Oncology Drug Research Articles

Pediatric oncology drug development and dosage optimization.

Oncology drug discovery and development has always been an area facing many challenges. Phase 1 oncology studies are typically small, open-label, sequential studies enrolling a small sample of adult patients (i.e., 3-6 patients/cohort) in dose escalation. Pediatric evaluations typically lag behind the adult development program. The pediatric starting dose is traditionally referenced on the recommended phase 2 dose in adults with the incorporation of body size scaling. The size of the study is also small and dependent upon the prevalence of the disease in the pediatric population. Similar to adult development, the dose is escalated or de-escalated until reaching the maximum tolerated dose (MTD) that also provides desired biological activities or efficacy. The escalation steps and identification of MTD are often rule-based and do not incorporate all the available information, such as pharmacokinetic (PK), pharmacodynamic (PD), tolerability and efficacy data. Therefore, it is doubtful if the MTD approach is optimal to determine the dosage. Hence, it is important to evaluate whether there is an optimal dosage below the MTD, especially considering the emerging complexity of combination therapies and the long-term tolerability and safety of the treatments. Identification of an optimal dosage is also vital not only for adult patients but for pediatric populations as well. Dosage-finding is much more challenging for pediatric populations due to the limited patient population and differences among the pediatric age range in terms of maturation and ontogeny that could impact PK. Many sponsors defer the pediatric strategy as they are often perplexed by the challenges presented by pediatric oncology drug development (model of action relevancy to pediatric population, budget, timeline and regulatory requirements). This leads to a limited number of approved drugs for pediatric oncology patients. This review article provides the current regulatory landscape, incentives and how they impact pediatric drug discovery and development. We also consider different pediatric cancers and potential clinical trial challenges/opportunities when designing pediatric clinical trials. An outline of how quantitative methods such as pharmacometrics/modelling & simulation can support the dosage-finding and justification is also included. Finally, we provide some reflections that we consider helpful to accelerate pediatric drug discovery and development.

De novo drug design through artificial intelligence: an introduction

Developing new drugs is a complex and formidable challenge, intensified by rapidly evolving global health needs. De novo drug design is a promising strategy to accelerate and refine this process. The recent introduction of Generative Artificial Intelligence (AI) algorithms has brought new attention to the field and catalyzed a paradigm shift, allowing rapid and semi-automatic design and optimization of drug-like molecules. This review explores the impact of de novo drug design, highlighting both traditional methodologies and the recently introduced generative algorithms, as well as the promising development of Active Learning (AL). It places special emphasis on their application in oncological drug development, where the need for novel therapeutic agents is urgent. The potential integration of these AI technologies with established computational and experimental methods heralds a new era in the rapid development of innovative drugs. Despite the promising developments and notable successes, these technologies are not without limitations, which require careful consideration and further advancement. This review, intended for professionals across related disciplines, provides a comprehensive introduction to AI-driven de novo drug design of small organic molecules. It aims to offer a clear understanding of the current state and future prospects of these innovative techniques in drug discovery.

The genetic and immune features of salivary gland secretory carcinoma with high-grade transformation.

To compare the clinicopathological, molecular, and immune features of conventional and high-grade transformation (HGT) secretory carcinoma (SC) in salivary glands. The clinicopathological data of 88 cases including 74 conventional SCs and 14 SCs with HGT were reviewed. Targeted next-generation sequencing was performed in 11 SCs with HGT and 7 conventional SCs. The level of PD-L1 and CD8+ TILs was determined by immunohistochemistry. Compared with the conventional group, the rates of nodal metastasis, local recurrence, distant metastasis and mortality were significantly higher in the HGT cohort. Mutations of ARID1A/B, KMT2A, HOXD13, NRG1 and ETV6 genes were identified in HGT SCs. A recurrent E307G mutation in GATA6 gene was also observed in two cases. Two deceased HGT patients with distant metastasis harboured NOTCH3 mutations. ETV6-RET translocation was prone to occur in the HGT SCs. Additionally, PD-L1 expression was low, and CD8+ TILs were sparse in most HGT cases. Our findings reveal novel gene alterations involved in the progression of HGT in SCs. Most HGT SCs patients cannot benefit from PD-L1 blocking and may be approached with a distinct treatment strategy including the lymph node dissection and application of molecular target drugs in precision oncology.

Detection of Genomic Structural Variations Associated with Drug Sensitivity and Resistance in Acute Leukemia.

Acute leukemia is a particularly problematic collection of hematological cancers, and, while somewhat rare, the survival rate of patients is typically abysmal without bone marrow transplantation. Furthermore, traditional chemotherapies used as standard-of-care for patients cause significant side effects. Understanding the evolution of leukemia to identify novel targets and, therefore, drug treatment regimens is a significant medical need. Genomic rearrangements and other structural variations (SVs) have long been known to be causative and pathogenic in multiple types of cancer, including leukemia. These SVs may be involved in cancer initiation, progression, clonal evolution, and drug resistance, and a better understanding of SVs from individual patients may help guide therapeutic options. Here, we show the utilization of optical genome mapping (OGM) to detect known and novel SVs in the samples of patients with leukemia. Importantly, this technology provides an unprecedented level of granularity and quantitation unavailable to other current techniques and allows for the unbiased detection of novel SVs, which may be relevant to disease pathogenesis and/or drug resistance. Coupled with the chemosensitivities of these samples to FDA-approved oncology drugs, we show how an impartial integrative analysis of these diverse datasets can be used to associate the detected genomic rearrangements with multiple drug sensitivity profiles. Indeed, an insertion in the gene MUSK is shown to be associated with increased sensitivity to the clinically relevant agent Idarubicin, while partial tandem duplication events in the KMT2A gene are related to the efficacy of another frontline treatment, Cytarabine.

Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen.

Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor, which is approved as monotherapy for relapsed follicular lymphoma in adult patients who have received at least two systemic therapies. In an April 2022 US Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC), the benefit-risk profile of the class PI3K inhibitors were scrutinized for use in hematological malignancies. Specifically, their unique toxicities may contribute to the high incidences in reported serious and high-grade treatment emergent adverse events (TEAEs), thereby reducing their overall tolerability and potentially limiting their successful use. These tolerability concerns may be contributed by or compounded by inadequate dose optimization. The recommended dosing regimen of copanlisib 60 mg administered on days 1, 8, and 15 of a 28-day cycle was selected as the maximal tolerated dose (MTD) during phase I. Thus, this analysis sought to justify the copanlisib dose regimen selection. Copanlisib exposure-efficacy relationships were considered from its large phase III trial, CHRONOS-3, whereas copanlisib safety was investigated by pooling data across its two large clinical trials to comprehensively assess its exposure-safety relationships. Results demonstrated a statistically significant positive linear exposure-efficacy relationship at the MTD. Exposure-safety analyses revealed a borderline significant linear relationship for grade ≥3 TEAEs and no significant exposure-safety relationships for other investigated safety end points. The model-based benefit/risk framework considered the established exposure-response models and defined clinical utility function which confirmed the appropriateness of the copanlisib dosing regimen across the range of its achieved exposures.

Polydopamine-Based Resveratrol-Hyaluronidase Nanomedicine Inhibited Pancreatic Cancer Cell Invasive Phenotype in Hyaluronic Acid Enrichment Tumor Sphere Model.

The dense storm microenvironment formed by an excessively cross-linked extracellular matrix, such as hyaluronic acid and collagens, serves as a major barrier that prevents drugs from reaching the deeper tumor. Current traditional two-dimensional (2D) cultures are not capable of modeling this drug delivery barrier in vitro. Thus, tumor spheroids have become increasingly important in cancer research due to their three-dimensional structure. Currently, various methods have been developed to construct tumor spheroids. However, there are still challenges, such as lengthy construction time, complex composition of added growth factors, and high cultivation costs. To address this technical bottleneck, our study combined the GelMA hydrogel system to develop a rapid and high-yield method for tumor spheroids generation. Additionally, we proposed an evaluation scheme to assess the effects of drugs on tumor spheroids. Building on the hyaluronic acid-rich pathological tumor microenvironment, we constructed a resveratrol-loaded nano-drug delivery system with tumor stroma modulation capability and used a three-dimensional (3D) tumor sphere model to simulate in vivo tumor conditions. This process was utilized to completely evaluate the ability of the nano-drug delivery system to enhance the deep penetration of resveratrol in the tumor microenvironment, providing new insights into future oncology drug screening, efficacy assessment, and drug delivery methods.

Validation of overall survival extrapolations made by TLV in the assessment of cost-effectiveness of oncology drugs in Sweden – A pilot study comparing extrapolated and observed life-years gained

Aim The aim of the study is to assess the accuracy of overall survival (OS) extrapolations in cost-effectiveness analysis made by the Dental and Pharmaceutical Benefits Agency (TLV) to decide on the reimbursement and use of oncology drugs in Sweden. Material and methods TLV appraisals for oncology drugs were identified during a 5-year period (2013-2017). To be included each appraisal and health economic model must include a TLV base case extrapolation of OS. Further, Kaplan-Meier (KM) estimates on OS from the original and follow-up clinical trials must be available. Potential follow-up trials on OS were identified in ClinicalTrials.gov and the Lund University Libraries databases, and in the Swedish Medical Products Agency (MPA) and the European Medicines Agency (EMA) databases. In cases where the KM estimates were not available, data points from figures published in TLV’s appraisals were extracted using the semi-automated tools Digitizelt and WebPlotDigitizer. The accuracy of survival extrapolations was assessed by comparing extrapolated and observed life-years (LYs), using three different measures: 1) difference in LYs between the treatment and control group; 2) LYs in the treatment group, 3) LYs in the control group. Results We study TLV’s preferred OS extrapolations and show that on average they overestimate the observed mean gain in LYs by 24%, and underestimate observed LYs by 3% and 11% in the treatment and control group, respectively. Conclusions We conclude that it is feasible to validate OS extrapolations by comparing extrapolated and observed life-years. Even if survival extrapolations are reasonably accurate for the treatment group, this may still imply that extrapolations of LYs gained deviates to a larger extent. Follow-up studies on OS should be carried out to an increased extent to be able to validate, update and improve OS extrapolations in cost-effectiveness analysis of oncology drugs.

DODII: Bayesian Dose Optimization Design for Randomized Phase II Trials

The traditional MTD-based dose selection paradigm commonly used for cytotoxic chemotherapies might not be optimal for targeted therapies because a higher dose does not necessarily result in improved anti-cancer activity. With the initiation of “Project Optimus” at the FDA, a randomized dose optimization study at the early stage of drug development has become necessary for oncology drug development. We propose a Bayesian Dose Optimization Design for Randomized Phase II trials (DODII) that integrates Bayesian continuous monitoring and Bayesian pick-the-winner approach in a randomized design, where efficacy and toxicity endpoints are jointly used to inform the dose selection. The adaptive feature of the DODII design will terminate a suboptimal dose at an interim analysis under two circumstances: (a) when efficacy or safety data is unpromising, (b) when the other dose option is clearly better. The critical values of the decision rule for the DODII design can be enumerated prior to the initiation of the clinical study, which makes it practically easy to implement. Through simulation studies, we showed that the DODII design has favorable operating characteristics with controlled selection error, higher power to select the optimal dose option, and reduced total sample size as compared to the other commonly used methods.

Single-cell genomics analysis reveals complex genetic interactions in an in vivo model of acquired BRAF inhibitor resistance.

The evolution of therapeutic resistance is a major obstacle to the success of targeted oncology drugs. While both inter- and intratumoral heterogeneity limit our ability to detect resistant subpopulations that pre-exist or emerge during treatment, our ability to analyze tumors with single-cell resolution is limited. Here, we utilized a cell-based transposon mutagenesis method to identify mechanisms of BRAF inhibitor resistance in a model of cutaneous melanoma. This screen identified overexpression of NEDD4L and VGLL3 as significant drivers of BRAF inhibitor resistance in vivo. In addition, we describe a novel single-cell genomics profiling method to genotype thousands of individual cells within tumors driven by transposon mutagenesis. This approach revealed a surprising genetic diversity among xenograft tumors and identified recurrent co-occurring mutations that emerge within distinct tumor subclones. Taken together, these observations reveal an unappreciated genetic complexity that drives BRAF inhibitor resistance.

Statistical classification of treatment responses in mouse clinical trials for stratified medicine in oncology drug discovery

Translational oncology research strives to explore a new aspect: identifying subgroups that exhibit treatment response even during pre-clinical phases. In this study, we focus on PDX models and their implementation in mouse clinical trials (MCT). Our primary objective was to identify subgroups with different treatment responses using Latent Class Mixed Model (LCMM).We used a public dataset and focused on one treatment, encorafenib, and two indications, melanoma and colorectal cancer, for which efficacy depends on a specific mutation BRAF V600E. One LCMM per indication was implemented to classify treatment responses at the PDX level, analyzing the growth kinetics of treated tumors and matched controls within the PDX models. A simulation study was carried out to explore the performance of LCMM in this context. For both applications, LCMM identified classes for which the higher the proportion of mutated BRAF V600E PDX models the greater the treatment effect, which is aligned with encorafenib use recommendations. The simulation study showed that LCMM could identify classes with large differences in treatment effects. LCMM is a suitable tool for MCT to explore treatment response subgroups of PDX. Once these subgroups are defined, characterization of their phenotypes/genotypes could be performed to explore treatment response predictors.

US FDA's Dose Optimization Postmarketing Requirements and Commitments of Oncology Approvals and the Impact on Product Labels from 2010 to 2022: An Emerging Landscape from Traditional to Novel Therapies.

Dose optimization is a focal point of many US Food and Drug Administration (FDA) drug approvals. We sought to understand the impact of the FDA's Postmarketing Commitments/Postmarketing Requirements (PMCs/PMRs) on dose optimization and prescriber labeling for oncology drugs. Publicly available information was aggregated for all FDA oncology drug approvals between January 1, 2010, and December 31, 2022. Study completion dates were compared to product labeling before and after PMC/PMR fulfillment dates to evaluate labeling changes associated with dose-related PMCs/PMRs. Data were analyzed individually (2010-2015 and 2016-2022) due to differences in available information. From 2010 to 2015, 14 of 42 (33.3%) new molecular entities (NMEs) had dose-related PMCs/PMRs, with 6 of 14 (42.9%) resulting in a relevant label change. From 2016 to 2022, of the 314 new or supplemental applications approved, 21 had dose-related PMCs/PMRs (6.7%), which trended upward over time; 71.4% of dose-related PMCs/PMRs were NMEs. Kinase inhibitors (KIs) and antibody/peptide drug conjugates (ADCs/PDCs) were the most affected drug classes. Ten of the 21 approvals with dose-related PMCs/PMRs fulfilled their dosing PMCs/PMRs, and 3 of the 10 (30%) had relevant label changes. Most dose-related PMRs/PMCs were issued for NMEs. Of these, KIs and ADCs/PDCs were highly represented, reflecting their novelty and greater uncertainty around their safety profile. PMC/PMR issuance broadly increased over time. With the implementation of the FDA's Project Optimus in 2021, it remains to be seen whether fewer dose-related PMCs/PMRs emerge in future due to enhanced dose optimization in the premarketing setting.

Galenic Laboratory: State of the Art-A Scientific and Technological Discipline, Innovation and Management

The term galenic imply a scientific and technical matter but also an art. Related the hospital practice the future of pharmacy pass though the innovation of the galenic lab. Observing the today hospital practice HP in many countries and the international literature involved it is clear how clinical pharmacy is linked to the galenic lab practice LP. Today more than recent past due to the various kinds of magistral formula requested by the clinicians It is necessary that the clinical pharmacist CP perspective must to be added to the classic galenic lab competencies: this make possible to complete the profile of efficacy and safety of this fundamental and crucial Drugs like the magistral formula and officinal and their use. Aim of this ancient discipline and art is today to provide efficacy and safe drugs for the need of single patient when it is not possible to use the industrial product. The clinical galenic activity can be divided into sterile and non-sterile. (Total parenteral nutrition TPN bags, Pain therapy, oncological parenteral drugs lab UFA, radio drugs and diagnostics and non-sterile galenics).Aim of this work is to deeply investigate this relevant link (Clinical Pharmacy CP with Lab Practice LP) in order to get the really best clinical results for the patients and healthcare org need. Clinical pharmacy CP principle, Pharmaceutical care PC, the managerial competencies and personalized pharmacy added to the best knowledge and competencies in the galenic lab. Make the difference in order to obtain the right final clinical results. The same in this work are submitted to the international pharmacy practitioner, directors, researcher or students the Normative rules operating in an advanced country like Italy: the simplified NBP (NORME DI BUONA PREPARAZIONE), example that can be applied also in the non-advanced nations. In Italy pharmacist can follow or the full NBP (NORME DI BUONA PREPARAZIONE) rules of the official pharmacopeia or the simplified according DM Salute 18.nov.2003. (Related the kind of galenic formula prepared if sterile or not). The NBP (NORME DI BUONA PREPARAZIONE) (good manufacturing rules) introduce a QUALITY CQ SYSTEM MANAGEMENT. The full NBP (NORME DI BUONA PREPARAZIONE) are more used in more complex labs in ex. involved in specialist products (Like oncologic or radio drugs, sterile colliria and other). These rules guarantee the quality, security and the efficacy of a drug prepared in galenic lab. These are based on the responsibility principles, plan, and documentation of all activity. (QUALITY SYSTEM OF INSURANCE CQ). All the phases of the preparation are under the responsibility of the pharmacist. The final quality of the products depends on the correct use of API and excipients, on the right calculations operation, right volume measure or weight operation and the Check on the final products: -following of the procedure, aspects, pakaging and closing system and other request by ITALIAN FU related the specific pharmaceutical form. According NBP (NORME DI BUONA PREPARAZIONE) the lab. Must to be separated (or it must to be separable) form the rest of pharmacy and a second pharmacist (that is different form the pharmacist that prepare) must to check the final preparation. The locals must to be according strictly environmental condition required normative rules by to make possible to prepare in safety way drugs. And it is mandatory to follow the written procedure: instrument verify, training of the pharmacists Cleaning procedure, significations. For Raw materials: it is needed to have certifications, technical sheet, safety sheet, data of the first use, expiry data Working sheet is mandatory to testify the operations. The pharmacist can follow this 2 option related the kind of drugs produced and the characteristic of the lab. It is not the main focus of this work to produce a literal translation of the DM 18/nov /2003 only to submit its general meanings. This can be considered for the authors useful to be added also to the normative rules in force in other non-advanced countries. In order to make more interesting this book some useful concepts of physiology of the stomach and GI tract are reported. The same relevant pharmaceutical concepts and technique with a focus on the capsules CPS as pharmaceutical form (gastro resistance, delayed release), some oral suspension, gels and other few preparation. This work is produced whit a non-conventional approach: it is not a book of pharmaceutical technique. Innovation and management of the system make possible to increase the power of the galenic laboratories In the hospital or in private pharmacy. This work is produced only for international purpose.

The Backfill i3+3 Design for Dose-Finding Trials in Oncology

We consider a formal statistical design that allows simultaneous enrollment of a main cohort and a backfill cohort of patients in a dose-finding trial. The goal is to accumulate more information at various doses to facilitate dose optimization. The proposed design, called Bi3+3, combines the simple dose-escalation algorithm in the i3+3 design and a model-based inference under the framework of probability of decisions (POD), both previously published. As a result, Bi3+3 provides a simple algorithm for backfilling patients to lower doses in a dose-finding trial once these doses exhibit safety profile in patients. The POD framework allows dosing decisions to be made when some backfill patients are still being followed with incomplete toxicity outcomes, thereby potentially expediting the clinical trial. At the end of the trial, Bi3+3 uses both toxicity and efficacy outcomes to estimate an optimal biological dose (OBD). The proposed inference is based on a dose-response model that takes into account either a monotone or plateau dose-efficacy relationship, which are frequently encountered in modern oncology drug development. Simulation studies show promising operating characteristics of the Bi3+3 design in comparison to existing designs.

Global Statistics and Data Sciences (GSDS), BeiGene USA, Fulton, MD

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

Global Statistics and Data Sciences (GSDS), BeiGene USA, Fulton, MD

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail.

Humanized mouse models for anti-cancer therapy.

Patient-derived xenograft (PDX) models are the golden standard for preclinical oncology as they can recapitulate the genotypic and phenotypic complexity of human tumors, thus enabling the development of effective therapeutic strategies. PDX models are typically established in immunocompromised animals that allow efficient growth of the xenografted tumor. Given the recent success of immune therapies in different tumors however, the establishment of humanized PDX models is critical to evaluate immune oncology drugs and/or combinations thereof. Here, we describe the detailed methods to obtain humanized PDX models for anti-cancer therapy testing.

고가 의약품 건강보험 급여 현황 분석

In recent years, the introduction of high-priced innovative pharmaceuticals has been on the rise, placing a burden on the national pharmaceutical expenditure. This study aimed to analyze the spending trends of high-priced drugs in South Korea over the past ten years and derive policy implications for the management of pharmaceutical expenditure. The claims data of National Health Insurance (NHI) were used as the data source, and drugs with annual per-patient costs exceeding ten million KRW were defined as 'high-priced drugs.' The study selected the each year’s list of high-priced drugs from 2010 to 2021 and analyzed the trends considering their spending size, manufacturer types, therapeutic groups, Risk-Sharing Agreements, and Economic Evaluation Exemption. The spending on high-priced drugs accounted for 8.0% of the NHI pharmaceutical expenditure in 2021, and it has been increasing annually by 14.3% since 2010. The expenditure on high-priced drugs introduced through the RSA (Risk-Sharing Agreement) rapidly increased, especially for oncology drugs and immunosuppressants. This study defined high-priced drugs based on per-patient costs and observed the trends in the expenditure of these drugs according to pharmaceutical characteristics. Based on this, it is significant in proposing issues and policy implications for noteworthy drug categories.

In Ukrainian

The purpose of the review is to find, generalize and analyze scientific data related to the specifics of the interaction of chemotherapeutic official drugs and nanocomposites based on them with malignant cells and tumors, primarily characterized by the emergence of drug resistance, the determination of promising directions and ways to overcome it, and the creation of new effective nanocomposite remedies for use in antitumor chemotherapy. The given data indicate the relevance of the topic. Targeted studies of the resistance of malignant cells and neoplasms to chemotherapeutic drugs have been carried out since the 1990s. The majority of works were performed according to the methodology, that involves the traditional use of chemotherapeutic drugs. In these works, the principle of the multifactorial nature of resistance was determined, the processes and mechanisms of its implementation were studied, related to the reduction of the accumulation of the chemotherapeutic drug in cells, the increase in the activity of detoxification systems, the strengthening of DNA repair processes, the reduction of apoptosis, and autophagy. A number of promising substances and influencing factors contributing to overcoming of resistance have been identified. However, the discovered ways to overcome the resistance of malignant cells and neoplasms to the corresponding drugs are at the stages of laboratory, preclinical, or, in the best case, clinical research. At the same time, it is not excluded that the use of the latest highly effective chemotherapeutic drugs will lead to the emergence of new mechanisms of resistance. Thus, at this time the results of research on the traditional use of chemotherapeutic drugs constitute a significant fundamental and practically important development regarding the determination of mechanisms of drug resistance, however, the problem of its medicinal overcoming remains far from being solved, and the used approaches give the impression of dead ends. With the development of nanotechnology, new scientific directions have been initiated and a significant amount of researches has been carried out, devoted to the creation and search for promising applications in oncology of nanocomposites based on bioinert, biocompatible and bioactive nanoparticle materials and modern chemotherapeutic drugs. It should be emphasized that all these works contain data indicating the advantages of introducing nanocomposite drugs into clinical practice, compared to the use of chemotherapeutic drugs in traditional forms. Against this background, purposeful researches are distinguished carried out by scientists of O.O. Chuiko Institute of Surface Chemistry of National Academy of Sciences of Ukraine and R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of National Academy of Sciences of Ukraine in the field of creation of modern polyfunctional nanocomposite chemotherapeutic agents for use in antitumor therapy, capable of overcoming drug resistance of malignant cells and neoplasms. So, at O.O. Chuiko Institute of Surface Chemistry of National Academy of Sciences of Ukraine for the first time magnetic fluids were synthesized containing antitumor drugs cisplatin, doxorubicin, gemcitabine, corresponding antibodies, their physicochemical properties were studied, and parameters for standardization were determined. At R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of National Academy of Sciences of Ukraine the antitumor properties of magnetic fluids were studied. On the basis of magnetic fluid with cisplatin, the first native magnetosensitive oncological drug "Feroplat" has been proposed, which has no analogues in the world. Feroplat is a standardized tool for increasing the effectiveness of chemotherapy and overcoming drug resistance of malignant neoplasms, intended for the delivery of cytostatics directly to the tumor tissue. This ensures its maximum entry into the cells and helps to increase the therapeutic effect. In order to introduce "Feroplat" into production and clinical practice, its preclinical tests were successfully performed. The analysis of the given data indicates the priority of works in the field of creation of new nanocomposite chemotherapeutic drugs for use in antitumor therapy, capable of overcoming drug resistance of malignant cells and neoplasms. The facts of overcoming the drug resistance of malignant neoplasms to cisplatin with the new native oncological drug "Feroplat", as well as high indicators of cytotoxic / cytostatic activity of nanobiocomposites based on saline solution, magnetite and cisplatin, doxorubicin, gemcitabine, etc., may indicate the fundamental need to change approaches to the use of modern antitumor chemotherapeutic agents – by replacing their traditional molecular forms with appropriate nanocomposite forms.

Platform trial for off-label oncology drugs using comprehensive genomic profiling under the universal public healthcare system: the BELIEVE trial

BackgroundPrecision medicine has transformed cancer treatment by focusing on personalized approaches based on genomic abnormalities. However, comprehensive genomic profiling (CGP) and access to targeted therapies are limited in Japan. This study investigates the BELIEVE trial, which aims to improve drug accessibility for patients with actionable genetic abnormalities through off-label drug administration.MethodsThe BELIEVE trial is a platform trial with a single master protocol, conducted under the Clinical Trials Act and the patient-proposed health services (PPHS) scheme. Eligible patients with solid tumors exhibiting actionable alterations were enrolled, and CGP tests covered by national health insurance were employed. Treatment selection, study drugs from collaborating pharmaceutical companies, and treatment schedules adhered to predefined protocols. Primary and secondary endpoints were evaluated, and statistical analysis was conducted based on patient response rates.ResultsThe BELIEVE trial offered treatment opportunities for patients with relapse/refractory disease who lacked standard therapies or clinical trial options. This study addresses unmet medical needs and contributes to the establishment of precision medicine systems. Similar trials like NCI-MATCH and TAPUR are being conducted globally. The BELIEVE trial provides a platform for off-label drug administration, collects essential clinical data, and contributes to drug approval applications.ConclusionThe BELIEVE trial provides hope for patients with actionable genetic abnormalities by facilitating access to targeted therapies through off-label drug administration. It establishes a regulatory framework and promotes collaboration between industry and academia by expanding organ-specific and cross-organ biomarker-based treatments.

Changing trends in phase 1 oncology clinical trials

The Ph1 oncology trial landscape is evolving in response to advances in understanding of cancer biology, novel drug discovery platforms, and therapeutic modalities. To uncover emerging trends in oncology drug development, we identified 7,061 solid tumour Ph1 trials (2009–2021) from clinicaltrials.gov to determine the numbers of trials commenced, therapeutic classes, combinations, tumour streams, and geographical distribution. Ph1 oncology trials increased by an average of 5.2 %/year. There was a significant relative increase in the number of immunotherapy studies and a significant relative decrease in trials containing chemotherapy. Between 2009 and 2021, multi-agent combination trials outnumbered single-agent trials and single-class trials outnumbered multimodal combination trials. The proportion conducted in the Asia-Pacific significantly increased. Multiregional trials decreased during the COVID-19 pandemic, reducing projected trial numbers in Asia-Pacific and Europe whilst increasing single-region trials in North America. Further study is required to track recovery post-pandemic, and the emergence of novel modalities (e.g. ADCs and cellular therapies).