The introduction of targeted therapies to the field of oncology has prolonged the survival in several tumor types. Despite extensive research and numerous trials, similar outcomes have unfortunately not been realized for glioblastoma. For more than 15 years, the standard treatment of glioblastoma has been unchanged. This review walks through the elements that have challenged the success of previous trials and highlight some future promises. Concurrently, this review describes how institutions, through a multimodal and comprehensive strategy with four essential components, may increase the probability of finding a meaningful role for targeted therapies in the treatment of glioblastoma. These components are (1) prudent trial designs, (2) considered drug and target selection, (3) harnessed real-world clinical and molecular evidence, and (4) incorporation of translational research.
INTRODUCTION The survival in glioblastoma has been unchanged since 2005. The introduction of targeted treatments, which have improved survival in several cancers has yet to influence the treatment of glioblastoma. In Gliotarget, we will individualize the targeted treatment, and give it in the primary setting alongside standard therapy with the intention to improve the likelihood of effect. METHODS Gliotarget is a biomarker enriched phase I/II platform trial with initially 4 predefined biomarker selected arms, one miscellaneous biomarker arm and one control arm. All patients receive standard therapy with concomitant radiochemotherapy and adjuvant Temozolomide. The experimental treatment is given alongside the adjuvant Temozolomide. Molecular analysis, including Whole Genome Sequencing, is performed on all patients, to identify actionable biomarkers. The miscellaneous arm gathers patients with not previously defined biomarkers upon which the weekly molecular tumor board decides to treat. Gliotarget includes newly diagnosed IDH-wt glioblastoma patients. In addition, to exclude the patients where the inherent poor prognosis might conceal the drug efficacy, the patients must have a 50% probability of being alive 12 months after initial surgery, according to a prognostic model developed in our institution. The sample size is calculated with Simon’s two-stage design using treatment effect at 9-months progression free survival (PFS9). We anticipate 9 patients for stage one and 24 in total, for each arm. Treatment effect is defined as 65% of the patients in an experimental arm reaching PFS9. For the survival analysis, supplementing the control arm data with leveraged external controls taken from our prospectively registered database will decrease the probability of false positive results. CONCLUSION Gliotarget complements the field of ongoing platform trials with its distinctive trial design. The chosen biomarkers and treatments will be presented at the annual meeting. Enrollment is set to open in Q4 2021.
Introduction: Glioblastoma (GBM) is an aggressive brain cancer with a median overall survival of 16-24 months. Evaluation of treatment effect can be difficult as pseudo progression is seen in approximately 15% of patients. Hence, effective treatment can be stopped prematurely and no approved or standard second line treatment exist. Genomic alterations during treatment can cause treatment resistance and treatment failure. In order to investigate the genomic alterations, consecutive tissue samples are wanted. However, this is often not possible due to risk doing surgery. Therefore, liquid biopsies from plasma, containing circulating cell-free DNA (cfDNA) and circulating cell-free tumor DNA (ctDNA) might be an alternative. Based on findings by our group, we aim to improve treatment evaluation and suggest targeted treatment possibilities by investigating the role of cfDNA and ctDNA in a large prospective cohort, included from a neurooncological out-patient clinic. Materials and Methods: Newly diagnosed patients with GBM, a performance status of 0-1 and planned for concurrent chemo/radiation will be eligible. Whole genome sequencing (WGS) will be done on tissue. Peripheral blood will be collected in cell stabilizing Blood Collection Tubes (STRECK) and cfDNA quantified on a Qubit Fluorometer. Samples will be collected before the concurrent treatment and at fixed time points until progression with a total of 8-10 samples per patient. For the ctDNA analyses, a patient specific tumor mutation will be selected based upon WGS from tumor tissue. The identified mutation will be quantified in plasma (ctDNA) by droplet digital PCR (ddPCR). Dual labeled fluorescent probes for the mutation and the wild type loci will be used and PCR reaction mixtures will be run. Mutant allele fractions (AFs) ≥0.001 (0.1%) will be detected. An increase in ctDNA AF will be recorded if the AF increases from non-detectable to detectable levels (AF ≥ 0.001) or increases in two consecutive samples. Results: Inclusion began in June 2022 and by time of abstract deadline, we have 27 patients included. Of these, 16 have completed the concurrent setting with a total of five samples per patient. One patient has died and two have progressed. Hence, 24 patients are still on-treatment and sampling and accrual will continue. The first analyses for cfDNA will be run in the winter of 2022/2023 and results will be presented at the conference. CtDNA analyses are planned for autumn 2023. Expected Impact: The expected impacts of this study are specifically in two clinical areas: treatment evaluation and development of new treatment strategies. We aim to 1) find correlation between cfDNA/ctDNA and the clinical course2) detect a relapse earlier than imaging with MRI and FET/PET analyses3) aid to diagnose pseudo progression4) use ctDNA for detection of clonal selection5) test concordance between mutations detected in tissue and in plasma Citation Format: Dorte Schou Nørøxe, Lise Barlebo Ahlborn, Vincent Fougner, Thomas Urup, Benedikte Hasselbalch, Christina Westmose Yde, Hans Skovgaard Poulsen, Ulrik Lassen. Tracking tumor mutations in ctDNA through repetitive plasma samples in patients with newly diagnosed brain cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1046.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.