The 1994 National Cancer Institute’s strategy to fund multi-institutional, multidisciplinary consortia to design and conduct early phase clinical trials in patients with high grade gliomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2003-2003
Author(s):  
Stuart A. Grossman ◽  
Louis B. Nabors ◽  
Joy D. Fisher ◽  
Patrick Y. Wen ◽  
William C. Timmer ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Tumor ◽  
Early Phase ◽  
Adult Brain ◽  
High Grade ◽  
Tumor Research ◽  
High Grade Gliomas ◽  
Brain Tumor Research ◽  
Early Phase Clinical Trials ◽  
The Brain

2003 Background: : In the early 1990’s, the NCI suspended activities of the Brain Tumor Study Group seeking to shift clinical brain tumor research from phase III trials to innovative and correlative rich phase I/II studies. In 1994, NCI funded three early phase brain tumor consortia, later reduced to two consortia in 1999 and one in 2009. In 2020, the NCI announced it would discontinue funding the brain tumor consortium and emphasize pre-clinical glioblastoma drug development (RFA-CA-20-047). Methods: The activities of the New Approaches to Brain Tumor Therapy (NABTT: 1994-2009) and Adult Brain Tumor Consortium (ABTC: 2009-2021) were summarized using data from the Central Operations Office that served the consortia for 27 years. Results: From 1994-2020, 48 consortium meetings were held to discuss, develop, conduct, and evaluate early phase clinical trials. These involved multidisciplinary brain tumor experts (neuro-oncologists, neurosurgeons, radiation oncologists, neuropathologists, statisticians, pharmacologists, imaging experts, immunologists, etc) from 27 US academic centers and hospitals. 85 clinical trials were written, approved by NCI and the Brain Malignancy Steering Committee, and conducted. Most trials evaluated NCI-provided therapeutic agents. 34 trials were conducted in collaboration with 27 pharmaceutical companies eager to develop malignant brain tumor therapeutics; for 9 of these the consortia held the IND. 4870 patients were accrued: 3375 to therapeutic and 1495 to non-therapeutic studies. 49 grant proposals were submitted to fund consortium activities with a 46% approval rate. 91 peer reviewed manuscripts were published, with 174 presentations and abstracts. 18 pharmaceutical symposia were conducted to attract new agents toward early phase brain tumor research. Consortia sponsored 34 Guest Lectureships and multidisciplinary symposia to focus on relevant critical research areas. Additionally, the consortia provided unique opportunities for young faculty to lead multicenter NABTT/ABTC trials with appropriate support and mentorship. Conclusions: Therapeutic progress for high grade gliomas has been slow for many reasons (95% of systemically administered agents do not penetrate the blood-brain barrier, inherent treatment resistance, immunologically “cold” phenotype, etc). NABTT/ABTC focused multidisciplinary, multi-institutional experts on major challenges unique to brain tumor research. The consortia developed innovative early phase clinical studies rich in correlative endpoints, fostered research grants, hosted relevant topical symposia, and provided leadership roles for young investigators while bringing together the NCI, industry, and committed multidisciplinary academicians to explore novel therapeutic options for patients with primary brain tumors.

scholarly journals Outcome of high-grade gliomas (HGGs) treated into immunotherapeutic early-phase clinical trials (ieCTs): A single-center experience

2019 ◽  
Vol 30 ◽  
pp. v155-v156
Author(s):  
M. Simonelli ◽  
P. Persico ◽  
A. Dipasquale ◽  
E. Lorenzi ◽  
L. Giordano ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Early Phase ◽  
High Grade ◽  
Single Center ◽  
Single Center Experience ◽  
High Grade Gliomas ◽  
Early Phase Clinical Trials

scholarly journals P05.08 High-grade gliomas and immunotherapeutic early phase clinical trials: a single-center experience

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii35-iii36
Author(s):  
M Simonelli ◽  
P Persico ◽  
A Dipasquale ◽  
E Lorenzi ◽  
L Giordano ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Early Phase ◽  
Univariate Analysis ◽  
Methylation Status ◽  
High Grade ◽  
Clinical Factors ◽  
Lymphocyte Ratio ◽  
High Grade Gliomas ◽  
Early Phase Clinical Trials

Abstract BACKGROUND Patients with high-grade gliomas (HGGs) have historically been excluded from immunotherapeutic early-phase clinical trials (ieCTs) due to unavailability of serial bioptic sampling, the frequent need of corticosteroids, concerns regarding activity of immunotherapy in central nervous system, and rapid clinical deterioration. MATERIAL AND METHODS We retrospectively reviewed data of all recurrent HGG patients enrolled in ieCTs at Humanitas Cancer Center Phase I Unit between 2014 and 2019. Disease control rate (DCR) according to RANO criteria, six-months progression-free and overall survival (PFS-6; OS-6), and treatment-related adverse events (TRAEs), were evaluated. A control-cohort (CC) of patients treated with standard treatments (temozolomide, fotemustine, lomustine and procarbazine, bevacizumab) matched (1:1) for sex, age, line of treatment, MGMT methylation status, and IDH mutational status, was selected for comparison. A series of clinical parameters with an established prognostic value for patients with solid tumors treated into ieCTs were correlated with survivals through an univariate analysis. These include: use of steroids, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, lactate dehydrogenase, albumin, total protein. RESULTS Five among the 23 ieCTs conducted at our Phase I Unit allowed inclusion of HGG patients. 25 patients were enrolled in the experimental cohort (EC): 22 (88%) glioblastoma, 3 (12%) anaplastic astrocytoma. Median age was 50 years (range 25–71); 16 patients (64%) were men, 9 (36%) women; 17 pts (68%) required steroid therapy, with a median baseline dexamethasone dose of 2 mg (range 1–6). The median number of prior systemic therapies was 1 (range 1–2). Twelve patients (48%) received monotherapies (anti PD-1, anti CSFR-1, anti TGF-ß, anti cereblon), 13 (52%) combination regimens (anti PD-L1 + anti CD38, anti PD-1 + anti CSFR-1). DCR was 40% (1 CR + 2 PR + 7 SD) and 37% (9 SD), in EC and CC, respectively. Four patients (16%) in EC had grade ≥3 TRAEs (1 neutropenia, 1 pneumonia, 2 hepatitis). With a median follow-up of 14 months PFS-6 were 35% and 16% (p=0.075), in EC and CC respectively, while OS-6 was significantly improved in the EC (82% vs 44%, p=0.004). In our small series, none of clinical factors resulted prognostic. CONCLUSION Survival outcomes of ourHGG patients treated into ieCTs compared very favorably with a matched CC. Inclusion of HGGs patients into ieCTs should be strongly encouraged. Identification of clinical factors to select who may benefit from ieCTs still remains crucial.

scholarly journals COT-11 EFFECT OF PHYSICIAN SUPPORTS ON QUALITY CONTROL AND QUALITY ASSURANCE IN CLINICAL BRAIN TUMOR RESEARCH

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii42-ii42
Author(s):  
Keiko Furukawa ◽  
Yoshiki Arakawa ◽  
Yohei Mineharu ◽  
Masahiro Tanji ◽  
Akifumi Takaori ◽  
...  
Keyword(s):  
Quality Control ◽  
Clinical Trials ◽  
Quality Assurance ◽  
Brain Tumor ◽  
Ethical Review ◽  
Evaluation Score ◽  
Periodic Monitoring ◽  
Tumor Research ◽  
Brain Tumor Research ◽  
Physician Support

Abstract BACKGROUND Clinical physicians have difficulties in conducting investigator-initiated-trials because of increasing clinical duties in Japan. Therefore, physician support can be one of the important factors for quality control and quality assurance. In Kyoto University Hospital, clinical research professional’s support for physician had started at November 2012. In this study, we evaluate effect of physician supports on quality control and quality assurance in clinical brain tumor research. METHODS Our department of Neurosurgery has been a member of Brain Tumor Study Group in Japan Clinical Oncology Group (JCOG) since 2007. The number of registered patients, the status of periodic monitoring, the occurrence of inquiries per case, and details of physicians’ support (items, frequency, methods, etc.) in each clinical trial were investigated. The factors affecting the audit results conducted by JCOG Audit Committee on January 2013 and February 2019 are examined. RESULTS There are seven trials have been ongoing on or started since November 2012. There are fifty patients registered in the clinical studies until July 2019. Periodic monitoring has been carried out in 214 patients of cumulative total number since 2012. Physicians’ support mainly involved the preparation of ethical review documents, CRF documentation, responses to data queries, preparation of SAE reports, study schedule check and monitoring of observation items. The audit results of site visit were acceptable, total evaluation score 68.80 on January 2013 and excellent, total evaluation score 99.9 on February 2019. CONCLUSION Clinical Trials Act has been implemented, and further improvement in the quality of clinical trials has been demanded. As the results of this study, we clarified the necessity for physician support and the contribution to quality improvement.

scholarly journals CLRM-03. BGB-290 AND TEMOZOLOMIDE IN TREATING ISOCITRATE DEHYDROGENASE (IDH)1/2-MUTANT GRADE I-IV GLIOMAS – A NOVEL MODEL OF AYA TRIAL DEVELOPMENT AND DEPLOYMENT

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv1-iv1
Author(s):  
Asher Marks ◽  
Ranjit Bindra
Keyword(s):  
Clinical Trials ◽  
Brain Tumor ◽  
Early Phase ◽  
Parp Inhibitor ◽  
High Grade Glioma ◽  
Adult Brain ◽  
Adolescent And Young Adult ◽  
Patients Âgés ◽  
Synergistic Interactions ◽  
The Pacific

Abstract DESCRIPTION The lack of enrollment of AYA patients on clinical trials is well documented and multivariant. Here we present the basic science, examination of its relevance to the AYA population specifically, and the parallel deployment of two international clinical trials via a pediatric neuro-oncology and adult brain tumor consortium. DISCUSSION In February of 2017, the laboratory of Ranjit Bindra, MD, PhD, published a manuscript describing the finding that tumors with IDH1/2 mutations induce a BRCAness state leading to PARP inhibitor (PARPi) sensitivity and synergistic interactions with temozolomide chemotherapy [2]. Despite IDH1/2 mutations being rare in the pediatric high-grade glioma population, three independent groups confirmed that the incidence is significantly increased to ~30% in the adolescent and young adult (AYA) population. Upon discovery of a high blood-brain-barrier penetrant, high potency PARPi by BeiGene Pharmaceuticals, an international trial was launched through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) [3] to test this drug in an AYA specific trial recruiting patients ages 13 to 25, with a concurrent trial being run for patients older than 25 years of age through the Adult Brain Tumor Consortium (ABTC) [4]. While most trials that enroll AYA patients are forced to assess them as a unique cohort in post-analysis, if at all, the PNOC trial mentioned above was designed from the ground up with the AYA population in mind. It has allowed us to base initial dosing, recruitment strategies, psychosocial assessments, and outcomes, specifically on the AYA population. Ultimately, we expect their distinctive biology to yield unique results when compared to the ABTC trial. We propose that this is a model that could potentially be replicated in other disease processes and early phase drugs with the buy-in of the pharmaceutical industry and early phase consortiums. Acknowledgements: BeiGene Pharmaceuticals, PNOC, ABTC, CureSearch, Gateway Foundation

Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 2033-2033
Author(s):  
Matthias Holdhoff ◽  
Xiaobu Ye ◽  
Louis B. Nabors ◽  
Arati Suvas Desai ◽  
Tom Mikkelsen ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase I ◽  
Sequential Therapy ◽  
Adult Brain ◽  
High Grade ◽  
High Grade Gliomas

Patient experience of early high grade symptomatic adverse events on early phase clinical trials using the PRO-CTCAE.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 12051-12051
Author(s):  
Geoffrey Alan Watson ◽  
Zachary William Neil Veitch ◽  
Daniel Shepshelovich ◽  
Zhihui (Amy) Liu ◽  
Anna Spreafico ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Phase I ◽  
Early Phase ◽  
Daily Life ◽  
High Grade ◽  
Negative Experience ◽  
Patient Reported ◽  
Grade 3 ◽  
Early Phase Clinical Trials

12051 Background: There are limited data describing the patients’ experience of symptomatic adverse events (syAEs) on early phase clinical trials. This information is critical to understand the tolerability of experimental agents. The patient reported outcome version of the CTCAE (PRO-CTCAE) evaluates syAE components such as severity and interference in daily life. The aim of this study was to correlate clinician reported early, high grade (grade 3-4) AEs with patients’ reported experience of these toxicities. Methods: Advanced solid tumor patients (pts) enrolled on early phase clinical trials at Princess Margaret Cancer Centre were surveyed electronically using the full library of 78 items for PRO-CTCAE v1.0, which was administered at baseline (prior to therapy), mid-cycle 1, and mid-cycle 2. AEs on study were recorded by physicians using the CTCAE v4.0. Worst responses for severity items are ‘severe’ and ‘very severe’ and for interference items are ‘quite a bit’ and ‘very much’. A logistic regression model was used to assess the association between CTCAE grade and PRO-CTCAE severity and interference. Results: A total of 292 pts were approached in phase 1 clinics from May 2017 to January 2019, and 219 pts were included in the analysis: median age 60 years (range 18-82), 111 (51%) were male; all were ECOG ≤1. A total of 140 pts (64%) received combination therapy (immunotherapy and targeted therapy), and 73 pts (33%) had received ≥3 previous lines of treatment. In terms of patient reported syAEs, a total of 114 pts (52%) reported a symptomatic AE as either severe or very severe at any timepoint and 79 pts (36%) reported a syAE with an interference that was either ‘quite a bit’ or ‘very much’. With regards to clinician reported AEs, a total of 82 pts (37%) had a clinician reported grade 3 or 4 syAE, and of these 34 pts (41%) reported these as either severe or very severe; and 26 pts (32%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Additionally 137 pts (66%) had a clinician reported grade 1 or 2 syAE, and of these 39 pts (28%) reported these as either severe or very severe; and 19 (14%) found these AEs interfered with daily life either ‘quite a bit’ or ‘very much’. Higher grade clinician reported syAEs (CTCAE grade 3-4 vs 1-2) was associated with higher patient reported severity levels (odds ratio, OR = 1.78, 95% CI 1-3.16, p = 0.049), and was associated with higher patient reported interference levels (OR = 2.88, 95% CI 1.47-5.64, p = 0.002). Conclusions: A majority of patients had a very negative experience of syAEs on a phase I trial. Higher grades of clinician reported AEs correlated with greater severity and interference with daily living. Future phase I studies could incorporate the PRO-CTCAE and other PRO tools which could inform the tolerability of experimental regimens and enhance the description of symptomatic AEs.

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