Figure 2 - uploaded by Dafydd G Thomas
Content may be subject to copyright.
Partial response and cystic change in uterine leiomyosarcoma patient. Lung metastasis at baseline (A) demonstrated shrinkage after six cycles of combination chemotherapy and two cycles of single-agent cixitumumab (B). Lesion underwent cystic degeneration after an additional seven cycles of single-agent cixitumumab therapy (C). High expression of IGF-1R by immunohistochemistry in resected tumor specimen (D).
Source publication
IGF-1R has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single-agent in STS. We performed a dose escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combinatio...
Contexts in source publication
Context 1
... myxoid liposarcoma patient had over 70% shrink- age to large volume target lesions and a leiomyosarcoma patient had stable disease on treatment for 22 cycles. Figure 2 depicts images from a patient with a uterine leiomyosarcoma metastatic to lung with significant shrinkage after combination therapy ( Figure 2B) and cystic changes with continued cixitumumab alone ( Figure 2C). After nine cycles of cixitumumab therapy, the patient underwent metastatectomy, which revealed leiomyo- sarcoma with cystic degeneration. ...
Context 2
... myxoid liposarcoma patient had over 70% shrink- age to large volume target lesions and a leiomyosarcoma patient had stable disease on treatment for 22 cycles. Figure 2 depicts images from a patient with a uterine leiomyosarcoma metastatic to lung with significant shrinkage after combination therapy ( Figure 2B) and cystic changes with continued cixitumumab alone ( Figure 2C). After nine cycles of cixitumumab therapy, the patient underwent metastatectomy, which revealed leiomyo- sarcoma with cystic degeneration. ...
Context 3
... myxoid liposarcoma patient had over 70% shrink- age to large volume target lesions and a leiomyosarcoma patient had stable disease on treatment for 22 cycles. Figure 2 depicts images from a patient with a uterine leiomyosarcoma metastatic to lung with significant shrinkage after combination therapy ( Figure 2B) and cystic changes with continued cixitumumab alone ( Figure 2C). After nine cycles of cixitumumab therapy, the patient underwent metastatectomy, which revealed leiomyo- sarcoma with cystic degeneration. ...
Similar publications
Background:
Epidermal growth factor receptor (EGFR) is a new target for nasopharyngeal carcinoma (NPC) therapy. This prospective phase I study sought to determine the safety and recommended phase II dose of icotinib, a novel highly selective oral EGFR tyrosine kinase inhibitor, in combination with intensity-modulated radiotherapy (IMRT) in patient...
Purpose:
Afatinib, an irreversible ErbB family blocker, has demonstrated preclinical antitumor activity with chemotherapy.
Methods:
As part of a phase I trial in patients with advanced solid tumors (NCT00809133; 3 + 3 dose-escalation design), we determined the maximum tolerated dose (MTD) of afatinib with carboplatin (A/C) or with carboplatin pl...
Background
Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy.Objective
This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations...
Background
Ridaforolimus is a mammalian target of rapamycin inhibitor that has activity in solid tumors. Paclitaxel and carboplatin have broad antineoplastic activity in many cancers. This phase I trial was conducted to determine the safety profile, maximal tolerated dose, and recommended phase II dose and schedule of oral ridaforolimus combined wi...
Citations
... 10,18 Usage of TiTE-CRM methodology has become increasingly popular, with various trials having implemented the TiTE-CRM, in the RT combination setting [20][21][22][23][24] and more widely. [25][26][27] Application of the TiTE-CRM requires up-front specification of a target toxicity level (TTL), denoting an acceptable dose limiting toxicity (DLT) probability with the treatment under investigation. Typically this is based on review of current literature and expected DLT probabilities with standard of care treatment. ...
PURPOSE
CONCORDE is the first phase I drug-radiotherapy (RT) combination platform in non–small-cell lung cancer, designed to assess multiple different DNA damage response inhibitors in combination with radical thoracic RT. Time-to-event continuous reassessment method (TiTE-CRM) methodology will inform dose escalation individually for each different DNA damage response inhibitor-RT combination and a randomized calibration arm will aid attribution of toxicities. We report in detail the novel statistical design and implementation of the TiTE-CRM in the CONCORDE trial.
METHODS
Statistical parameters were calibrated following recommendations by Lee and Cheung. Simulations were performed to assess the operating characteristics of the chosen models and were written using modified code from the R package dfcrm.
RESULTS
The results of the simulation work showed that the proposed statistical model setup can answer the research questions under a wide range of potential scenarios. The proposed models work well under varying levels of recruitment and with multiple adaptations to the original methodology.
CONCLUSION
The results demonstrate how TiTE-CRM methodology may be used in practice in a complex dose-finding platform study. We propose that this novel phase I design has potential to overcome some of the logistical barriers that for many years have prevented timely development of novel drug-RT combinations.
... STSs are relatively rare, accounting for approximately 1% of all adult cancers (6). Due to its rarity, heterogeneity, and limited overall response to chemotherapy, STSs represent a therapeutic challenge (7). Surgical excision is the mainstay of current treatment options, sometimes accompanied by radiotherapy and chemotherapy (8). ...
Soft tissue sarcomas (STSs) are heterogeneous malignancies derived from mesenchymal cells. Due to its rarity, heterogeneity, and limited overall response to chemotherapy, STSs represent a therapeutic challenge. Necroptosis is a novel therapeutic strategy for enhancing immunotherapy of cancer. Nevertheless, no research has explored the relationship between necroptosis-related genes (NRGs) and STSs. In this study, differentially expressed NRGs were identified using The Cancer Genome Atlas (TCGA) and The Cancer Genotype-Tissue Expression (GTEx) project. The expression levels of 34 NRGs were significantly different. Several key NRGs were validated using RT-qPCR and our own sequencing data. Patients with STSs were divided into two clusters using consensus cluster analysis, and significant differences were observed in their survival (p=0.002). We found the differentially expressed genes (DEGs) between the two clusters and carried out subsequent analysis. The necroptosis-related gene signatures with 10 key DEGs were identified with a risk score constructed. The prognosis of TCGA-SARC cohort with low necroptosis-related risk score was better (p<0.001). Meanwhile, the low-risk group had a significantly increased immune infiltration. Using the data of GSE17118 and another immunotherapy cohort as external validations, we observed significant survival differences between the two risk groups (p=0.019). The necroptosis-related risk score proved to be an independent prognostic factor, and a nomogram was further established and integrated with other clinical features. Notably, the necroptosis-related gene signature could also act as the prognostic indicator in other malignancies based on pan-cancer analysis. In summary, the study outlines NRGs in STSs and their potential role in prognosis and will be one of the important directions for future research.
... Such studies utilize information gathered at the bench to apply a given therapeutic to an appropriate cohort of patients in the clinical setting, and they are becoming increasingly precise. For example, traditional cancer cell lines are now being scrutinized for their applicability to human cancer in situ, which has resulted in improvements in the prioritization of therapeutic targets and drug molecules based on several genomic considerations [5][6][7]. ...
Simple Summary
Phase I clinical trials are a cornerstone of pharmaceutical development in oncology. Many studies have now attempted to incorporate pharmacogenomics into phase I studies; however, many of these studies have fundamental flaws that that preclude interpretation and application of their findings. Study populations are often small and heterogeneous with multiple disease states, multiple dose levels, and prior therapies. Genetic testing typically includes few variants in candidate genes that do no encapsulate the full range of phenotypic variability in protein function. Moreover, a plurality of these studies do not present scientifically robust clinical or preclinical justification for undertaking pharmacogenomics studies. A significant amount of progress in understanding pharmacogenomic variability has occurred since pharmacogenomics approaches first began appearing in the literature. This progress can be immediately leveraged for the vast majority of Phase I studies. The purpose of this review is to summarize the current literature pertaining to Phase I incorporation of pharmacogenomics studies, analyze potential flaws in study design, and suggest approaches that can improve design of future scientific efforts.
Abstract
While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24–31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions.
... Many of these studies were limited by small sample size and identified no significant SNPs. [11][12][13][14][15][16][17][18][19][20][21][22] Among CGAS that identified significant variants, candidate genes were related to drug metabolism (CBR3, 23 UGT1A6, 24,25 and POR 26 ), drug transport (SLC28A3, 25,27 SLC22A17, 28 SLC22A7, 28 ABCC2, 29 ABCC1, [30][31][32] ABCC5, 33 and ABCG2 34 ), iron metabolism (HFE 29,35 ), cell signalling (RAC2, 29,31 NOS3, 33 and PLCE1 36 ), DNA repair (ERCC2, 37 BRCA1, 38 and BRCA2 38 ), splicing regulation (CELF4 24 ), response to oxidative stress (CAT, 39 NCF4, 31,40,41 GSTP1, 42 and CYBA 31,41 ), calcium homeostasis (ATP2B1 36 ), myosin synthesis (MYH7 43 ), and extracellular matrix synthesis (HAS3 24,44 ). Additionally, two exome array analyses identified candidate genes (ETFB 45 and GPR35 46 ) that were significant only when analysed with a gene-based approach. ...
The genomic predisposition to oncology-drug-induced cardiovascular toxicity has been postulated for many decades. Only recently has it become possible to experimentally validate this hypothesis via the use of patient-specific human-induced pluripotent stem cells (hiPSCs) and suitably powered genome-wide association studies (GWAS). Identifying the individual single nucleotide polymorphisms (SNPs) responsible for the susceptibility to toxicity from a specific drug is a daunting task as this precludes the use of one of the most powerful tools in genomics: comparing phenotypes to close relatives, as these are highly unlikely to have been treated with the same drug. Great strides have been made through the use of candidate gene association studies (CGAS) and increasingly large GWAS studies, as well as in vivo whole-organism studies to further our mechanistic understanding of this toxicity. The hiPSC model is a powerful technology to build on this work and identify and validate causal variants in mechanistic pathways through directed genomic editing such as CRISPR. The causative variants identified through these studies can then be implemented clinically to identify those likely to experience cardiovascular toxicity and guide treatment options. Additionally, targets identified through hiPSC studies can inform future drug development. Through careful phenotypic characterization, identification of genomic variants that contribute to gene function and expression, and genomic editing to verify mechanistic pathways, hiPSC technology is a critical tool for drug discovery and the realization of precision medicine in cardio-oncology. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]
... A recent meta-analysis suggested that the let-7 family of miRNAs are potential biomarkers for tumor grade prediction in breast cancer [59] as well as in other cancers, since let-7 family is highly conserved across species [60]. Among other miRNAs with a significant number of interactions, miR-637 links to main networks through Adrenocortical [65], ovarian [66], non-small cell lung [67], colorectal [68, 69] carcinomas and soft tissue sarcoma [70] PDGFC platelet derived growth factor C Sunitinib Renal cell carcinoma [71] and breast carcinomas [72] PDGFRA platelet-derived growth factor receptor, alpha polypeptide Motesanib, Ramucirumab, Midostaurin, Amuvatinib, Nintedanib, Pazopanib, Tandutinib, Crenolanib, Nilotinib, Masitinib, Sorafenib, Sunitinib, Regorafenib, Dovitinib, Telatinib, Vatalanib, Axitinib, Lenvatinib, Imatinib Colorectal [73, 74], hepatocellular [75][76][77][78], kidney [79], non-small [80] and small cell lung [81], pancreatic [82][83][84], colon [85], gastrointestinal [86], renal cell [71, 87], breast [72, 88], melanoma [89], thyroid [90] carcinomas and soft tissue sarcoma [91] VEGFA vascular endothelial growth factor A Ziv-aflibercept, Bevacizumab, Sorafenib tosylate, Lenalidomide, Thalidomide, Aflibercept Colorectal [92, 93] ovarian [94], non-small cell lung [95], hepatocellular [96] carcinomas and multiple myeloma [97] direct interactions with VEGFA and CEACAM; the latter interacting with miR-9 and miR-939. Functional data has shown that miR-637 is one of the effective regulators of HER2 signaling; in HER2-positive trastuzumab nonresponsive cell lines, miR-637 was efficient to inhibit breast cancer cell growth [61]. ...
Background:
Hemangioma is a common benign tumor in the childhood; however our knowledge about the molecular mechanisms of hemangioma development and progression are still limited. Currently, microRNAs (miRNAs) have been shown as gene expression regulators with an important role in disease pathogenesis. Our goals were to identify miRNA-mRNA expression networks associated with infantile hemangioma.
Methods:
We performed a meta-analysis of previously published gene expression datasets including 98 hemangioma samples. Deregulated genes were further used to identify microRNAs as potential regulators of gene expression in infantile hemangioma. Data were integrated using bioinformatics methods, and genes were mapped in proteins, which were then used to construct protein-protein interaction networks.
Results:
Deregulated genes play roles in cell growth and differentiation, cell signaling, angiogenesis and vasculogenesis. Regulatory networks identified included microRNAs miR-9, miR-939 and let-7 family; these microRNAs showed the most number of interactions with deregulated genes in infantile hemangioma, suggesting that they may have an important role in the molecular mechanisms of disease. Additionally, results were used to identify drug-gene interactions and druggable gene categories using Drug-Gene Interaction Database. We show that microRNAs and microRNA-target genes may be useful biomarkers for the development of novel therapeutic strategies for patients with infantile hemangioma.
Conclusions:
microRNA-regulated pathways may play a role in infantile hemangioma development and progression and may be potentially useful for future development of novel therapeutic strategies for patients with infantile hemangioma.
Background: Adaptive designs (ADs) are intended to make clinical trials more flexible, offering efficient and potentially cost-saving benefits. Despite a large number of methods-based research papers in the literature on different adaptations to trials, the advantages and limitations of such designs remain unfamiliar to large parts of the clinical community including those in pediatric medicine where efficient clinical trials are essential to inform care. This systematic review provides an overview of the use of ADs in published clinical trials (Part I) and compares the application of AD in trials in adult and pediatric studies, providing real-world examples and recommendations for the child health community (Part II).
Methods: Published studies from 2010 to April 2020 were searched in the following databases: MEDLINE (Ovid), Embase (Ovid), and International Pharmaceutical Abstracts (Ovid). Protocols, reports, and a secondary analysis using AD were included. We did not include any trial registrations and interventions other than drugs or vaccines. Data from the published literature on study characteristics, types of adaptations, statistical analysis, stopping boundaries, logistical challenges, operational considerations and ethical considerations were extracted and summarized herein.
Results: Out of 23,886 retrieved studies, 317 publications of adaptive trials, 267 (84.2%) trial reports, and 50 (15.8%) study protocols), were included. Most trials included only adult participants (265, 83.9%), 16 trials (5.4%) were limited to only children and 28 (8.9%) were for both children and adults. Dose finding designs were used in the highest proportion of the included AD (82, 22.4 %), followed by adaptive randomization (56, 14.4%), group sequential design in 47 trials (12.8%), then drop-the-losers (pick-the-winner) design in 28 trials (7.6%) and seamless phase 2-3 design in 27 trials (7.4%). Approximately 203 (64%) studies used frequentist statistical methods and 75 (23.7%) used Bayesian methods.
Conclusion: In Part I of this review, we provide a comprehensive overview of the landscape and methodological features of adaptive clinical trials. We found that adaptive designs were applied mostly in Phase II oncology trials, aimed to establish efficacy and determine the choice of doses for the Phase III of the trials. Phase I trials of new drugs that included adaptations most frequently aimed to identify the maximum tolerable dose. Adaptation details were not uniformly reported across all trials and were hardly reported in the pediatric trials.
Study protocol registration: DOI:10.1186/s13063-018-2934-7
Simple Summary
Rhabdomyosarcoma (RMS) is a rare pediatric sarcoma affecting skeletal muscle in children and young adults. It is responsible for 3% of all childhood malignant tumors and is the third most prevalent pediatric extracranial solid tumor. Despite advances in diagnostic and treatment methods and clinical trials to improve pediatric RMS survival rates, children with high-risk RMS and recurrent disease have 5-year survival rates of less than 30% and 17%, respectively. The cure rate remains low and the current RMS therapies continue to pose potential life-threatening toxicities, which can lead to lifelong morbidity. The treatment strategies for RMS include multi-agent chemotherapies after surgical resection with or without radiotherapy. Here, we focus on chemotherapy strategies and discuss the impact of apoptosis, autophagy, and the UPR that are involved in the chemotherapy response. Then, to screen future therapeutic approaches and promote muscle regeneration, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models.
Abstract
Rhabdomyosarcoma is a rare cancer arising in skeletal muscle that typically impacts children and young adults. It is a worldwide challenge in child health as treatment outcomes for metastatic and recurrent disease still pose a major concern for both basic and clinical scientists. The treatment strategies for rhabdomyosarcoma include multi-agent chemotherapies after surgical resection with or without ionization radiotherapy. In this comprehensive review, we first provide a detailed clinical understanding of rhabdomyosarcoma including its classification and subtypes, diagnosis, and treatment strategies. Later, we focus on chemotherapy strategies for this childhood sarcoma and discuss the impact of three mechanisms that are involved in the chemotherapy response including apoptosis, macro-autophagy, and the unfolded protein response. Finally, we discuss in vivo mouse and zebrafish models and in vitro three-dimensional bioengineering models of rhabdomyosarcoma to screen future therapeutic approaches and promote muscle regeneration.
Purpose:
Antibodies against IGF-1R have shown meaningful but transient tumor responses in patients with rhabdomyosarcoma (RMS). The SRC family member YES has been shown to mediate IGF-1R antibody acquired resistance, and cotargeting IGF-1R and YES resulted in sustained responses in murine RMS models. We conducted a phase I trial of the anti-IGF-1R antibody ganitumab combined with dasatinib, a multi-kinase inhibitor targeting YES, in RMS patients (NCT03041701).
Patients and methods:
Patients with relapsed/refractory alveolar or embryonal RMS and measurable disease were eligible. All patients received ganitumab 18 mg/kg intravenously every 2 weeks. Dasatinib dose was 60 mg/m2/dose (max 100 mg) oral once daily [dose level (DL)1] or 60 mg/m2/dose (max 70 mg) twice daily (DL2). A 3+3 dose escalation design was used, and maximum tolerated dose (MTD) was determined based on cycle 1 dose-limiting toxicities (DLTs).
Results:
Thirteen eligible patients, median age 18 years (range 8-29) enrolled. Median number of prior systemic therapies was 3; all had received prior radiation. Of 11 toxicity-evaluable patients, 1/6 had a DLT at DL1 (diarrhea) and 2/5 had a DLT at DL2 (pneumonitis, hematuria) confirming DL1 as MTD. Of nine response-evaluable patients, one had a confirmed partial response (PR) for four cycles, and one had stable disease (SD) for six cycles. Genomic studies from cell-free DNA correlated with disease response.
Conclusions:
The combination of dasatinib 60 mg/m2/dose daily and ganitumab 18 mg/kg every two weeks was safe and tolerable. This combination had a disease control rate of 22% at five months.
Background
Awareness of model-based designs for dose-finding studies such as the Continual Reassessment Method (CRM) is now becoming more commonplace amongst clinicians, statisticians and trial management staff. In some settings toxicities can occur a long time after treatment has finished, resulting in extremely long, interrupted, CRM design trials. The Time-to-Event CRM (TiTE-CRM), a modification to the original CRM, accounts for the timing of late-onset toxicities and results in shorter trial duration. In this article, we discuss how to design and deliver a trial using this method, from the grant application stage through to dissemination, using two radiotherapy trials as examples.
Methods
The TiTE-CRM encapsulates the dose-toxicity relationship with a statistical model. The model incorporates observed toxicities and uses a weight to account for the proportion of completed follow-up of participants without toxicity. This model uses all available data to determine the next participant’s dose and subsequently declare the maximum tolerated dose.
We focus on two trials designed by the authors to illustrate practical issues when designing, setting up, and running such studies.
Results
In setting up a TiTE-CRM trial, model parameters need to be defined and the time element involved might cause complications, therefore looking at operating characteristics through simulations is essential. At the grant application stage, we suggest resources to fund statisticians’ time before funding is awarded and make recommendations for the level of detail to include in funding applications. While running the trial, close contact of all involved staff is required as a dose decision is made each time a participant is recruited. We suggest ways of capturing data in a timely manner and give example code in R for design and delivery of the trial. Finally, we touch upon dissemination issues while the trial is running and upon completion.
Conclusion
Model-based designs can be complex. We hope this paper will help clinical trial teams to demystify the conduct of TiTE-CRM trials and be a starting point for using this methodology in practice.
Chemotherapy-induced cardiovascular toxicity (CICT) is a well-established risk for cancer survivors and causes diseases such as heart failure, arrhythmia, vascular dysfunction, and atherosclerosis. As our knowledge of the precise cardiovascular risks of each chemotherapy agent has improved, it has become clear that genomics is one of the most influential predictors of which patients will experience cardiovascular toxicity. Most recently, GWAS-led, top-down approaches have identified novel genetic variants and their related genes that are statistically related to CICT. Importantly, the advent of human-induced pluripotent stem cell (hiPSC) models provides a system to experimentally test the effect of these genomic findings in vitro, query the underlying mechanisms, and develop novel strategies to mitigate the cardiovascular toxicity liabilities due to these mechanisms. Here we review the cardiovascular toxicities of chemotherapy drugs, discuss how these can be modeled in vitro, and suggest how these models can be used to validate genetic variants that predispose patients to these effects.
