Search

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore

This is a single arm, open label perioperative trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with safusidenib following biopsy, and prior to surgical resection in patients with IDH1 mutated glioma who have not received radiation therapy or chemotherapy. Fifteen participants will receive treatment in two parts. First, biopsy followed by one cycle (28 days) of safusidenib, an orally available, small molecular inhibitor of mutated IDH1, then maximal safe resection of the tumor (Part A). Second, after recovery from surgery, safusidenib until disease progression or unacceptable toxicity (Part B). This research will enable objective measurement of biological activity of safusidenib in patients with IDH1 mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention. Clinical Trial Registration:NCT05577416 (ClinicalTrials.gov) Plain Language Summary Adult low-grade gliomas (aLGG) are primary brain cancers, defined by mutations in IDH1 or IDH2. When the IDH gene becomes abnormal (mutated), production of a metabolite that causes cancer cells to grow is increased. These tumors grow slowly but invade the normal functioning brain, making them nearly impossible to cure. The current standard of care treatment includes surgery, followed by radiation therapy and chemotherapy, the timing of which depends on the risk of cancer regrowth. Some patients may be suitable for monitoring with MRI scans alone, however recurrences will inevitably occur. Recently developed targeted mutant IDH inhibitors for aLGG patients may be beneficial both at diagnosis and recurrence. Notably, early treatment prior to radiation therapy and chemotherapy delays growth of aLGG and the need for subsequent radiation therapy and chemotherapy. Nevertheless, most patients will eventually suffer further tumor growth and the optimal timing and sequencing of these therapies remains an area of active research. This research investigates the mutant IDH1 inhibitor safusidenib. The researchers are conducting an innovative clinical trial where patients with aLGG, who have not received radiation therapy or chemotherapy, are treated with safusidenib following a biopsy and prior to surgical removal of their tumor. In this study they investigate whether this trial design is safe and feasible, and how safusidenib works; with the goal to better understand the optimal use of IDH inhibitors for patients with aLGG. Article highlights Introduction Background & rationale Adult low-grade gliomas (aLGGs) are defined by IDH1/2 mutations which lead to accumulation of 2-HG, an oncometabolite affecting tumorigenesis. 2-HG inhibits α-KG-dependent enzymes, affecting epigenetic regulation, collagen synthesis and cell signaling, hindering progenitor cell differentiation and promoting cancer. In addition, 2-HG promotes angiogenesis, an immunosuppressive tumor microenvironment and oxidative damage. aLGGs grow slowly, diffusely infiltrating the brain and are difficult to cure. Emergence of targeted mutant IDH inhibitors has shifted focus toward identifying prognostic markers and future combination studies. Current treatment of aLGG Treatment includes maximal safe surgical resection, radiation therapy and sequential chemotherapy. Early, extensive surgery improves overall survival. Active surveillance with MRI is suitable for some patients to delay side effects. Mutant IDH inhibitors for glioma Multiple mutant IDH inhibitors have shown promise in glioma. Vorasidenib (IDH1/2 inhibitor) improved progression-free survival in the INDIGO Phase III trial. Safusidenib (DS-1001b, AB-218) is an orally available small molecule inhibitor of mutant IDH1 with demonstrated brain penetration and clinical activity in Phase I trials. Perioperative trials There have been few therapeutic advances in glioma due to challenges in measuring drug penetration and pharmacodynamic (PD) evaluation. Perioperative trials, including biopsy to obtain pre-treatment tissue, are feasible and offer a means to examine the direct effects of new drugs. These studies allow evaluation of drug pharmacokinetics (PK) and PD outcomes. Objectives Hypothesis: Treatment with safusidenib following biopsy and prior to resection in newly diagnosed IDH1 mutated glioma is feasible. Estimate: >60% of screened patients completing planned investigations and procedures. Primary objective: Assess feasibility and acceptability of a perioperative study in IDH1 mutated aLGG patients. Secondary end points: Determine safusidenib toxicity, safety of two-stage surgery and biological activity by changes in 2-HG levels. Methods Participants, interventions, & outcomes Key inclusion: Adults ≥18 years with aLGG diagnosis not requiring urgent resection. Key exclusion: prior chemotherapy/radiation, cerebellar/brainstem tumors. Procedures: Open biopsy, oral safusidenib, second-stage resection, continued safusidenib post-resection. Data collection: tumor tissue, CSF and blood samples processed per protocols. PK/PD relationships: Evaluated by blood, tumor and CSF samples. Biological activity: Assessed by changes in 2-HG levels and IDH1 ctDNA. Data collection, management, & analysis Tumor tissue, CSF and blood samples collected for research. Safusidenib PK will be investigated to evaluate PK/PD relationships. Translational end points include paired whole-genome transcriptome profiling, single nuclei RNA sequencing, bulk metabolomics and DNA methylation. Spatial transcriptomics using in situ digital sequencing and spatial metabolomics on sections pre- and post-safusidenib treatment. Descriptive statistics for demographics, safety, PK, PD, efficacy and biomarker data by dose and time. Monitoring Toxicity: Monitored by adverse events, clinical tests and vital signs. Safety of surgery: 30-day morbidity and mortality recorded post-biopsy and resection. Radiological response: Determined by MRI changes and LGG-RANO criteria. Progression-free survival and time to treatment failure: Calculated from biopsy date. Conclusion Perioperative studies in aLGG offer a unique opportunity to study drug effects and are feasible, ethical and acceptable to patients. [ABSTRACT FROM AUTHOR]

Background: Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian‐Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade. Methods: This cross‐sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics. Results: Over the 10‐year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10‐year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination. Conclusions: There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is a complex disease comprising discrete histological and molecular subtypes, for which survival rates remain unacceptably low. Tailored approaches for this deadly heterogeneous disease are urgently needed. Efflux pumps belonging to the ATP‐binding cassette (ABC) family of transporters are known for roles in both drug resistance and cancer biology and are also highly targetable. Here we have investigated the association of ABCC4/MRP4 expression to clinical outcome and its biological function in endometrioid and serous tumors, common histological subtypes of EOC. We found high expression of ABCC4/MRP4, previously shown to be directly regulated by c‐Myc/N‐Myc, was associated with poor prognosis in endometrioid EOC (P =.001) as well as in a subset of serous EOC with a "high‐MYCN" profile (C5/proliferative; P =.019). Transient siRNA‐mediated suppression of MRP4 in EOC cells led to reduced growth, migration and invasion, with the effects being most pronounced in endometrioid and C5‐like serous cells compared to non‐C5 serous EOC cells. Sustained knockdown of MRP4 also sensitized endometrioid cells to MRP4 substrate drugs. Furthermore, suppression of MRP4 decreased the growth of patient‐derived EOC cells in vivo. Together, our findings provide the first evidence that MRP4 plays an important role in the biology of Myc‐associated ovarian tumors and highlight this transporter as a potential therapeutic target for EOC. What's new? Epithelial ovarian cancer (EOC) generally has an extremely poor prognosis, and new therapies are urgently needed. In this study, the authors examined a multidrug‐resistance efflux pump called MRP4, which is regulated by the Myc oncogene. They found that increased expression of MRP4 was associated with poor prognosis, and that siRNA‐mediated knockdown of MRP4 led to decreased growth, migration, and invasion of EOC cells in vitro and tumors in vivo. These results suggest that MRP4 may provide a valuable therapeutic target for certain EOC tumors. [ABSTRACT FROM AUTHOR]

Background: Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian-Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade., Methods: This cross-sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics., Results: Over the 10-year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10-year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination., Conclusions: There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies., (© 2024 John Wiley & Sons Australia, Ltd.)