future design opportunities. PROGRESS Recruitment commenced in September 2020. To date, 60 patients have been recruited from an initial sample size target of 250 patients for each of these initial two treatment questions. Of these 60 patients, 45 have been randomized in Question 1 (neoadjuvant chemotherapy) whilst 50 randomized in Question 2 (prolonged adjuvant chemotherapy). To date, 14 of the 27 intended sites are open to recruitment.

scholarly journals SS-1 Therapeutic challenges for glioblastoma: Temozolomide and its issues?

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii1-ii1
Author(s):  
Motoo Nagane
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Standard Of Care ◽  
Phase Iii ◽  
Lower Grade ◽  
Newly Diagnosed ◽  
Current Standard ◽  
Who Grade ◽  
Phase Iii Trial ◽  
Mgmt Gene

Abstract Glioblastoma (GBM), the most malignant form (WHO grade IV) of gliomas, remains incurable despite recent advances in medical technologies and molecular knowledge, with 5-year survival rate being just beyond 10%, thus undoubtedly leaving unmet needs to develop effective therapeutics to improve outcome. Current standard of care for patients with newly diagnosed GBM is maximum safe resection of the enhancing tumor bulk, followed by involved-field radiotherapy with temozolomide (TMZ) given concomitantly and as an adjuvant therapy thereof with or without Tumor-Treating Fields (TTF). The efficacy of TMZ for GBM was proved in 2005 by a randomized phase III trial (EORTC25981) for the first time ever in history, since then, however, any other agents have failed to show benefit to improve survival until now. O6-methylguanine-DNA methyltransferase (MGMT), a specific DNA repair enzyme, has been shown to restore the cytotoxic O6-methylguanine lesion induced by TMZ to normal, responsible for a major reason of TMZ resistance. Expression of MGMT is tightly regulated by methylation of the promoter region of the MGMT gene, where promoter methylation results in suppression of its expression. Accordingly, the promoter methylation of the MGMT gene (meth-MGMT) has been consistently associated with a better response to and outcome by TMZ treatment, and furthermore a favorable prognostic factor for patients with newly diagnosed GBM in a number of prospective clinical trials. In this line, efforts have been made to overcome TMZ resistance including intensifying dose schedulings of TMZ, one of which has been currently tested in a multi-institutional prospective phase III trial in Japan (JCOG1308C). TMZ has also been investigated in lower grade gliomas. A major issue in treating lower grade glioma with TMZ is potential development of the hypermutated tumors by virtue of O6-methylguanine-induced mutagenesis. The clinical and molecular consideration related to TMZ in glioma treatment will be presented.

scholarly journals Assessing the utility and attitudes toward molecular testing in neuro-oncology: a survey of the Society for Neuro-Oncology members

2021 ◽  
Author(s):  
Shannon Fortin Ensign ◽  
Maya Hrachova ◽  
Susan Chang ◽  
Maciej M Mrugala
Keyword(s):  
Online Survey ◽  
Clinical Decision Making ◽  
Unmet Needs ◽  
Practice Patterns ◽  
Response Rate ◽  
Clinical Decision ◽  
Molecular Testing ◽  
Newly Diagnosed ◽  
Tumor Boards ◽  
Oncology Practice

Abstract Background Molecular testing (MT) is utilized in neuro-oncology with increasing frequency. The aim of this study was to determine clinical practice patterns to acquire this information, interpret and utilize MT for patient care, and identify unmet needs in the practical clinical application of MT. Methods We conducted a voluntary online survey of providers within the Society for Neuro-Oncology (SNO) membership database between March and April 2019. Results We received 152 responses out of 2022 SNO members (7.5% of membership). 88.8% of respondents routinely order MT for newly diagnosed gliomas. Of those who do not, testing is preferentially performed in younger patients or those with midline tumors. 82.8% use MT in recurrent gliomas. Other common indications included: metastatic tumors, meningioma, and medulloblastoma. Many providers utilize more than one resource (36.0%), most frequently using in-house (41.8%) over commercially available panels. 78.1% used the results for clinical decision-making, with BRAF, EGFR, ALK, and H3K27 mutations most commonly directing treatment decisions. Approximately, half (48.5%) of respondents have molecular tumor boards at their institutions. Respondents would like to see SNO-endorsed guidelines on MT, organized lists of targeted agents available for specific mutations, a database of targetable mutations and clinical trials, and more educational programs on MT. Conclusion This survey was marked by several limitations including response rate and interpretation of MT. Among respondents, there is routine use of MT in Neuro-Oncology, however, there remains a need for increased guidance for providers to effectively incorporate the expanding genomic data resulting from MT into daily Neuro-Oncology practice.

scholarly journals Implementation of pharmacogenomic testing in oncology care (PhOCus): study protocol of a pragmatic, randomized clinical trial

2020 ◽  
Vol 12 ◽  
pp. 175883592097411
Author(s):  
Natalie Reizine ◽  
Everett E. Vokes ◽  
Ping Liu ◽  
Tien M. Truong ◽  
Rita Nanda ◽  
...  
Keyword(s):  
Clinical Laboratory ◽  
Drug Effects ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Clinical Decision ◽  
Drug Dose ◽  
Patient Specific ◽  
Drug Dosing ◽  
Patient Reported ◽  
Dose Modifications

Background: Many cancer patients who receive chemotherapy experience adverse drug effects. Pharmacogenomics (PGx) has promise to personalize chemotherapy drug dosing to maximize efficacy and safety. Fluoropyrimidines and irinotecan have well-known germline PGx associations. At our institution, we have delivered PGx clinical decision support (CDS) based on preemptively obtained genotyping results for a large number of non-oncology medications since 2012, but have not previously evaluated the utility of this strategy for patients initiating anti-cancer regimens. We hypothesize that providing oncologists with preemptive germline PGx information along with CDS will enable individualized dosing decisions and result in improved patient outcomes. Methods: Patients with oncologic malignancies for whom fluoropyrimidine and/or irinotecan-inclusive therapy is being planned will be enrolled and randomly assigned to PGx and control arms. Patients will be genotyped in a clinical laboratory across panels that include actionable variants in UGT1A1 and DPYD. For PGx arm patients, treating providers will be given access to the patient-specific PGx results with CDS prior to treatment initiation. In the control arm, genotyping will be deferred, and dosing will occur as per usual care. Co-primary endpoints are dose intensity deviation rate (the proportion of patients receiving dose modifications during the first treatment cycle), and grade ⩾3 treatment-related toxicities throughout the treatment course. Additional study endpoints will include cumulative drug dose intensity, progression-free survival, dosing of additional PGx supportive medications, and patient-reported quality of life and understanding of PGx. Discussion: Providing a platform of integrated germline PGx information may promote personalized chemotherapy dosing decisions and establish a new model of care to optimize oncology treatment planning.

scholarly journals Single-inhaler triple therapy in symptomatic COPD patients: FULFIL subgroup analyses

2018 ◽  
Vol 4 (2) ◽  
pp. 00119-2017 ◽  
Author(s):  
David M.G. Halpin ◽  
Ruby Birk ◽  
Noushin Brealey ◽  
Gerard J. Criner ◽  
Mark T. Dransfield ◽  
...  
Keyword(s):  
Disease Severity ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Forced Expiratory Volume ◽  
Phase Iii ◽  
Chronic Obstructive ◽  
Double Blind Study ◽  
Double Blind ◽  
Subgroup Analyses ◽  
Long Acting

Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear.FULFIL, a phase III, randomised, double-blind study, compared 24 weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg using the Ellipta inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg using the Turbuhaler. Subgroup analyses of forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) Total score and exacerbation rates were carried out. Subgroups were defined by COPD medication at screening (ICS+LABA, BUD+FOR, ICS+LABA+LAMA, LAMA alone, tiotropium alone and LAMA+LABA), by disease severity (lung function and exacerbations) and by exacerbation history (exacerbation severity and frequency).In the intent-to-treat population (n=1810) at week 24, FF/UMEC/VI (n=911) versus BUD/FOR (n=899) improved FEV1 and SGRQ Total score and reduced mean annual exacerbation rates in all disease severity and exacerbation history subgroups. FF/UMEC/VI versus BUD/FOR improved FEV1 and SGRQ Total score in all medication subgroups and reduced mean annual exacerbation rates in all medication subgroups, except LAMA+LABA. Adverse events were similar across subgroups.These findings support the benefit of FF/UMEC/VI compared with dual ICS/LABA therapy in patients with symptomatic COPD regardless of disease severity or prior treatment and may help to inform clinical decision making.

Serial plasma and CSF cell-free tumor DNA (cf-tDNA) tracking in diffuse midline glioma patients undergoing treatment with ONC201.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2012-2012
Author(s):  
Evan Cantor ◽  
Kyle Wierzbicki ◽  
Rohinton Tarapore ◽  
Chase Thomas ◽  
Rodrigo Cartaxo ◽  
...  
Keyword(s):  
Tumor Size ◽  
Clinical Decision Making ◽  
Phase 1 ◽  
Complete Response ◽  
Clinical Decision ◽  
Experimental Therapy ◽  
Plasma Samples ◽  
Mri Scans ◽  
Tumor Dna ◽  
Diffuse Midline Glioma

2012 Background: Diffuse midline glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. There are few available means of monitoring the disease beyond serial MRI scans, making clinical decision making slow, difficult, and often reactive. Methods: We conducted a multi-site phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n=24) underwent serial lumbar puncture (baseline, 2 and 6 months) for cell-free tumor DNA (cf-tDNA) analysis at time of MRI. Additionally, patients on all arms of the trial at the University of Michigan underwent serial plasma collection. CSF collection was feasible in this cohort, with no procedural complications. We collected a total of 96 plasma samples and 53 CSF samples from 29 patients, including those with H3F3A (H3.3) (n=13), HIST13HB (H3.1) (n= 4), and unknown H3 status/not biopsied (n=12) [range of 0-8 CSF samples and 0-10 plasma samples]. We performed digital droplet polymerase chain reaction (ddPCR) analysis and/or amplicon-based electronic sequencing (Oxford Nanopore) of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). Results: Preliminary analysis of samples (n=58) demonstrates a correlation between changes in tumor size and H3K27M cf-tDNA VAF, when removing samples with concurrent bevacizumab. Analysis of remaining CSF and plasma samples is ongoing, including analysis of novel biomarkers of response. In multiple cases, early reduction in CSF cf-tDNA predicts long-term clinical response (>1 year) to ONC201 and does not increase in cases of later-defined pseudo-progression (radiation necrosis). For example, a now 9-year old patient with thalamic H3K27M-mutant DMG underwent treatment with ONC201 after initial radiation and developed an increase in tumor size at 4 months post-radiation (124% baseline) of unclear etiology at the time. Meanwhile, her ddPCR declined from baseline 6.76% VAF to <1%, which has persisted, with now near complete response (85% tumor reduction) at 30 months on treatment from diagnosis. Conclusions: In summary, we present the feasibility and utility of serial CSF/plasma monitoring of a promising experimental therapy for DMG.

scholarly journals Quantifying the Impact of Patient-Specific Factors and Disease Severity on Clinical Decision Making in Cuff Tear Arthropathy: A Case-Based Survey

2019 ◽  
Vol 15 (3) ◽  
pp. 276-285
Author(s):  
Adam P. Schumaier ◽  
Yehia H. Bedeir ◽  
Joshua S. Dines ◽  
Keith Kenter ◽  
Lawrence V. Gulotta ◽  
...  
Keyword(s):  
Decision Making ◽  
Disease Severity ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Patient Specific ◽  
Cuff Tear Arthropathy ◽  
Cuff Tear ◽  
Specific Factors ◽  
The Impact ◽  
Case Based

Complementing sparse vascular imaging data by physiological adaptation rules

2020 ◽  
Author(s):  
Maarten H.G. Heusinkveld ◽  
Robert J. Holtackers ◽  
Bouke P. Adriaans ◽  
Jos Op't Roodt ◽  
Theo Arts ◽  
...  
Keyword(s):  
Clinical Decision Making ◽  
Mechanical Load ◽  
Wall Stress ◽  
Clinical Decision ◽  
Physiological Adaptation ◽  
Patient Specific ◽  
Data Sets ◽  
Imaging Data ◽  
Artery Segment ◽  
Flow Waveforms

Introduction:Mathematical modeling of pressure and flow waveforms in blood vessels using pulse wave propagation (PWP)-models has tremendous potential to support clinical decision-making. For a personalized model outcome, measurements of all modeled vessel radii and wall thicknesses are required. In clinical practice, however, data sets are often incomplete. To overcome this problem, we hypothesized that the adaptive capacity of vessels in response to mechanical load could be utilized to fill in the gaps of incomplete patient-specific data sets. Methods:We implemented homeostatic feedback loops in a validated PWP model to allow adaptation of vessel geometry to maintain physiological values of wall stress and wall shear stress. To evaluate our approach, we gathered vascular MRI and ultrasound data sets of wall thicknesses and radii of central and arm arterial segments of ten healthy subjects. Reference models (i.e. termed RefModel, n=10) were simulated using complete data, whereas adapted models (AdaptModel, n=10) used data of one carotid artery segment only while the remaining geometries in this model were estimated using adaptation. We evaluated agreement between RefModel and AdaptModel geometries, as well as between pressure and flow waveforms of both models. Results:Limits of agreement (bias±2SD of difference) between AdaptModel and RefModel radii and wall thicknesses were 0.2±2.6 mm and -140±557 μm, respectively. Pressure and flow waveform characteristics of the AdaptModel better resembled those of the RefModels as compared to the model in which the vessels were not adapted.Conclusions:Our adaptation-based PWP-model enables personalization of vascular geometries even when not all required data is available.

State-of-the-Art Management for the Patient with Castration-Resistant Prostate Cancer in 2012

2012 ◽  
pp. 289-291 ◽  
Author(s):  
Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Optimal Sequence ◽  
Molecular Stratification ◽  
Castration Resistant ◽  
Radium 223 ◽  
Phase Iii Trials

Overview: Much progress has been made in metastatic castration-resistant prostate cancer (CRPC), and multiple new U.S. Food and Drug Administration (FDA)-approved survival-prolonging drugs are now available. In 2004, docetaxel/prednisone was the first therapy shown to prolong survival. In 2010 and 2011, sipuleucel-T, cabazitaxel/prednisone, and abiraterone/prednisone were FDA approved. Two new agents, radium-223 and MDV-3100, have recently reported large phase III trials prolonging overall survival and will be submitted for regulatory approval in 2012. One can now begin to ask, is there an optimal sequence for therapies in metastatic CRPC? Despite the recent progress, there is much we do not know and virtually no information on this important question. We know that abiraterone/prednisone and cabazitaxel/prednisone are appropriate choices for a patient after receiving docetaxel, but we do not know what, if anything, represents the optimal sequence for abiraterone and cabazitaxel. In fact we do not understand how one therapy may affect the response to a subsequent therapy. We are also aware that the pre- and postdocetaxel spaces represent regulatory rather than biologic divisions. In addition, despite the proven role of docetaxel/prednisone, many patients with CRPC are not considered to be suitable for chemotherapy, and worldwide many never receive any form of chemotherapy. What is the optimal management for these patients? Taken together it is reasonable to assess patient preferences, prior therapies and response/tolerance to prior therapies, burden of disease, comorbidities, current symptoms, drug toxicities, out-of-pocket costs, etc., in clinical decision making. Given the many factors we do not know, it is hard to be dogmatic in approaching the therapeutic options for the patient with CRPC. We will likely soon move beyond the current sequencing paradigm and begin to assess new combinations in a systematic and rational fashion. Perhaps one day, in the not too distant future, we will develop molecular “stratification systems” to better guide therapeutic choices in CRPC.

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