ONC201 is a small-molecule selective antagonist of the G protein-coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was ...conducted to determine its recommended phase II dose (RP2D).
This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information.
No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a
of 1.5 to 7.5 μg/mL (∼3.9-19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients.
ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks.
.
To evaluate the results of the randomized, double-blind, placebo-controlled phase II clinical trial of ICT-107 in patients with newly diagnosed glioblastoma.
We conducted a double-blinded randomized ...phase II trial of ICT-107 in newly diagnosed patients with glioblastoma (GBM) and tested efficacy, safety, quality of life (QoL), and immune response. HLA-A1
and/or -A2
-resected patients with residual tumor ≤1 cm
received radiotherapy and concurrent temozolomide. Following completion of radiotherapy, 124 patients, randomized 2:1, received ICT-107 autologous dendritic cells (DC) pulsed with six synthetic peptide epitopes targeting GBM tumor/stem cell-associated antigens MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2 or matching control (unpulsed DC). Patients received induction ICT-107 or control weekly × 4 followed by 12 months of adjuvant temozolomide. Maintenance vaccinations occurred at 1, 3, and 6 months and every 6 months thereafter.
ICT-107 was well tolerated, with no difference in adverse events between the treatment and control groups. The primary endpoint, median overall survival (OS), favored ICT-107 by 2.0 months in the intent-to-treat (ITT) population but was not statistically significant. Progression-free survival (PFS) in the ITT population was significantly increased in the ICT-107 cohort by 2.2 months (
= 0.011). The frequency of HLA-A2 primary tumor antigen expression was higher than that for HLA-A1 patients, and HLA-A2 patients had higher immune response (via Elispot). HLA-A2 patients achieved a meaningful therapeutic benefit with ICT-107, in both the MGMT methylated and unmethylated prespecified subgroups, whereas only HLA-A1 methylated patients had an OS benefit.
PFS was significantly improved in ICT-107-treated patients with maintenance of QoL. Patients in the HLA-A2 subgroup showed increased ICT-107 activity clinically and immunologically.
Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) ...Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.
Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.
Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.
AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.
NCT, NCT03400917 , Registered 10 January 2018.
Co-production is an umbrella term used to describe the process of generating knowledge through partnerships between researchers and those who will use or benefit from research. Multiple advantages of ...research co-production have been hypothesized, and in some cases documented, in both the academic and practice record. However, there are significant gaps in understanding how to evaluate the quality of co-production. This gap in rigorous evaluation undermines the potential of both co-production and co-producers.
This research tests the relevance and utility of a novel evaluation framework: Research Quality Plus for Co-Production (RQ + 4 Co-Pro). Following a co-production approach ourselves, our team collaborated to develop study objectives, questions, analysis, and results sharing strategies. We used a dyadic field-test design to execute RQ + 4 Co-Pro evaluations amongst 18 independently recruited subject matter experts. We used standardized reporting templates and qualitative interviews to collect data from field-test participants, and thematic assessment and deliberative dialogue for analysis. Main limitations include that field-test participation included only health research projects and health researchers and this will limit perspective included in the study, and, that our own co-production team does not include all potential perspectives that may add value to this work.
The field test surfaced strong support for the relevance and utility of RQ + 4 Co-Pro as an evaluation approach and framework. Research participants shared opportunities for fine-tuning language and criteria within the prototype version, but also, for alternative uses and users of RQ + 4 Co-Pro. All research participants suggested RQ + 4 Co-Pro offered an opportunity for improving how co-production is evaluated and advanced. This facilitated our revision and publication herein of a field-tested RQ + 4 Co-Pro Framework and Assessment Instrument.
Evaluation is necessary for understanding and improving co-production, and, for ensuring co-production delivers on its promise of better health.. RQ + 4 Co-Pro provides a practical evaluation approach and framework that we invite co-producers and stewards of co-production-including the funders, publishers, and universities who increasingly encourage socially relevant research-to study, adapt, and apply.
Preclinical animal experiments support the use of an antisense oligodeoxynucleotide directed against the insulin-like growth factor type I receptor (IGF-IR/AS ODN) as an effective potential antitumor ...agent. We performed a human pilot safety and feasibility study using an IGF-IR/AS ODN strategy in patients with malignant astrocytoma.
Autologous glioma cells collected at surgery were treated ex vivo with an IGF-IR/AS ODN, encapsulated in diffusion chambers, reimplanted in the rectus sheath within 24 hours of craniotomy, and retrieved after a 24-hour in situ incubation. Serial posttreatment assessments included clinical examination, laboratory studies, and magnetic resonance imaging scans.
Other than deep venous thrombosis noted in some patients, no other treatment-related side effects were observed. IGF-IR/AS ODN-treated cells, when retrieved and assessed, were < or = 2% intact by trypan blue exclusion, and none of the intact cells were viable in culture thereafter. Parallel Western blots disclosed IGF-IR downregulation to < or = 10% after ex vivo antisense treatment. At follow-up, clinical and radiographic improvements were observed in eight of 12 patients, including three cases of distal recurrence with unexpected spontaneous or postsurgical regression at either the primary or the distant intracranial site.
Ex vivo IGF-IR/AS ODN treatment of autologous glioma cells induces apoptosis and a host response in vivo without unusual side effects. Subsequent transient and sustained radiographic and clinical improvements warrant further clinical investigations.
Research co-production is an umbrella term used to describe research users and researchers working together to generate knowledge. Research co-production is used to create knowledge that is relevant ...to current challenges and to increase uptake of that knowledge into practice, programs, products, and/or policy. Yet, rigorous theories and methods to assess the quality of co-production are limited. Here we describe a framework for assessing the quality of research co-production-Research Quality Plus for Co-Production (RQ+ 4 Co-Pro)-and outline our field test of this approach.
Using a co-production approach, we aim to field test the relevance and utility of the RQ+ 4 Co-Pro framework. To do so, we will recruit participants who have led research co-production projects from the international Integrated Knowledge Translation Research Network. We aim to sample 16 to 20 co-production project leads, assign these participants to dyadic groups (8 to 10 dyads), train each participant in the RQ+ 4 Co-Pro framework using deliberative workshops and oversee a simulation assessment exercise using RQ+ 4 Co-Pro within dyadic groups. To study this experience, we use a qualitative design to collect participant demographic information and project demographic information and will use in-depth semi-structured interviews to collect data related to the experience each participant has using the RQ+ 4 Co-Pro framework.
This study will yield knowledge about a new way to assess research co-production. Specifically, it will address the relevance and utility of using RQ+ 4 Co-Pro, a framework that includes context as an inseparable component of research, identifies dimensions of quality matched to the aims of co-production, and applies a systematic and transferable evaluative method for reaching conclusions. This is a needed area of innovation for research co-production to reach its full potential. The findings may benefit co-producers interested in understanding the quality of their work, but also other stewards of research co-production. Accordingly, we undertake this study as a co-production team representing multiple perspectives from across the research enterprise, such as funders, journal editors, university administrators, and government and health organization leaders.
Research-based assessments represent a valuable tool for both instructors and researchers interested in improving undergraduate physics education. However, the historical model for disseminating and ...propagating conceptual and attitudinal assessments developed by the physics education research (PER) community has not resulted in widespread adoption of these assessments within the broader community of physics instructors. Within this historical model, assessment developers create high quality, validated assessments, make them available for a wide range of instructors to use, and provide minimal (if any) support to assist with administration or analysis of the results. Here, we present and discuss an alternative model for assessment dissemination, which is characterized by centralized data collection and analysis. This model provides a greater degree of support for both researchers and instructors in order to more explicitly support adoption of research-based assessments. Specifically, we describe our experiences developing a centralized, automated system for an attitudinal assessment we previously created to examine students' epistemologies and expectations about experimental physics. This system provides a proof of concept that we use to discuss the advantages associated with centralized administration and data collection for research-based assessments in PER. We also discuss the challenges that we encountered while developing, maintaining, and automating this system. Ultimately, we argue that centralized administration and data collection for standardized assessments is a viable and potentially advantageous alternative to the default model characterized by decentralized administration and analysis. Moreover, with the help of online administration and automation, this model can support the long-term sustainability of centralized assessment systems.
Verubulin (MPC-6827) is a microtubule-destabilizing agent that achieves high concentrations in the brain. Verubulin disrupts newly formed blood vessels in xenografts. We determined the safety and ...tolerability of verubulin administered in combination with carboplatin in patients with relapsed glioblastoma multiforme (GBM). Three pre-selected doses of verubulin were tested: 2.1, 2.7, and 3.3 mg/m
2
in a standard “3+3” design. Verubulin was given every second week of a 6-week cycle in the 2.1 mg/m
2
cohort or weekly for 3 weeks of a 4-week cycle in subsequent cohorts. Carboplatin was administered intravenously at an area under the curve (AUC) dosage 4 every 2 weeks for the 2.1 mg/m
2
cohort or on day 1 of each 4-week cycle in subsequent cohorts. Nineteen patients with GBM in first or second relapse were enrolled. Four patients (21 %) experienced a grade 3 or greater verubulin- or carboplatin-related adverse event, including hypesthesia, cerebral ischemia, anemia, and thrombocytopenia. The mean plasma half life of verubulin was 3.2 h (SD = 0.82). Two patients achieved at least a partial response by Macdonald criteria. One of these patients remains progression free and off treatment more than 24 months beyond his initiation of verubulin. Five patients had stable disease. Median progression-free survival (PFS) across all patients was 8 weeks, and the 6-month PFS rate was 21 %. The combination of verubulin at the previously determined single-agent maximum tolerated dose of 3.3 mg/m
2
with carboplatin in patients with recurrent/refractory GBM is safe and well tolerated. In this patient population with a highly vascularized tumor, no cerebral hemorrhage was observed.
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