53 results on '"Stefan Symeonides"'
Search Results
2. 525 Preliminary safety, PK/PD and efficacy results from a first-in-human phase I/IIa clinical trial of BNT411, a systemic Toll-like receptor 7 agonist in patients with solid tumors
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Hendrik-Tobias Arkenau, Emiliano Calvo, Alain Mita, Young Kwang Chae, Devalingam Mahalingam, Ugur Sahin, Elena Garralda, Oezlem Tuereci, Vladimir Galvao, Stefan Symeonides, Maria Miguel, Hariz Hassan, Annette Baumhauer, Timo Völker, Marie-Cristine Kühnle, Roman Rösemann, and Stefan Strobl
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2021
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3. 1173 ST101, a peptide antagonist of novel I/O target CEBPβ, reprograms MDSC polarization and decreases tumor-associated Tregs, suggesting an immune component to observed clinical responses
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Claudio Scuoppo, Gerald Falchook, Elisa Fontana, Anja Williams, Nehal Lakhani, Jeff Evans, Fabio Iwamoto, Meredith McKean, Stefan Symeonides, Alistair McLaren, Jason Henry, Gina Capiaux, Robert Michel, Stephen Kaesshaefer, Alice Bexon, and Jim Rotolo
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- 2022
4. 622 A phase 1 study exploring the safety and tolerability of the small-molecule PD-L1 inhibitor, INCB099318, in patients with select advanced solid tumors
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David Pinato, Ruth Plummer, Martin Gutierrez, Jeffrey Yachnin, Aglaia Schiza, Martin Hojgaard, Knut Smeland, William Edenfield, Hans Prenen, Lars Ny, Alan Anthoney, Nuria Kotecki, Stefan Symeonides, Louis Viviers, Jeannie Daniel, Jennifer Pulini, and Udai Banerji
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- 2022
5. 706 NOUS-PEV, a novel personalized viral-based prime/boost cancer immunotherapy targeting patient-specific neoantigens: interim results from the first subjects in the phase 1b study
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Oliver Bechter, Juan Martin-Liberal, Anna D’Alise, Guido Leoni, Gabriella Cotugno, Loredana Siani, Rosa Vitale, Valentino Ruzza, Elisa Micarelli, Irene Garzia, Thea Faivre, Sven Gogov, Patricia Delaite, Stefano Colloca, Maria Ambrosio, Rossella Merone, Elisa Scarselli, and Stefan Symeonides
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- 2022
6. The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms In Vitro and in a First-In-Human Phase I Clinical Trial
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Sebastian M.B. Nijman, Farasat Kazmi, In Hwa Um, Ruud G.P.M. van Stiphout, Gareth L. Bond, Mustafa Elshani, Valentina Ferrari, Ruth Plummer, David J. Harrison, Sarah P. Blagden, James Chettle, Mary Kudsy, Michaela Serpi, Stefan Symeonides, Josephine Morris, Hagen Schwenzer, Leticia Campo, Alistair Easton, and Erica De Zan
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Cancer Research ,biology ,Nucleoside analogue ,Chemistry ,Protide ,Phosphoramidate ,Adenosine kinase ,Adenosine ,fluids and secretions ,Adenosine deaminase ,Oncology ,Cancer cell ,Cancer research ,biology.protein ,medicine ,Nucleoside ,medicine.drug - Abstract
Purpose: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3′-Deoxyadenosine (3′-dA) is a naturally occurring adenosine analogue with established anticancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells, and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3′-dA was chemically modified to create the novel ProTide NUC-7738. Experimental Design: We describe the synthesis of NUC-7738. We determine the IC50 of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in patients with cancer. Results: We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3′-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate our in vitro findings and show NUC-7738 is an effective proapoptotic agent in cancer cells with effects on the NF-κB pathway. Conclusions: Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides.
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- 2021
7. Abstract LB196: NOUS-PEV, a personalized cancer immunotherapy targeting neoantigens, induces long lasting, tumor infiltrating memory T cells
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Oliver Bechter, Anna Morena D'Alise, Guido Leoni, Gabriella Cotugno, Loredana Siani, Rosa Vitale, Valentino Ruzza, Irene Garzia, Laura Antonucci, Elisa Micarelli, Sven Gogov, Alessia Capone, Juan Martin-Liberal, Emiliano Calvo, Victor Moreno, Stefan Symeonides, and Elisa Scarselli
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Cancer Research ,Oncology - Abstract
Personalized vaccines hold great promise to exert meaningful clinical efficacy, with durable tumor control maintained by a vaccine–induced memory response. NOUS–PEV is a personalized viral prime–boost cancer vaccine that expresses 60 patient–specific neoantigens identified by next generation sequencing (NGS) and selected with a proprietary algorithm VENUS (Leoni & D’Alise et al, Vaccines, 9, 2021). Administration is intramuscular, with a priming Great Ape Adenovirus (GAd) vaccination, followed by Modified Vaccinia Ankara (MVA) “boosts”, administered in combination with the PD–1 blocking antibody pembrolizumab in patients with metastatic malignant melanoma and non–small cell lung cancer. Data from the Part 1 dose–confirmation cohort of 3 patients demonstrated the combination of NOUS–PEV and pembrolizumab to be safe and well–tolerated, with early indications of efficacy and immunogenicity (Bechter, et al SITC 2022 Poster number: 706). Now in Part 2 extension–expansion cohorts, we present extended safety, immunogenicity and clinical data at 11 months median follow–up for 6 vaccinated melanoma patients. Tolerability remains good with no grade 3 or 4 vaccine related adverse events and activity encouraging, with 4 PRs, 1 SD and only 1 PD as best response. Immune responses were evaluated by ex–vivo interferon–gamma ELISpot on PBMC collected at baseline, post pembrolizumab, and post vaccination. Vaccine immunogenicity was demonstrated in all evaluable patients receiving the prime/boost regimen (n=4), with a mean of T cell response of ~ 650 IFN–γ spot forming cells (SFC) per million of PBMC (range 380–1,250 SFC/106) and with observed induction of both CD4 and CD8 T cell responses which lasted for at least 6 months. By analyzing the intratumoral TCR repertoire, we found increase of T cells by ~3 fold on average post treatment with NOUS–PEV in all evaluable patients (n=3), with expansion and diversification of intratumoral T cell clones. Vaccine–induced TCR clonotypes were found in on–treatment tumor biopsies of 2 vaccinated patients, providing the proof–of–concept for neoantigen induced T cells homing and infiltrating into the tumor. Overall, these data show that NOUS–PEV continues to be safe, and elicits a robust long lasting immune response and clinical activity. Citation Format: Oliver Bechter, Anna Morena D'Alise, Guido Leoni, Gabriella Cotugno, Loredana Siani, Rosa Vitale, Valentino Ruzza, Irene Garzia, Laura Antonucci, Elisa Micarelli, Sven Gogov, Alessia Capone, Juan Martin-Liberal, Emiliano Calvo, Victor Moreno, Stefan Symeonides, Elisa Scarselli. NOUS-PEV, a personalized cancer immunotherapy targeting neoantigens, induces long lasting, tumor infiltrating memory T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB196.
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- 2023
8. Abstract CT256: Modi-1, anti-citrullinated neoepitope vaccine alone and combined with checkpoint inhibitors in patients with head and neck, breast, renal and ovarian carcinoma: protocol for the ModiFY phase I/II basket clinical Ttial
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Lindy G. Durrant, Fayaz Masters, Samantha Paston, Robert Miller, David J. Pinato, Rebecca Herbertson, Anne Armstrong, Stefan Symeonides, and Christian Ottensmeier
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Cancer Research ,Oncology - Abstract
Stressful conditions in the tumor microenvironment induce autophagy in cancer cells as a mechanism to promote their survival. High levels of calcium within autophagosomes activates peptidylarginine deaminase enzymes which convert arginine residues within polypeptides to citrulline and alters proteolytic cleavage. In the presence of inflammation, the MHC-II pathway presents these new citrullinated peptides to CD4 T cells. Modi-1 vaccine comprising three citrullinated, adjuvanted peptides induces and expands a population of activated CD4 T cells. On reaching the tumor site the CD4 T cells release proinflammatory cytokines including, INFγ, which upregulates MHC class II and the same, but endogenous, modified peptides are presented on the tumor cell surface. This likely causes a positive feed-forward loop with killing of tumor cells. The objective of this study is to evaluate the safety, tolerability, cellular immune and tumor response to 2 citrullinated vimentin and one citrullinated enolase peptide each conjugated to the toll-like receptor 1/2 adjuvant Amplivant® ModiFY is an open-label, prospective, multicohort, multicenter, phase I/II basket trial. Eligible patients have unresectable disease in one of the following tumor types: Squamous Cell Carcinoma of the Head and Neck (SCCHN), Triple Negative Breast Cancer, Renal Cell Carcinoma and High Grade Serous Ovarian Carcinoma. Depending on the status of the disease and eligibility for standard of care (SOC) checkpoint inhibitor (CPI) monotherapy, patients will be treated either with Modi-1 alone or Modi-1 +SOC CPI. A randomized neoadjuvant sub-study in patients with SCCHN scheduled to have tumor resection surgery is included in the protocol. These patients are randomized 1:1 to receive either Modi-1 alone or Modi-1+ pembrolizumab. The primary endpoints are the adverse event rate as measured by CTCAE v5.0 in the initial dose escalation cohorts and the strength of the cellular immune response IFNγ enzyme-linked immune absorbent spot (ELISpot) assay in the dose expansion cohorts. Secondary endpoints (RECIST 1.1 and iRECIST), are objective response rate duration of response, progression-free survival, and overall survival. In the SCCHN neoadjuvant cohort, tumor infiltrating lymphocytes in resected tumor tissue will be profiled using scRNAseq and immunohistochemistry. The study is an adaptive trial, comprising 3+3 dose escalation cohorts followed by a Simon 2-stage design in the dose expansion cohorts. The Modi-1 only dose expansion cohort will recruit 16 patients of each of the target tumor types, whilst the Modi-1+CPI will recruit a total of 21 patients. A total of 21/138 patients have been treated to date. ClinicalTrials.gov NCT05329532 Citation Format: Lindy G. Durrant, Fayaz Masters, Samantha Paston, Robert Miller, David J. Pinato, Rebecca Herbertson, Anne Armstrong, Stefan Symeonides, Christian Ottensmeier. Modi-1, anti-citrullinated neoepitope vaccine alone and combined with checkpoint inhibitors in patients with head and neck, breast, renal and ovarian carcinoma: protocol for the ModiFY phase I/II basket clinical Ttial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT256.
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- 2023
9. Abstract 5962: NUC-7738 causes reduction of soluble and exosome-associated PD-L1 in melanoma cell lines and patients
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Mustafa Elshani, Ying Zhang, Boback Kaghazchi, Alison L. Dickson, Sarah P. Blagden, Stefan Symeonides, Ruth Plummer, and David J. Harrison
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Cancer Research ,Oncology - Abstract
Background: Immune checkpoint inhibitors (ICIs), including PD-(L)1 pathway inhibitors, are now standard of care for a variety of cancers. Characterization of PD-L1 protein has revealed multiple secreted forms; soluble (sPD-L1) and exosomal (ExoPD-L1) variants. In the tumor microenvironment these interfere with T-cell activation, facilitating tumor immune evasion. High circulating levels of sPD-L1 are correlated with advanced disease, a worse prognosis and/or poor response to ICIs. High levels of ExoPD-L1 are reported to contribute to T-cell dysfunction. NUC-7738, a ProTide transformation of 3'-deoxyadenosine (3’-dA), currently in Phase 1/2 in patients with solid tumors (NuTide:701 NCT03829254), has shown encouraging efficacy signals in several tumor types, including melanoma. This study investigates the dynamic between NUC-7738 and secreted forms of PD-L1 in a melanoma cell line and patients. Material and Methods: A375 malignant melanoma cells were treated with NUC-7738 (10 μM) or DMSO for 6 - 72 hours. Cell supernatant was collected for sPD-L1 and ExoPD-L1 analysis and cells were measured for mRNA and metabolites. sPD-L1 mRNA and protein expression were measured in supernatant using RT-qPCR and sandwich ELISA, respectively. NUC-7738 and 3’-dATP were measured by LC-MS. ExoPD-L1 protein levels were assessed by Jess Western analysis (normalized to CD81) and PD-L1 cell surface expression by flow cytometry. Findings were validated in patient plasma samples taken before and 24 hours after C1D1 treatment with NUC-7738 and prior to C2D1of a 14-day cycle. Results: NUC-7738 was converted into anti-cancer metabolite 3’-dATP within 6 hours of treatment with an average concentration of 80 pmoles/106 cells, which was maintained for at least 24 hours and decreased by approximately 50% by 72 hours. The levels are comparable to those measured in PBMCs from patients treated with NUC-7738. NUC-7738 treatment reduced sPD-L1 mRNA expression by up to 40% and caused a time dependent decrease in sPD-L1 protein in the media supernatant by up to 3-fold. NUC-7738 also reduced ExoPD-L1 protein by 50%. NUC-7738 did not alter cell surface PD-L1 expression. Preliminary studies in serum from 4 study patients treated with NUC-7738 showed reductions in Exo-PD-L1 of ≤50% compared to pre-treatment levels. Conclusion: NUC-7738 reduces secreted forms of PD-L1 whilst having no effect on cell surface protein levels. These in vitro results (melanoma cell line) were validated in the clinical setting, whereby ExoPD-L1 was reduced in plasma samples from patients treated with NUC-7738. These findings indicate that, by reducing sPD-L1 levels, NUC-7738 may have the potential to act as an immune sensitizer. We propose that NUC-7738 given in combination with PD-(L)1 pathway inhibitors may offer a promising treatment option, and are currently exploring this in patients who have experienced therapeutic resistance to ICI treatment. Citation Format: Mustafa Elshani, Ying Zhang, Boback Kaghazchi, Alison L. Dickson, Sarah P. Blagden, Stefan Symeonides, Ruth Plummer, David J. Harrison. NUC-7738 causes reduction of soluble and exosome-associated PD-L1 in melanoma cell lines and patients [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 5962.
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- 2023
10. The Immunopeptidome From a Genomic Perspective: Establishing Immune-Relevant Regions for Cancer Vaccine Design
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Georges Bedran, Tongjie Wang, Dominika Pankanin, Kenneth Weke, Alexander Laird, Christophe Battail, Fabio Massimo Zanzotto, Catia Pesquita, Håkan Axelson, Ajitha Rajan, David J. Harrison, Aleksander Palkowski, Maciej Pawlik, Maciej Parys, Robert O’Neill, Paul M. Brennan, Stefan Symeonides, David R. Goodlett, Kevin Litchfield, Robin Fahraeus, Ted R. Hupp, Sachin Kote, and Javier A. Alfaro
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A longstanding disconnect between the growing number of MHC Class I immunopeptidomic studies and genomic medicine hinders cancer vaccine design. We develop COD-dipp to genomically map the full spectrum of detected canonical and non-canonical (non-exonic) MHC Class I antigens from 26 cancer studies. We demonstrate that patient mutations in regions overlapping physically identified antigens better predict immunotherapy response when compared to neoantigen predictions. We suggest a vaccine design approach using 140,966 highly immune-visible regions of the genome annotated by their expression and haplotype frequency in the human population. These regions tend to be highly conserved, mutated in cancer and harbor 7.8 times more immunogenicity. Intersecting pan-cancer mutations with these immune surveilled regions revealed a potential to create off-the-shelf multi-epitope vaccines against public neoantigens. Here we release COD-dipp, a cancer vaccine toolkit as a web-application (https://www.proteogenomics.ca/COD-dipp) and open-source high-throughput resource.
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- 2022
11. Abstract P3-11-09: ARISTACAT - Aromatase inhibition plus minus saracatinib as advanced breast cancer therapy: A randomised phase II study of aromatase inhibition plus/minus the Src-inhibitor AZD0530 in post-menopausal women with advanced breast cancer
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Peter Barrett-Lee, S Waters, Eve Macdonald Chisholm, Chris Twelves, Peter Schmid, Michelle Welsh, Tammy Piper, Robert W. Hill, David Cameron, Murray Brunt, John M. S. Bartlett, Stefan Symeonides, and Karen McAdam
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Oncology ,Cancer Research ,medicine.medical_specialty ,Aromatase inhibitor ,Performance status ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Phases of clinical research ,Cancer ,Bisphosphonate ,medicine.disease ,Metastatic breast cancer ,chemistry.chemical_compound ,Breast cancer ,Exemestane ,chemistry ,Internal medicine ,medicine ,business - Abstract
Background: Src, the first proto-oncogene to be described, is a non-receptor tyrosine kinase interacting with multiple oncogenic pathways, including cell proliferation, survival, angiogenesis and osteoclast activity. Src activation occurs in up to 40% of ER+ breast cancers, is linked with poor prognosis, and pre-clinically has been strongly implicated in endocrine resistance. Saracatinib (AZD0530) is a potent, oral selective Src inhibitor that enhances the anti-proliferative effect of endocrine agents in pre-clinical breast cancer models, preventing the development of endocrine-resistance and restoring endocrine sensitivity. In a murine model of prostate bony metastases saracatinib inhibits osteoclast activity, reducing bone resorption and the development and progression of bone lesions. Clinically, saracatinib is generally well-tolerated with mainly gastro-intestinal adverse events (AEs), clinically meaningful durations of stable disease as monotherapy, and partial responses observed in combination with other therapies. Methods: Multi-centre, placebo-controlled, double-blind, randomised phase II trial. Post-menopausal women with advanced/metastatic breast cancer suitable for 1st or 2nd second line hormonal treatment, were randomised to receive an aromatase inhibitor (AI) plus saracatinib 175mg mg/day or placebo. Patients were stratified as either (i) “AI-sensitive/naïve”, who received anastrazole 1mg daily ± saracatinib, or (ii) “prior-AI”, if they had progressed on a non-steroidal AI but were considered likely to retain some endocrine sensitivity, who received exemestane 25mg daily ± saracatinib. Other stratification factors were bone metastases, bisphosphonate use, performance status, and treatment centre. Treatment was until progression, intolerable toxicity or at the patient’s request. The primary endpoint was PFS; secondary endpoints were toxicity, ORR & OS; exploratory endpoints explored molecular correlates in on-treatment samples (including optional biopsies). Results: 140 patients were enrolled from 22 UK sites between August 2012 and April 2015 of whom 69 were in the “AI-sensitive/naïve” group and 71 in the “prior-AI” group; 134 patients were eligible for efficacy evaluation and 136 for safety. Interim safety data analyses by an IDMC identified no new safety signals. Treatment emergent AEs were generally low grade, the most frequent being fatigue (70%) and nausea (49%); AEs occurring significantly (p Conclusions: Saractinib did not improve outcomes in post-menopausal women with advanced breast cancer treated with exemestane with numerically inferior p response rate and PFS, and no apparent beneficial effect on bone metastases. These data do not support further evaluation of saracatinib in combination with AIs. ARISTACAT - Abstract - San Antonio 2019 Citation Format: David Cameron, Stefan Symeonides, Murray Brunt, Peter Schmid, Simon Waters, Christopher Twelves, Peter Barrett-Lee, John Bartlett, Tammy Piper, Karen McAdam, Eve Macdonald Chisholm, Michelle Welsh, Robert Hill. ARISTACAT - Aromatase inhibition plus minus saracatinib as advanced breast cancer therapy: A randomised phase II study of aromatase inhibition plus/minus the Src-inhibitor AZD0530 in post-menopausal women with advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-09.
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- 2020
12. Assessment of various continual reassessment method models for dose-escalation phase 1 oncology clinical trials : using real clinical data and simulation studies
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J Marshall, Glen Clack, J Young, Stefan Symeonides, and Gareth James
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Oncology ,Cancer Research ,medicine.medical_specialty ,Drug-Related Side Effects and Adverse Reactions ,Maximum Tolerated Dose ,Bayesian probability ,Phase 1 ,Bayesian ,lcsh:RC254-282 ,01 natural sciences ,Continual reassessment method ,010104 statistics & probability ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Genetics ,medicine ,Dose escalation ,Humans ,Computer Simulation ,0101 mathematics ,Skeleton ,Mathematics ,Dose limiting toxicity ,Clinical Trials, Phase I as Topic ,Dose-Response Relationship, Drug ,Models, Theoretical ,Prognosis ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Skeleton (computer programming) ,Confidence interval ,Clinical trial ,Research Design ,030220 oncology & carcinogenesis ,Maximum tolerated dose ,Research Article - Abstract
Background The continual reassessment method (CRM) identifies the maximum tolerated dose (MTD) more efficiently and identifies the true MTD more frequently compared to standard methods such as the 3 + 3 method. An initial estimate of the dose-toxicity relationship (prior skeleton) is required, and there is limited guidance on how to select this. Previously, we compared the CRM with six different skeletons to the 3 + 3 method by conducting post-hoc analysis on a phase 1 oncology study (AZD3514), each CRM model reduced the number of patients allocated to suboptimal and toxic doses. This manuscript extends this work by assessing the ability of the 3 + 3 method and the CRM with different skeletons in determining the true MTD of various “true” dose-toxicity relationships. Methods One thousand studies were simulated for each “true” dose toxicity relationship considered, four were based on clinical trial data (AZD3514, AZD1208, AZD1480, AZD4877), and four were theoretical. The 3 + 3 method and 2-stage extended CRM with six skeletons were applied to identify the MTD, where the true MTD was considered as the largest dose where the probability of experiencing a dose limiting toxicity (DLT) is ≤33%. Results For every true dose-toxicity relationship, the CRM selected the MTD that matched the true MTD in a higher proportion of studies compared to the 3 + 3 method. The CRM overestimated the MTD in a higher proportion of simulations compared to the 3 + 3 method. The proportion of studies where the correct MTD was selected varied considerably between skeletons. For some true dose-toxicity relationships, some skeletons identified the true MTD in a higher proportion of scenarios compared to the skeleton that matched the true dose-toxicity relationship. Conclusion Through simulation, the CRM generally outperformed the 3 + 3 method for the clinical and theoretical true dose-toxicity relationships. It was observed that accurate estimates of the true skeleton do not always outperform a generic skeleton, therefore the application of wide confidence intervals may enable a generic skeleton to be used. Further work is needed to determine the optimum skeleton.
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- 2021
13. Correction: Single-cell RNA sequencing of human breast tumour-infiltrating immune cells reveals a γδ T-cell subtype associated with good clinical outcome
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Katerina Boufea, Victor Gonzalez-Huici, Marcus Lindberg, Nelly N Olova, Stefan Symeonides, Olga Oikonomidou, and Nizar N Batada
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Ecology ,Health, Toxicology and Mutagenesis ,Plant Science ,Biochemistry, Genetics and Molecular Biology (miscellaneous) - Published
- 2022
14. CTNI-49. EARLY SIGNAL OF ACTIVITY FROM A PHASE 2 STUDY OF ST101, A FIRST-IN-CLASS PEPTIDE ANTAGONIST OF CCAAT/ENHANCER-BINDING PROTEIN Β (C/EBPΒ), IN RECURRENT GLIOBLASTOMA (GBM)
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Fabio Iwamoto, Vinai Gondi, Nicholas Butowski, Gerald Falchook, Anja Williams, Katherine B Peters, Jeff Evans, Nehal Lakhani, Meredith McKean, Stefan Symeonides, Benjamin Ellingson, Jim Rotolo, Gina Capiaux, Erol Wiegert, Rob Michel, Steve Kaesshaefer, and Alice Bexon
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Cancer Research ,Oncology ,Neurology (clinical) - Abstract
BACKGROUND C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ activates a proliferation/survival gene signature in multiple cancers, where it inversely correlates with disease prognosis and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradation. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN: This phase 2 study is enrolling adult patients with GBM that has recurred or progressed after one standard treatment regimen (surgery, radiotherapy +/-temozolomide). Patients require measurable disease at baseline and at least 3 months from prior radiotherapy. Subjects receive the recommended phase 2 dose of ST101 (500mg IV weekly). Recruitment in the phase 2 portion of this trial began in January, 2022. RESULTS As of June 1, 2022, 14 GBM patients were enrolled. One patient has a confirmed mRANO partial response (PR) after 18 weeks of therapy, seven patients have not reached the first on-study assessment and six patients progressed. The median duration of therapy was 5 weeks. ST101 has a favorable safety profile with minor infusion related reactions being the most common adverse event. Based on the confirmed PR, the GBM cohort will be expanded. CONCLUSION This first-in-class C/EBPβ inhibitor, ST101, showed an early signal of activity in recurrent GBM. More extensive follow-up and clinical experience will be presented as this trial expands and matures.
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- 2022
15. PLLBA-01 PEMBROLIZUMAB (PEMBRO) VS PLACEBO AS POST NEPHRECTOMY ADJUVANT THERAPY FOR PATIENTS (pts) WITH RENAL CELL CARCINOMA (RCC): RANDOMIZED, DOUBLE-BLIND, PHASE 3 KEYNOTE-564 STUDY
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Balaji Venugopal, Jaroslav Hajek, Naomi B. Haas, Se Hoon Park, Mauricio Mahave, Pingye Zhang, David I. Quinn, Yen-Hwa Chang, Jae-Lyun Lee, Piotr Sawrycki, Thomas W. Ferguson, Kentaro Imai, Toni K. Choueiri, Thomas Powles, Stefan Symeonides, Antoine Thiery-Vuillemin, Piotr Tomczak, Jaqueline Willemann-Rogerio, Marine Gross-Goupil, and Naveed Sarwar
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medicine.medical_specialty ,business.industry ,Urology ,medicine.medical_treatment ,Pembrolizumab ,medicine.disease ,Placebo ,Nephrectomy ,Unmet needs ,Double blind ,Renal cell carcinoma ,medicine ,Adjuvant therapy ,bacteria ,business ,Adjuvant - Abstract
INTRODUCTION AND OBJECTIVE:Effective therapy to reduce risk of RCC relapse after surgery remains an unmet need. Adjuvant immune therapy is a potential strategy for these pts. The KEYNOTE-564 trial ...
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- 2021
16. The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms
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Hagen, Schwenzer, Erica, De Zan, Mustafa, Elshani, Ruud, van Stiphout, Mary, Kudsy, Josephine, Morris, Valentina, Ferrari, In Hwa, Um, James, Chettle, Farasat, Kazmi, Leticia, Campo, Alistair, Easton, Sebastian, Nijman, Michaela, Serpi, Stefan, Symeonides, Ruth, Plummer, David J, Harrison, Gareth, Bond, and Sarah P, Blagden
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Neoplasms ,Humans ,Nucleosides ,Genome-Wide Association Study - Abstract
Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3'-Deoxyadenosine (3'-dA) is a naturally occurring adenosine analogue with established anticancer activityWe describe the synthesis of NUC-7738. We determine the ICWe show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate ourOur study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides.
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- 2021
17. Major Depression and Survival in People With Cancer
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Matteo Quartagno, Katy Burke, Stefan Symeonides, Michael Sharpe, Nicholas Magill, Amy Mulick, Aurélien Belot, Mark Toynbee, Maike van Niekerk, Jane Walker, Charlie Gourley, and Chris Frost
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Male ,medicine.medical_specialty ,Colorectal cancer ,Breast Neoplasms ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Breast cancer ,Internal medicine ,medicine ,Outpatient clinic ,Humans ,Applied Psychology ,Depression (differential diagnoses) ,Proportional Hazards Models ,Depressive Disorder, Major ,Proportional hazards model ,business.industry ,Depression ,Hazard ratio ,Cancer ,medicine.disease ,United Kingdom ,030227 psychiatry ,Psychiatry and Mental health ,business ,030217 neurology & neurosurgery - Abstract
OBJECTIVE: The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study. METHODS: We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis. RESULTS: Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (HR = 1.42, 95% confidence interval [CI] = 1.15-1.75), colorectal cancer (HR = 1.47, 95% CI = 1.11-1.94), gynecological cancer (HR = 1.36, 95% CI = 1.08-1.71), lung cancer (HR = 1.39, 95% CI = 1.24-1.56), and prostate cancer (HR = 1.76, 95% CI = 1.08-2.85). The pooled HR was 1.41 (95% CI = 1.29-1.54, p < .001, I2 = 0%). These findings were not materially different when we only considered the deaths (90%) that were attributed to cancer. CONCLUSIONS: Major depression is associated with worse survival in patients with common cancers. The mechanisms of this association and the clinical implications require further study.
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- 2021
18. Development of a LC-MS/MS method for the quantification of toxic payload DM1 cleaved from BT1718 in a Phase I study
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Catherine Gowland, Gareth J. Veal, Philip Berry, Phillip Jeffrey, Marc Pittman, Andrew Niewiarowski, Julie Errington, Lisa Godfrey, Stefan Symeonides, and Gavin Bennett
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Protein Conformation ,Clinical Biochemistry ,Peptide ,Peptides, Cyclic ,Analytical Chemistry ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Tandem Mass Spectrometry ,Lc ms ms ,General Pharmacology, Toxicology and Pharmaceutics ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Metalloproteinase ,Chromatography ,Bicyclic molecule ,Chemistry ,Protein Stability ,Payload (computing) ,General Medicine ,Hydrogen-Ion Concentration ,Anticancer drug ,Phase i study ,Medical Laboratory Technology ,030220 oncology & carcinogenesis ,Chromatography, Liquid - Abstract
Background: BT1718 is a novel bicyclic peptide anticancer drug targeting membrane type I matrix metalloproteinase to release its toxic payload DM1. A LC–MS/MS method was validated to quantify DM1 generated from BT1718 in a Phase I/IIa clinical trial. Materials & methods: Plasma samples underwent a reduction reaction to artificially cleave BT1718 into DM1 and its bicycle components. An alkylation step was carried out to stabilize the reaction products, and plasma proteins extracted using acetonitrile. LC–MS/MS analysis utilized a C18 column and Agilent 6460 triple quadrupole mass spectrometer (Agilent, Cheshire, UK). Results: The method was fully validated over a linear range of 200–50,000 ng/ml BT1718, with overall precision ≤10% and accuracy 89–102%. Conclusion: A novel method for quantifying DM1 yielded from BT1718 has been validated and is now being utilized clinically.
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- 2021
19. 566TiP A first-in-human study of NUC-7738, a ProTide transformation of 3’-deoxyadenosine, in patients with advanced solid tumours (NuTide:701)
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Ruth Plummer, M. Myers, Z. Boh, S. Blagden, Francesca Aroldi, Noor Md Haris, F. Kazmi, and Stefan Symeonides
- Subjects
Transformation (genetics) ,chemistry.chemical_compound ,Oncology ,Deoxyadenosine ,chemistry ,business.industry ,Cancer research ,Medicine ,Protide ,In patient ,Hematology ,First in human ,business - Published
- 2021
20. LBA29 Nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced renal cell carcinoma: A randomized phase II trial (PRISM)
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Gemma Ainsworth, Helen Howard, A. Jain, Paul Nathan, Ashish Sharma, E. Katona, Kate Fife, Lisa Pickering, Stefan Symeonides, Balaji Venugopal, Naveen S. Vasudev, Sarah Brown, Richard Griffiths, Fiona Collinson, Prashant Patel, Janet E. Brown, Anthony Maraveyas, Thomas Powles, T.S. Waddell, and Galina Velikova
- Subjects
medicine.medical_specialty ,business.industry ,Urology ,Ipilimumab ,Hematology ,medicine.disease ,First line treatment ,Oncology ,Renal cell carcinoma ,medicine ,Prism ,Nivolumab ,business ,medicine.drug - Published
- 2021
21. 653O Pembrolizumab (pembro) vs placebo as adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): Patient-reported outcomes (PRO) in KEYNOTE-564
- Author
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Piotr Tomczak, J. Hajek, Balaji Venugopal, Y.-H. Chang, Naveed Sarwar, David I. Quinn, M. Mahave, P. Zhang, J.-L. Lee, Naomi B. Haas, Toni K. Choueiri, Marine Gross-Goupil, Stefan Symeonides, T.B. Powles, Antoine Thiery-Vuillemin, P. Sawrycki, Tom Ferguson, S.H. Park, Jaqueline Willemann-Rogerio, and T. Saretsky
- Subjects
Oncology ,medicine.medical_specialty ,Renal cell carcinoma ,business.industry ,Internal medicine ,medicine ,Adjuvant therapy ,Hematology ,Pembrolizumab ,medicine.disease ,Placebo ,business - Published
- 2021
22. Different independent associations of depression and anxiety with survival in patients with cancer
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Michael Sharpe, Mark Toynbee, Maike van Niekerk, Chris Frost, Amy Mulick, Nicholas Magill, Matteo Quartagno, Katy Burke, Stefan Symeonides, Jane Walker, and Charlie Gourley
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Male ,medicine.medical_specialty ,Anxiety ,Hospital Anxiety and Depression Scale ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Internal medicine ,medicine ,Humans ,Outpatient clinic ,030212 general & internal medicine ,Depression (differential diagnoses) ,Depression ,business.industry ,Proportional hazards model ,Confounding ,Cancer ,medicine.disease ,Survival Analysis ,Psychiatry and Mental health ,Clinical Psychology ,Censoring (clinical trials) ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Objective Depression and anxiety have both been reported to predict worse subsequent survival in people with cancer. However, depression and anxiety are mutually associated and we lack understanding of their independent associations with survival. We therefore aimed to investigate these in a large sample of patients with common cancers. Methods We analysed data on 19,966 patients with common cancers (breast, colorectal, gynaecological, lung and prostate) who had attended specialist NHS outpatient clinics in Scotland, UK. Hospital Anxiety and Depression Scale (HADS) data were linked with demographic, cancer and mortality data. We estimated the independent associations of depression (HADS depression score) and anxiety (HADS anxiety score) with survival by fitting (separately for each cancer) Cox proportional hazards models which incorporated cubic splines to allow for non-linear associations. We also adjusted for potential confounders. Results The median time from HADS completion to death or censoring was 1.9 years. Greater depression was found to be strongly associated with worse survival from all cancers. When adjusted for anxiety, this association remained in males and increased in females. Greater anxiety was also associated with worse survival in nearly all cancers. However, when adjusted for depression, the association of anxiety with worse survival was lost. In females the association reversed direction so that greater anxiety was associated with better survival. Conclusion Although often considered together as aspects of ‘emotional distress’, depression and anxiety have different independent associations with survival in patients with cancer and should therefore be considered separately.
- Published
- 2020
23. CTNI-49. PHASE 1 STUDY OF ST101, A FIRST-IN-CLASS PEPTIDE ANTAGONIST OF CCAAT/ENHANCER-BINDING PROTEIN ß, IN PATIENTS WITH ADVANCED SOLID TUMORS, WITH A PHASE 2 EXPANSION IN RECURRENT GLIOBLASTOMA MULTIFORME
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Jim A. Rotolo, Emerson A. Lim, Rob Michel, Hendrik-Tobias Arkenau, Gerald Steven Falchook, Alice Bexon, Stefan Symeonides, Jeff Evans, Gina Capiaux, Nehal Lakhani, Meredith McKean, and Stephen Kaesshaefer
- Subjects
chemistry.chemical_classification ,Cancer Research ,Oncology ,chemistry ,Ccaat-enhancer-binding proteins ,Phase (matter) ,Recurrent glioblastoma ,Troponin I ,Antagonist ,Cancer research ,Peptide ,In patient ,Neurology (clinical) - Abstract
BACKGROUND C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ is upregulated or overactivated in multiple cancers, where it inversely correlates with disease prognosis and survival due to activation of a gene signature that promotes tumor cell proliferation and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradations. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN This phase 1-2 study is enrolling patients ≥ 18 years of age with advanced, unresectable metastatic solid tumors refractory to or intolerant of other therapeutic options. We began recruitment in August 2020. The primary objective of phase 1 is to evaluate safety and tolerability of ST101. Secondary objectives include the recommendation of a dose and regimen of ST101 for further evaluation, pharmacokinetics, several pharmacodynamic measures, and preliminary efficacy. Patients receive intravenous ST101 once weekly in a standard 3 + 3 design. Enrollment is ongoing, and by 21 May 2021, 15 patients have been recruited in four dose-escalation cohorts up to 4 mg/kg; a 5th cohort (6 mg/kg) is ongoing. The recommended phase 2 dose will be used in a 15-30 patient GBM expansion cohort, with a Simon 2-stage design, which requires one response or two patients with PFS6 in the first cohort to continue the study. Up to 120 patients are planned in a total of four expansion cohorts, which should be enrolling by Q3 2021.
- Published
- 2021
24. 525P Efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD) data from phase I dose escalation of a novel therapeutic peptide, ST101, targeting the oncogenic transcription factor C/EBPβ, in patients (pts) with advanced and metastatic solid tumors
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S.R. Chandana, T-E. Ding, Alistair Mclaren, Meredith McKean, Gerald Steven Falchook, Elisa Fontana, G. Capiaux, S. Kaesshaefer, Nehal Lakhani, M. Bupathi, R. Michel, Stefan Symeonides, Emerson A. Lim, J. Rotolo, H-T. Arkenau, T.R.J. Evans, and Alice Bexon
- Subjects
chemistry.chemical_classification ,business.industry ,Peptide ,Hematology ,Oncology ,chemistry ,Pharmacokinetics ,Pharmacodynamics ,Dose escalation ,Cancer research ,Medicine ,In patient ,business ,Transcription factor - Published
- 2021
25. Abstract LB114: Tumor uptake and predictable PK of ST101 - a peptide antagonist of C/EBPβ - in patients with advanced unresectable and metastatic solid tumors
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Rob Michel, Jim A. Rotolo, Meredith McKean, Tobias Arkenau, Stefan Symeonides, Nehal Lakhani, Emerson A. Lim, Jeff Evans, Alice Bexon, and Gerald Steven Falchook
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Cmax ,Cancer ,medicine.disease ,Prostate cancer ,Breast cancer ,Tolerability ,Pharmacokinetics ,Pharmacodynamics ,Internal medicine ,Medicine ,Adverse effect ,business - Abstract
Background: Increased activation of transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation and inhibits differentiation. ST101 is a therapeutic peptide designed to antagonize C/EBPβ; it penetrates the blood-brain barrier and has anti-tumor activity in multiple human cancer cell lines and animal models. Methods: This was a first-in-human, open-label, phase 1-2 dose-finding study. The primary objective was to evaluate safety and tolerability in patients with cancer. Secondary and exploratory objectives included ST101 pharmacokinetics (PK) and pharmacodynamics (PD). Phase 1 enrolled patients with advanced/metastatic solid tumors refractory or intolerant to all therapeutic options. Patients received ST101 intravenously 0.5, 1, 2, 4, 8 mg/kg QW and 16 mg/kg Q2W in a standard 3+3 design. The recommended phase 2 dose will be further investigated in expansion cohorts of patients with breast cancer, melanoma, glioblastoma, and castration-resistant prostate cancer. Results: As of 01.05.21 9 patients have enrolled into phase 1. Patients received 1-5 prior lines of therapy and had an ECOG status of 0 or 1. PK was predictable and consistent with pre-clinical data. Mean Cmax and AUC(0-t) increased proportionally with increasing dose. Maximum concentrations were observed at the end of 90-minute infusion and mean T1/2 was calculated as 18h and 31h, respectively in Cohort 1 and Cohort 2. Concentrations of ST101 were similar on Days 8 and 15 when compared to Day 1 in each cycle. Immunohistochemistry of tumor samples taken shortly after the 4th infusion from 2/2 patients in Cohort 1 and 1/1 patient in cohort 2 stained positive for ST101. No ST101-related serious adverse events were observed. There were no dose limiting toxicities, dose modifications or withdrawals due to toxicity. Symptoms of infusion related reactions (max grade 2) were reported in five patients and were managed with antihistamine and/or anti-inflammatory prophylaxis and by decreasing the infusion rate. Five patients withdrew due to progression of their cancer. Conclusions: ST101 was safe and well tolerated at the doses and schedule tested, and PK appeared predictable. ST101 was designed to have a prolonged plasma T1/2 and these results confirm preclinical observations, demonstrating a longer than expected T1/2 for a drug of this class. Tumor uptake of ST101 was demonstrated at the lowest dose level. ST101 dose(mg/Kg)CyclenMean Cmax (ng/mL)Mean Tmax (h)Mean AUC(0-t)(h*ng/mL)Mean Tlast (h)Mean AUC(0-inf)(h*ng/mL)Mean T1/2(h)Mean extrapolation(%)0.51316001.59000271500018230.52214001.539006NDNDND0.53211339001.5390007245000311512148001.5180008NDNDND131 Citation Format: Gerald Falchook, Meredith McKean, Nehal Lakhani, Tobias Arkenau, Stefan Symeonides, Jeff Evans, Emerson Lim, Jim Rotolo, Rob Michel, Alice Bexon. Tumor uptake and predictable PK of ST101 - a peptide antagonist of C/EBPβ - in patients with advanced unresectable and metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB114.
- Published
- 2021
26. Abstract CT136: NUC-7738, a novel ProTide transformation of 3′-deoxyadenosine, in patients with advanced solid tumors
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Stefan Symeonides, Farasat Kazmi, Ruth Plummer, Tze-en Ding, Noor Md Haris, Francesca Aroldi, Michelle Myers, and Sarah P. Blagden
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Metabolite ,Cmax ,Cancer ,medicine.disease ,Primary tumor ,Lymphoma ,chemistry.chemical_compound ,Adenosine deaminase ,Tolerability ,chemistry ,Internal medicine ,Cancer cell ,medicine ,biology.protein ,business - Abstract
Background: The novel ProTide NUC-7738 is a phosphoramidate transformation of 3'-deoxyadenosine (3'-dA or cordycepin), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3'-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3'-dATP, which inhibits DNA and RNA synthesis. Although 3'-dA has potent in vitro anti-tumor activity, it has not been successful in clinical studies due to its rapid breakdown by adenosine deaminase (ADA). NUC-7738 was designed to overcome the key cancer resistance mechanisms associated with 3'-dA. NUC-7738 is resistant to breakdown by ADA, enters cancer cells independently of the human equilibrative nucleoside transporter (hENT1) and it does not require adenosine kinase for phosphorylation. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors or lymphoma who have exhausted all standard treatment options. The primary objective is to determine the recommended phase 2 dose (RP2D) and schedule of NUC-7738. Secondary objectives include safety, pharmacokinetics and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and schedule of NUC-7738. Part 2 will further evaluate NUC-7738 in expansion cohorts of patients with advanced solid tumors or lymphomas. Results: As of 25 Sept 2020, 15 patients had received escalating doses of 14-600 mg/m2 (IV infusion from 30-120 mins) NUC-7738 q1w in Part 1. Patients had received a mean of 3 prior lines of therapy (range: 1 to 5), with melanoma (n=5) and lung (n=3) the most common primary tumor types enrolled. NUC-7738 was well tolerated, with no Grade 3 or 4 treatment-related AEs. No dose-limiting toxicities have been reported. Encouraging signals of anti-cancer activity were observed in three patients who continued to receive clinical benefit for over 6 months (1 patient remained on treatment for over 17 months). NUC-7738 has a predictable plasma PK profile, with a dose proportional increase in Cmax and AUC. High intracellular levels of the anti-cancer metabolite 3'-dATP in PBMCs were detected 2 hours after the start of infusion and maintained for at least 24 hours. Conclusion: NUC-7738 has shown promising anti-cancer activity and a favorable tolerability profile in patients with advanced, treatment-refractory tumors. Patients had high and durable intracellular levels of the anti-cancer metabolite 3'-dATP, supporting non-clinical data that NUC-7738 overcomes the key cancer resistance mechanisms associated with 3'-dA. Citation Format: Ruth Plummer, Farasat Kazmi, Noor Md Haris, Tze-en Ding, Francesca Aroldi, Michelle Myers, Stefan Symeonides, Sarah Blagden. NUC-7738, a novel ProTide transformation of 3′-deoxyadenosine, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT136.
- Published
- 2021
27. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study
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Piotr Tomczak, Thomas Powles, David I. Quinn, Naomi B. Haas, Mauricio Mahave, Tom Ferguson, Se Hoon Park, Jaroslav Hajek, Naveed Sarwar, Toni K. Choueiri, Marine Gross-Goupil, Piotr Sawrycki, Eric (Pingye) Zhang, Yen-Hwa Chang, Balaji Venugopal, Kentaro Imai, Jae-Lyun Lee, Stefan Symeonides, Antoine Thiery-Vuillemin, and Jaqueline Willemann Rogerio
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Urology ,Pembrolizumab ,Perioperative ,medicine.disease ,Placebo ,Nephrectomy ,Double blind ,Oncology ,Renal cell carcinoma ,Adjuvant therapy ,Medicine ,business ,Clear cell - Abstract
LBA5 Background: Relapse after surgery for high-risk clear cell RCC (ccRCC) is associated with shortened life expectancy. Effective perioperative therapy to reduce this risk remains an unmet need. Adjuvant immune therapy is an attractive potential strategy for these pts. We conducted the KEYNOTE-564 trial to evaluate pembro vs placebo as adjuvant therapy for pts with RCC. Methods: KEYNOTE-564 is a phase III multicenter trial of pembro vs placebo in pts with histologically confirmed ccRCC, with intermediate-high risk (pT2, Gr 4 or sarcomatoid, N0 M0; or pT3, any Gr, N0 M0), high risk (pT4, any Gr, N0 M0; or pT any stage, any Gr, N+ M0), or M1 NED (no evidence of disease after primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy) (Leibovich et al, 2003; Fuhrman et al, 1982). Pts had undergone surgery ≤12 wks prior to randomization; had no prior systemic therapy; had ECOG PS 0 or 1. Study treatment was given for up to 17 cycles (≈1 yr). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated pts. Results: Between Jun 30, 2017 and Sept 20, 2019, 994 pts were randomized 1:1 to pembro (n=496) or placebo (n=498). As of data cutoff date of Dec 14, 2020, median (range) follow-up, defined as time from randomization to data cutoff, was 24.1 (14.9−41.5) mo. No pts remain on study treatment. Baseline characteristics were generally balanced between arms. At first prespecified interim analysis, the primary endpoint of DFS was met (median not reached [NR] for both arms, HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided]). The estimated DFS rate at 24 mo was 77.3% with pembro vs 68.1% with placebo. Overall, DFS benefit was consistent across subgroups. A total of 51 OS events were observed (18 in the pembro arm, 33 in the placebo arm). Median OS was NR for both arms (HR 0.54, 95% CI 0.30−0.96; P=0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 mo was 96.6% with pembro vs 93.5% with placebo. 470 pts (96.3%) and 452 pts (91.1%) experienced ≥1 all-cause adverse events (AEs) with pembro vs placebo, respectively. Grade 3-5 all-cause AEs occurred in 158 pts (32.4%) with pembro and 88 pts (17.7%) with placebo. No deaths related to pembro occurred. Conclusions: Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo in pts with intermediate-high, high risk or M1 NED RCC. Additional follow-up is planned for the key secondary endpoint of OS. KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembro as a potential new standard of care for pts with RCC in the adjuvant setting. Clinical trial information: NCT03142334.
- Published
- 2021
28. Is improvement in comorbid major depression associated with longer survival in people with cancer? A long-term follow-up of participants in the SMaRT oncology-2 and 3 trials
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Stefan Symeonides, Jane Walker, Katy Burke, Stephen Puntis, Chris Frost, Marta Wanat, Michael Sharpe, Amy Mulick, and Charlie Gourley
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Male ,medicine.medical_specialty ,Long term follow up ,Comorbidity ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Depression (differential diagnoses) ,Depressive Disorder, Major ,business.industry ,Proportional hazards model ,Confounding ,Cancer ,Middle Aged ,medicine.disease ,Survival Analysis ,Checklist ,Confidence interval ,Psychiatry and Mental health ,Clinical Psychology ,Female ,business ,030217 neurology & neurosurgery ,Follow-Up Studies ,Cohort study - Abstract
Objective There is evidence that patients with cancer have worse survival if they have comorbid major depression, but uncertainty whether a reduction in depression severity improves survival. We aimed to address this question. Methods We did a secondary analysis of data from participants in the SMaRT Oncology-2 and 3 trials of depression treatment in patients with cancer and comorbid major depression (total n = 642). Participants' data were analysed as cohorts, defined by treatment (usual care or Depression Care for People with Cancer, an intensive treatment programme, in both trials) and cancer prognosis (good or poor, in SMaRT Oncology-2 and 3 respectively). We measured change in depression severity from randomisation to 12 weeks using Symptom Checklist Depression Scale (SCL-20) scores and assessed survival by linked mortality data. We used Cox regression to estimate the effect of a one-unit decrease in SCL-20 score on survival, controlling for measured confounders. Results We found no evidence for an association between improvement in depression and survival in any of the four cohorts, after adjusting for age, sex, primary cancer, baseline cancer severity and baseline depression severity. Pooling the cohorts in a fixed-effects meta-analysis yielded an estimated 7% reduction in the hazard of death per one-unit decrease in SCL-20 score. This finding was not statistically significant; the 95% confidence interval extended from a 26% decrease to an 18% increase in hazard of death. Conclusion We found no evidence that reduction in severity of comorbid major depression is associated with longer survival in patients with cancer.
- Published
- 2018
29. Prognostic value of simple blood biomarkers of systemic inflammation for metastatic renal cell carcinoma (mRCC) patients who undergo cytoreductive nephrectomy (CNx)
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Mark Stares, Steve Leung, Stefan Symeonides, Alex Laird, Jigi Moudgil-Joshi, Aravindhan Sundaramurthy, and Jahangeer Malik
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Cancer Research ,medicine.medical_specialty ,business.industry ,Urology ,Systemic inflammation ,medicine.disease ,Oncology ,Renal cell carcinoma ,Blood biomarkers ,Medicine ,In patient ,Cytoreductive nephrectomy ,medicine.symptom ,business ,Value (mathematics) - Abstract
350 Background: The role of cytoreductive nephrectomy (CNx) in patients with metastatic renal cell carcinoma (mRCC) is currently in question. Assessing the benefits and risks of CNx is challenging, with a lack of validated prognostic tools. Biomarkers of the systemic inflammatory response have prognostic utility in mRCC and are included in the IMDC score used to predict survival in patients with mRCC treated with systemic therapy. We sought to investigate their role in patients with mRCC who had undergone CNx. Methods: A cohort of 68 patients, suitable for first-line VEGFR inhibitor (VEGFRi) systemic therapy, who had undergone CNx for mRCC, were identified from a clinical database of patients referred to a regional mRCC service. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and overall survival and time to VEGFRi (tVEGFRi) was examined using Kaplan-Meier and Cox-regression methods. Results: Data were available for 68 patients. Median survival was 33.7 months. On multivariate analysis, albumin ( < 35g g/dL v ≥35 g/dL) and CRP (≤ 10 mg/L v > 10 mg/L) were independently associated with overall survival (p = 0.027 and p = 0.034 respectively). Albumin stratified survival from 24.7 to 87.2 months (p < 0.0001) and CRP from 29.4 to 82.3 months (p = 0.004). 40 (59%) patients subsequently commenced VEGFRi therapy. Median tVEGFRi was 18.1 months, with only 5 (7%) patients commencing treatment within 3 months. 16 (24%) patients yet to receive systemic therapy remain alive after a median 54.0 months follow-up. On multivariate analysis, albumin was also predictive of tVEGFRi (p = 0.037), stratifying tVEGFRi from 6.07 to 45.7 months (p = 0.002). Conclusions: These results highlight that biomarkers of the systemic inflammatory response are strong prognostic factors in mRCC patients who have undergone CNx. Albumin and CRP, but not IMDC, predict survival in this patient group. Significantly, the population investigated here differ from those included in the CARMENA and SURTIME studies, with a majority undergoing surveillance prior to VEGFRi therapy. Our results support a role for CNx in patients where deferred systemic therapy strategies may be employed. Albumin may assist in clinical decision making when considering when to start systemic therapy. We advocate further studies to investigate the prognostic role of these simple, routine clinical tests in patients with mRCC undergoing CNx.
- Published
- 2021
30. Prognostic biomarkers of systemic inflammation in patients on active surveillance for metastatic renal cell carcinoma (mRCC): A biobank analysis
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Aravindhan Sundaramurthy, Vishwani Chauhan, Stefan Symeonides, Jahangeer Malik, and Mark Stares
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.disease ,Systemic inflammation ,Biobank ,Disease course ,Renal cell carcinoma ,Internal medicine ,Toxicity ,medicine ,In patient ,medicine.symptom ,business - Abstract
348 Background: A subset of patients with metastatic renal cell carcinoma (mRCC) follow an indolent disease course. Given the toxicity and non-curative nature associated with systemic anti-cancer therapy (SACT), some patients may benefit from initial active surveillance (AS). However, selecting patients suitable for this approach is challenging. Biomarkers of systemic inflammation predict survival in mRCC, both independently and as part of the International Metastatic Database Consortium (IMDC) risk score. We sought to use these biomarkers to characterise the time to initiation of SACT (tSACT) in mRCC patients on AS. Methods: 126 mRCC patients clinically assessed and commenced on AS prior to any systemic therapy were retrospectively identified from a regional mRCC clinical database. Patients who underwent metastasectomy for oligometastatic disease at any time were excluded. The primary endpoint, tSACT, was defined as the time from radiological diagnosis of mRCC until SACT initiation, or death, or censorship if continuing AS at follow-up date. Inflammatory biomarkers from routine blood tests (haemoglobin, white cell count, neutrophil count, platelets, C-reactive protein (CRP), albumin) and the IMDC score, measured at the time of diagnosis of mRCC, were recorded. The relationship between these and tSACT was examined using Kaplan-Meier and Cox-regression methods. Results: 66 (52%) patients had commenced SACT. 17 (13.5%) had died without commencing SACT (median survival of the 17 was 40.4 months, range 9.1-130.2 months, and comorbidities may have affected fitness for starting therapy or led to all-cause mortality). 43 patients remained on AS, with minimum and median follow-up of 12.6 months and 39.6 months respectively. The median tSACT was 17.2 months (IQR 8.8-34.8 months). On univariate analysis, CRP and albumin were predictive of time on AS ( p= 0.01 and p= 0.049 respectively). On multivariate analysis, only CRP was independently associated with tSACT ( p= 0.035), stratifying tSACT from 9.1 months (CRP > 10) to 20.9 months (CRP≤10) ( p= 0.009). 111 (88.1%) patients were IMDC 0-1, while 12 (9.5%) and 3 (2.4%) were IMDC 2 or 3 and may have had comorbidities that influenced the initial AS decision. In our cohort the IMDC risk score did not predict time on AS. Conclusions: These results highlight that some patients with mRCC may undergo active surveillance for a marked time period before SACT initiation. We identify routine biomarkers of the systemic inflammatory response that predict time to systemic therapy. In particular CRP, a simple measure of inflammation, stratifies the time to initiation of SACT across a clinically significant time period. This simple, widely available test may help to objectively inform clinical decisions about AS in patients in mRCC. Additional experience is necessary to further define the risks and benefits of this approach.
- Published
- 2021
31. Single-cell RNA sequencing of human breast tumour-infiltrating immune cells reveals a γδ T-cell subtype associated with good clinical outcome
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Katerina Boufea, Victor Gonzalez-Huici, Marcus Lindberg, Nelly N Olova, Stefan Symeonides, Olga Oikonomidou, and Nizar N Batada
- Subjects
Resource ,Adult ,0301 basic medicine ,Health, Toxicology and Mutagenesis ,medicine.medical_treatment ,T cell ,Antigen presentation ,Blood Donors ,Breast Neoplasms ,Kaplan-Meier Estimate ,Plant Science ,Biology ,Major histocompatibility complex ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Cancer immunotherapy ,Antigen ,Tumor Microenvironment ,medicine ,Humans ,Cytotoxic T cell ,RNA-Seq ,Intraepithelial Lymphocytes ,Cells, Cultured ,Base Sequence ,Ecology ,Cancer ,Receptors, Antigen, T-Cell, gamma-delta ,Prognosis ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Case-Control Studies ,biology.protein ,Cancer research ,Female ,Single-Cell Analysis ,030217 neurology & neurosurgery - Abstract
Single-cell sequencing of γδ-T cells from human blood and tumours revealed novel markers of subtypes with distinct effector functions and a subtype that is associated with favourable clinical outcome., The association of increased levels of tumour-infiltrating gamma-delta (γδ) T cells with favorable prognosis across many cancer types and their ability to recognize stress antigens in an MHC unrestricted manner has led to an increased interest in exploiting them for cancer immunotherapy. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood γδ T cells from healthy adult donors and from fresh tumour biopsies of breast cancer patients. We identified five γδ T cells subtypes in blood and three subtypes of γδ T cells in breast tumour. These subtypes differed in the expression of genes contributing to effector functions such as antigen presentation, cytotoxicity, and IL17A and IFNγ production. Compared with the blood γδ T cells, the breast tumour-infiltrating γδ T cells were more activated, expressed higher levels of cytotoxic genes, yet were immunosuppressed. One subtype in the breast tumour that was IFNγ-positive had no obvious similarity to any of the subtypes observed in the blood γδ T cell and was the only subtype associated with improved overall survival of breast cancer patients. Taken together, our study has identified markers of subtypes of human blood γδ T cells and uncovered a tumour-infiltrating γδ T cells subtype associated improved overall cancer survival.
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- 2020
32. 600TiP A first-in-human study of, NUC-7738, a 3'-dA phosphoramidate, in patients with advanced solid tumours (NuTide:701)
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Ruth Plummer, Francesca Aroldi, S. Kestenbaumum, S. Blagden, N. Md Harris, and Stefan Symeonides
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Oncology ,business.industry ,Cancer research ,Medicine ,Phosphoramidate ,In patient ,Hematology ,First in human ,business - Published
- 2020
33. Abstract A047: MT1-MMP Immunohistochemistry (IHC) analysis of tumor microarrays (TMAs) using a novel scoring system guides patient selection for BT1718 expansion cohorts
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Fiona Kelly, Chris M. Bacon, Philip Sloan, Stefan Symeonides, Michael Rigby, Stephanie Guerrera, Stephen J. Blakemore, and Tara Gelb
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Oncology ,Cancer Research ,medicine.medical_specialty ,Cancer ,Histology ,medicine.disease ,Clinical trial ,In vivo ,Internal medicine ,medicine ,Immunohistochemistry ,MMP14 ,Adenocarcinoma ,Ovarian cancer - Abstract
Introduction: BT1718 is a targeted Bicycle peptide-conjugate designed to deliver the anti-tubulin agent, DM1 to tumors expressing membrane type 1-matrix metalloprotease (MT1-MMP; MMP14; MT1). In vivo preclinical studies demonstrated that anti-tumor activity of BT1718 is dependent on the level of tumor MT1-MMP expression. In patient tumors MT1-MMP expression has been reported in tumor and stromal cells, both of which may contribute to the potential for anti-tumor effects following BT1718 dosing. BT1718 is currently being investigated in a Phase 1/2 clinical trial, which includes both dose escalation (ongoing) and dose expansion cohorts enrolling patients with advanced solid tumors that have exhausted standard therapeutic options. The dose expansion cohorts will enroll patients with tumors expressing high levels of MT1-MMP following establishment of the recommended Phase 2 dose. Here we describe the analysis of TMAs stained using a clinical grade MT1-MMP IHC assay to guide which patient populations to include in BT1718 dose expansion cohorts. Methods: A clinical grade MT1-MMP IHC assay was developed on the Ventana platform using a Millipore MT1-MMP primary antibody (MAB3328) at 1:6000 and detected using Optiview chemistry. Cancer indications reported in the literature with high MT1-MMP expression including ovarian, bladder, triple negative breast, esophageal, and NSCLC were stained and MT1-MMP expression levels estimated by consensus review of two pathologists using an H-score scale (staining intensity*percent positivity). H-scores (0-300) were derived separately for tumor membrane (TM), cytoplasm (TC), and stroma (TS) for each case. Results: MT1-MMP expression in TM/TS, but not TC is likely to yield the greatest potential for BT1718 binding and subsequent anti-tumor activity. Therefore, analyses of TM/TS H-scores were used to identify BT1718 dose expansion cohorts. Histograms were generated separately for TM and TS H-scores with a bin-width of 50. The distribution of MT1-MMP staining in TM and TS was different (Table 1) with H-score between 0-49 being the most frequently populated TM bin, regardless of indication. In contrast, TS scores were typically higher (e.g. H-score=100-149), with the clearest example being ovarian cancer (89% of cases TM 0-49 & only 20% of cases TS 0-49). In addition, within NSCLC, tumor subtype analysis demonstrated that cases of squamous histology appeared enriched for higher TM H-scores (TM≥150=36%) compared to adenocarcinoma cases (TM≥150=2%). Moreover, various TM and/or TS H-score boundaries were modelled with the aim of delivering a proposed cut-off for recruiting patients with high MT1-MMP expression to the expansion cohorts, the results of this modelling will be presented. Table 1: Distribution of MT1-MMP TM and TS H-scores across multiple indications p> Citation Format: Tara Gelb, Chris Bacon, Philip Sloan, Mike Rigby, Stephanie Guerrera, Fiona Kelly, Stefan Symeonides, Stephen J Blakemore. MT1-MMP Immunohistochemistry (IHC) analysis of tumor microarrays (TMAs) using a novel scoring system guides patient selection for BT1718 expansion cohorts [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A047. doi:10.1158/1535-7163.TARG-19-A047
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- 2019
34. Pharmacokinetic (PK) assessment of BT1718: A phase I/II a study of BT1718, a first in class bicycle toxin conjugate (BTC), in patients (pts) with advanced solid tumours
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M. Rigby, P. Jeffrey, Manreet Randhawa, S. Blakemore, Gavin Bennett, Udai Banerji, Maria Koehler, Natalie Cook, Marc Pittman, Theodora Germetaki, A. Biondo, J. Evans, Stefan Symeonides, Lisa Godfrey, A. Niewiarowski, and S. Leslie
- Subjects
Oncology ,medicine.medical_specialty ,Manchester Cancer Research Centre ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Phases of clinical research ,Cancer ,Hematology ,medicine.disease ,Clinical trial ,Breast cancer ,Pharmacokinetics ,Tolerability ,Internal medicine ,medicine ,Dosing ,business ,Triple-negative breast cancer - Abstract
Background BT1718 contains a constrained bicyclic peptide with high affinity and selectivity for cell surface target MT1-MMP (MMP14) linked to a toxin (DM1) via a cleavable disulphide linker. BT1718 has demonstrated significant anti-tumor activity in preclinical studies in tumors that express MT1-MMP. Following intravenous (IV) administration to preclinical species, BT1718 exhibited PK typical of a BTC. We report clinical progress on QW and BIW dosing, plasma and tumor PK results. Methods This is a first in human, multicenter, dose escalation study in advanced solid tumor pts with the aims of establishing the recommended phase 2 dose (RP2D) for QW & BIW IV BT1718 dosing (3 out of every 4 weeks per cycle), and exploratory PK. Following determination of RP2Ds, expansion cohorts will enroll to further explore efficacy, tolerability and PD of BT1718 in ∼70 pts with MT1-MMP expressing tumors such as NSCLC and TNBC. Results 24 pts were enrolled with various types of solid tumors across both dose escalation cohorts (see table). BIW RP2D was determined as 7.2 mg/m2. The 2 pts with DLTs at 9.6 mg/m2 BIW experienced grade 3 increased GGT or fatigue. QW dose escalation continues at 20 mg/m2. Mean number of cycles received = 2.3 months (N = 24), with no objective responses observed to date in this unselected population. Consistent with preclinical data, preliminary clinical PK results with BT1718 confirm moderate plasma clearance (∼10 mL/min/kg) linear with dose, a volume of distribution similar to extracellular fluid (∼0.20 L/kg) and a t1/2 of ∼0.3 h. Analysis of pts biopsy samples confirms distribution of DM1 in tumors at similar concentrations observed in mouse xenograft models. Results will be updated at time of presentation. Table . 464P BT1718 Dose (mg/m2) Twice weekly schedule (BIW) Once weekly schedule (QW) DLT evaluable pts DLTs DLT evaluable pts DLTs 0.6 1 0 NA NA 1.2 1 0 NA NA 2.4 1 0 NA NA 4.8 1 0 NA NA 7.2 6 0 NA NA 9.6 4 2 3 0 15 NA NA 3 0 20 NA NA 2 0 Conclusions BT1718 is a first in class BTC which is generally well tolerated at the present dose level. Current plasma and tumor PK data are consistent with proposed preclinical mechanism of tumor targeted toxin delivery. Clinical trial identification NCT03486730. Legal entity responsible for the study Cancer Research UK. Funding Cancer Research UK and BicycleRD Limited. Disclosure N. Cook: Advisory / Consultancy: Tarveda Therapeutics; Advisory / Consultancy: Epigene Therapeutics. U. Banerji: Advisory / Consultancy: Astellas; Advisory / Consultancy: Novartis; Advisory / Consultancy: Karus Therapeutics; Advisory / Consultancy: Phoenix ACT; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Astex; Advisory / Consultancy: Vernalis; Research grant / Funding (institution), ONX-0801: funding for investigator-initiated Phase I trial: Onyx Pharmaceuticals; Research grant / Funding (institution), ONX-0801: funding for investigator-initiated Phase I trial: BTG International; Research grant / Funding (institution), RAF/MEK: funding for investigator-initiated Phase I trial: Chugai; Research grant / Funding (institution), TAX-TORC: funding for investigator-initiated Phase I trial: AstraZeneca; Research grant / Funding (institution), FRAME: funding for investigator-initiated Phase I trial: Verastem; Full / Part-time employment, ICR is involved in the development of PI3K, HSP90, HDAC, AKT, ROCK, RAF and CHK1: Institute of Cancer Research. J. Evans: Speaker Bureau / Expert testimony: BMS, Eisai, Bayer, Roche, Celgene, MSD; Officer / Board of Directors, Committee Member: Genmab (chair), BMS; Advisory / Consultancy: Karus Therapeutics; Research grant / Funding (self): AstraZeneca, Basliea, BMS, Bayer, Celgene, MSD, MiNa therapeautics, Roche, Medicina, Pfizer, Sierra, Verastem, Lilly, Eisai, NuCana, GSK, Novartis, Immunocore, Bicycle Therapeutics, Haloxyme, Berg, JJ Leadership role, Non-remunerated: Cancer Research UK, NCRN, Breast Cancer Now, Pancreatic Cancer Research Fund, EORTC GI group member, British Council of Cancer, Wales Clinical Trial Unit, ILCA; Non-remunerated activity/ies, Member: BACR, EACT, ACP, ESMO, ASCO, AACR. A. Biondo: Full / Part-time employment, ICR is involved in the development of PI3K, HSP90, HDAC, AKT, ROCK, RAF and CHK1: Institute of Cancer Research. P. Jeffrey: Full / Part-time employment: BicycleRD Limited. M. Rigby: Full / Part-time employment: BicycleRD Limited. G. Bennett: Full / Part-time employment: BicycleRD Limited. S. Blakemore: Full / Part-time employment: BicycleRD Limited. All other authors have declared no conflicts of interest.
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- 2019
35. A Cancer Research UK phase I/IIa trial of BT1718 (a first in class Bicycle Drug Conjugate) given intravenously in patients with advanced solid tumours
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Claire L. S. Kelly, Stefan Symeonides, Udai Banerji, Gavin Bennett, T.R. Jeffry Evans, Sawretse Leslie, Natalie Cook, Marc Pittman, Patricia Roxburgh, Sidath Katugampola, Narmatha Sabaratnam, Lisa Godfrey, Irene Moreno Candilejo, Neil Tremayne, Rashmi Passi, Gillian Langford, and Maria Koehler
- Subjects
0301 basic medicine ,Drug ,Cancer Research ,Metalloproteinase ,medicine.diagnostic_test ,Manchester Cancer Research Centre ,business.industry ,Proteolysis ,media_common.quotation_subject ,ResearchInstitutes_Networks_Beacons/mcrc ,Matrix metalloproteinase ,03 medical and health sciences ,030104 developmental biology ,Oncology ,medicine ,Cancer research ,In patient ,business ,Conjugate ,media_common - Abstract
TPS2610Background: Membrane type I matrix metalloproteinase (MT1-MMP) is a member of the matrix metalloproteinase (MMP) family which are involved in tissue remodelling through proteolysis of extrac...
- Published
- 2018
36. Does depression treatment improve the survival of depressed patients with cancer? A long-term follow-up of participants in the SMaRT Oncology-2 and 3 trials
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Chris Frost, Michael Sharpe, Stefan Symeonides, Jane Walker, Amy Mulick, Marta Wanat, Charlie Gourley, Katy Burke, and Stephen Puntis
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Oncology ,Male ,medicine.medical_specialty ,Comorbidity ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Randomized controlled trial ,law ,Internal medicine ,Neoplasms ,medicine ,Humans ,030212 general & internal medicine ,Biological Psychiatry ,Depression (differential diagnoses) ,Survival analysis ,Aged ,Depressive Disorder, Major ,business.industry ,Proportional hazards model ,Hazard ratio ,Cancer ,Middle Aged ,medicine.disease ,Survival Analysis ,humanities ,Psychiatry and Mental health ,Treatment Outcome ,Scotland ,030220 oncology & carcinogenesis ,Quality of Life ,Female ,business ,Follow-Up Studies - Abstract
Background: Comorbid major depression has been associated with worse survival in patients with cancer. However, we do not know if treating depression improves survival. In the SMaRT Oncology-2 (good prognosis cancers) and SMaRT Oncology-3 (lung cancer, a poor prognosis cancer) trials, we found that a depression treatment programme, Depression Care for People with Cancer (DCPC), was effective in reducing comorbid major depression. In this analysis, we aimed to identify whether DCPC also had an effect on survival.Methods: The trials were conducted in three cancer centres and their associated clinics in Scotland, UK. In SMaRT Oncology-2, outpatients with good prognosis cancers and major depression were randomly assigned in a 1:1 ratio to DCPC or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. In SMaRT Oncology-3, outpatients with lung cancer and major depression were randomly assigned (1:1 ratio) to DCPC or usual care with stratification (by trial centre) and minimisation (by age, sex, and cancer type) with allocation concealment. For this analysis, we obtained long-term data on deaths (all causes) in the SMaRT Oncology-2 and 3 trial participants, censored at July 31, 2015, and analysed survival as a trial outcome. We estimated unadjusted hazard ratios (HRs) for each trial using Cox regression, and pooled the log HRs in a fixed-effects meta-analysis.Findings: We recruited 642 participants; between May 12, 2008, and May 13, 2011, 500 participants were recruited to the SMaRT Oncology-2 trial and between Jan 5, 2009, and Sept 9, 2011, 142 participants were recruited to the SMaRT Oncology-3 trial. We followed up SMaRT Oncology-2 and SMaRT Oncology-3 participants for a median of 5 years and 1 year, respectively. 135 (27%) of 500 SMaRT Oncology-2 participants and 114 (80%) of 142 SMaRT Oncology-3 participants died within this period. We found no significant effect of DCPC on survival in the total follow-up period for either SMaRT Oncology 2 (HR 1·02, 95% CI 0·72–1·42, p=0·93) or SMaRT Oncology-3 (HR 0·82, 95% CI 0·56–1·18, p=0·28; pooled HR 0·92, 95% CI 0·72–1·18, p=0·51).Interpretation: DCPC is highly effective in improving depression and quality of life in depressed patients with cancer, but there was no evidence for a significant effect on survival. Despite the absence of an effect on length of life, the management of depression remains important for its beneficial effect on quality of life.Funding: NIHR CLAHRC Oxford, Cancer Research UK, and the Chief Scientist Office of the Scottish Government.
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- 2018
37. A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer
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Joanita Ocen, Hendrik-Tobias Arkenau, Louise Carter, Mark Marion Kowalski, Elizabeth Ruth Plummer, T.R. Jeffry Evans, Manreet Randhawa, Sarah Danson, Debashis Sarker, Sarah P. Blagden, Robert H. Jones, Udai Banerji, Elena Cojocaru, Andrew Dye, Noor Md Haris, Rebecca Kristeleit, Ines Verdon, Stefan Symeonides, and Harriet S. Walter
- Subjects
Cancer Research ,business.industry ,First in human ,Highly selective ,Advanced cancer ,03 medical and health sciences ,0302 clinical medicine ,Phase i ii ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,CHEK1 ,business ,030215 immunology - Abstract
3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The Cmax and AUC0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the Cmin (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.
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- 2019
38. A first-in-human study of, NUC-7738, a 3'dA phosphoramidate, in patients with advanced solid tumors or lymphoma (NuTide 701)
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Gareth P Bond, Elizabeth Ruth Plummer, Sarah P. Blagden, Hagen Schwenzer, and Stefan Symeonides
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Cancer Research ,Nucleoside analogue ,Clinical effectiveness ,business.industry ,Phosphoramidate ,First in human ,medicine.disease ,Lymphoma ,Oncology ,medicine ,Cancer research ,In patient ,business ,medicine.drug - Abstract
TPS3147 Background: Nucleoside analogs form the backbone therapy for both hematological and solid malignancies. However, their clinical effectiveness is severely limited by key cellular resistance mechanisms linked to increased breakdown, impaired activation and transport. NUC-7738 is a phosphoramidate transformation of cordycepin (3’-deoxyadenosine; 3’-dA), a derivative of adenosine that was first isolated from Cordyceps sinensis. The cytotoxic effect of 3’-dA is largely attributed to intracellular generation of the triphosphate metabolite, 3’-dATP, terminating DNA and RNA synthesis. Although 3’-dA has shown potent anti-tumor activity in non-clinical studies, it has not been successful in clinical studies mainly because of rapid enzymatic degradation by adenosine deaminase. NUC-7738 is not a substrate for adenosine deaminase and has been designed to bypass the key resistance pathways which have limited the clinical effectiveness of cordycepin. Methods: NuTide:701 is a two-part, first-in-human Phase I study in patients with advanced solid tumors and lymphoma who have exhausted all standard treatment options. The primary objective is to determine the RP2D and schedule of NUC-7738. Secondary objectives include safety, PK/PD and anti-tumor activity. Part 1, in patients with advanced solid tumors, will establish the RP2D and dose administration schedule of NUC-7738 for Part 2. Part 2 will further evaluate the selected RP2D and designated dosing schedule in an expansion cohort of patients with advanced solid tumors or lymphoma. The study initiated in Q1 2019. Clinical trial information: NCT03829254.
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- 2019
39. A CRUK first-in-human phase I trial of a CDC7 Inhibitor, LY3143921 hydrate, in patients with advanced solid tumors
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Lesley McGuigan, Richard H. Wilson, Barbara Stanley, Stefan Symeonides, Gregory Naylor, Lisa Godfrey, Saira Bashir, T.R. Jeffry Evans, Peter Gallagher, Elizabeth Ruth Plummer, Patricia Roxburgh, Noor Md Haris, Moira A. Elliott, Nicola Dobbs, Victoria Coyle, Sue Brook, Sally Clive, and Gavin Halbert
- Subjects
Cancer Research ,DNA replication initiation ,business.industry ,A protein ,First in human ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Phase (matter) ,Cancer research ,Medicine ,In patient ,business ,Hydrate ,030215 immunology - Abstract
TPS3167 Background: CDC7 is a protein with key roles in DNA replication initiation, the intra-S-phase checkpoint and M-phase completion. CDC7 is over-expressed in malignant compared to non-malignant cells, particularly those with TP53 mutations, making it an attractive therapeutic target. LY3143921 hydrate is an orally administered ATP-competitive CDC7 inhibitor. Pre-clinical studies in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC) demonstrate favourable anti-cancer activity, particularly in squamous NSCLC and in CRC with TP53 null and missense mutations. We hypothesise that solid tumours mutated in TP53 will be sensitive to LY3143921 therapy. Methods: This is a first-in-human, phase I trial of LY3143921 hydrate (LY3143921) monotherapy given twice daily, continuously on a 21 day schedule until disease progression, patient (pt) withdrawal or unacceptable toxicity (NCT03096054). Eligible pts have histologically proven advanced/metastatic solid tumours for which no further standard therapy exists and WHO PS 0-1. Pts have regular clinical assessment and tumour imaging every 2 cycles. Phase Ia (dose escalation) is recruiting in a 3+3 design following 3 initial single patient cohorts (starting dose 30 mg OD), enriching for patients with malignancies associated with p53 mutations (CRC, sqNSCLC, high grade serous ovarian, squamous cell oesophageal, squamous cell head & neck, urothelial, pancreatic and triple negative breast cancer). Recruitment to cohort 6 (180 mg BD) is ongoing. On determination of the maximum tolerated dose (MTD) and recommended phase II dose and schedule (RP2D), 2 expansion cohorts (≤ 25 pts each) of patients with CRC and sqNSCLC will be evaluated. Primary objectives: assess safety and tolerability of LY3143921, determine MTD and RP2D. Secondary objectives: evaluate preliminary efficacy and PK profile of LY3143921. All pts will have archival tumour tissue retrospectively analysed, while patients in phase Ib will also have pre- and on-treatment tumour biopsies. Evaluation of potential predictive and pharmacodynamic biomarkers including p53 mutations, phosphorylated MCM2, cyclin B1 and molecular subgroups of target tumours will be included. Clinical trial information: NCT03096054.
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- 2019
40. Cabozantinib in metastatic renal cell carcinoma (mRCC): Data from UK expanded access program (EAP)
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Naveen S. Vasudev, Balaji Venugopal, Thomas Powles, C. Pettinger, Ekaterini Boleti, S. Rudman, A. Gomez de Liano Lista, L. Khasati, Kate Fife, S. Vohra, Stefan Symeonides, L. Morrison, and Bernadett Szabados
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Cabozantinib ,business.industry ,Hematology ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Renal cell carcinoma ,030220 oncology & carcinogenesis ,Internal medicine ,Expanded access ,medicine ,business - Published
- 2018
41. Treatment of depression in adults with cancer: a systematic review of randomized controlled trials
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Michael Sharpe, Aarti Sawhney, Gordon D Murray, C. Holm Hansen, Paul Martin, Stefan Symeonides, Jane Walker, and S. Ahmed
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medicine.medical_specialty ,education.field_of_study ,Depression ,business.industry ,Population ,MEDLINE ,Cancer ,PsycINFO ,medicine.disease ,law.invention ,Clinical trial ,Psychiatry and Mental health ,Randomized controlled trial ,law ,Neoplasms ,medicine ,Humans ,Psychiatry ,Intensive care medicine ,education ,business ,Applied Psychology ,Disease burden ,Depression (differential diagnoses) ,Randomized Controlled Trials as Topic - Abstract
BackgroundDepression is a leading cause of disease burden worldwide and is especially problematic in people with chronic diseases, including cancer. Although depression can be effectively treated in the general population using antidepressant medication and psychological treatments, these treatments may have different benefits and harms in cancer patients. Previous reviews have not adequately addressed this topic. We therefore aimed to determine which, if any, treatments are effective for patients with diagnoses of both cancer and depression.MethodWe conducted a systematic review of relevant randomized controlled trials identified through searches of Medline, EMBASE, PsycINFO and The Cochrane Central Register of Controlled Trials (CENTRAL).ResultsSeven relatively small trials met the selection criteria. These provided some evidence that antidepressant medication, given alone or in combination with a psychological treatment, may be effective. We found no good evidence for psychological treatments given alone or for any other forms of treatment.ConclusionsThere is very limited evidence from clinical trials to guide the treatment of cancer patients with a diagnosis of depression, especially for psychological treatments. High quality trials of treatments for depression in patients with cancer are urgently needed.
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- 2013
42. Prevalence of depression in adults with cancer: a systematic review
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Paul Martin, Gordon D Murray, Michael Sharpe, C. Beale, Stefan Symeonides, Aarti Sawhney, Jane Walker, Lucy Wall, C. Holm Hansen, and Parvez Thekkumpurath
- Subjects
Adult ,Male ,medicine.medical_specialty ,Palliative care ,Cost-Benefit Analysis ,MEDLINE ,Quality of life ,Neoplasms ,Prevalence ,Humans ,Medicine ,Psychiatry ,Depression (differential diagnoses) ,Aged ,Response rate (survey) ,Depression ,business.industry ,Hematology ,medicine.disease ,Oncology ,Mood disorders ,Sample size determination ,Meta-analysis ,Quality of Life ,Female ,business - Abstract
Background Depression has substantial effects on cancer patients' quality of life. Estimates of its prevalence vary widely. We aimed to systematically review published studies to obtain the best estimate of the prevalence of depression in clinically meaningful subgroups of cancer patients. Design Systematic review that addressed the limitations of previous reviews by (i) including only studies that used diagnostic interviews; (ii) including only studies that met basic quality criteria (random or consecutive sampling, ≥70% response rate, clear definition of depression caseness, sample size ≥100); (iii) grouping studies into clinically meaningful subgroups; (iv) describing the effect on prevalence estimates of different methods of diagnosing depression. Results Of 66 relevant studies, only 15 (23%) met quality criteria. The estimated prevalence of depression in the defined subgroups was as follows: 5% to 16% in outpatients, 4% to 14% in inpatients, 4% to 11% in mixed outpatient and inpatient samples and 7% to 49% in palliative care. Studies which used expert interviewers (psychiatrists or clinical psychologists) reported lower prevalence estimates. Conclusions Of the large number of relevant studies, few met our inclusion criteria, and prevalence estimates are consequently imprecise. We propose that future studies should be designed to meet basic quality criteria and employ expert interviewers.
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- 2013
43. Continual reassessment method for dose escalation clinical trials in oncology:A comparison of prior skeleton approaches using AZD3514 data
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Julia Young, Glen Clack, Gareth James, Stefan Symeonides, and Jayne Marshall
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Oncology ,Male ,medicine.medical_specialty ,Cancer Research ,Maximum Tolerated Dose ,Phases of clinical research ,Antineoplastic Agents ,Phase 1 ,01 natural sciences ,Bayesian ,Continual reassessment method ,010104 statistics & probability ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Dose escalation ,Genetics ,Humans ,Computer Simulation ,0101 mathematics ,Skeleton ,Clinical Trials, Phase I as Topic ,Dose-Response Relationship, Drug ,business.industry ,Androgen Antagonists ,Bayes Theorem ,Models, Theoretical ,Skeleton (computer programming) ,Clinical trial ,Pyridazines ,Prostatic Neoplasms, Castration-Resistant ,030220 oncology & carcinogenesis ,Maximum tolerated dose ,business ,Algorithms ,Research Article - Abstract
Background The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship (“prior skeleton”) and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses. Methods Post-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches. Results All methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches. Conclusions Prior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important. Trial registration NCT01162395, Trial date of first registration: July 13, 2010. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2702-6) contains supplementary material, which is available to authorized users.
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- 2016
44. Ovarian Cancer Molecular Stratification and Tumor Heterogeneity: A Necessity and a Challenge
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Charlie Gourley and Stefan Symeonides
- Subjects
Opinion ,Cancer Research ,Bevacizumab ,Population ,Context (language use) ,Disease ,bevacizumab ,Bioinformatics ,olaparib ,lcsh:RC254-282 ,Olaparib ,chemistry.chemical_compound ,stratification ,Medicine ,education ,education.field_of_study ,business.industry ,Cancer ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Serous fluid ,ovarian cancer ,Oncology ,chemistry ,heterogeneity ,business ,Ovarian cancer ,medicine.drug - Abstract
Only two new drugs have been licensed for the treatment of epithelial ovarian cancer in the last 5 years (bevacizumab and olaparib). These are also the only two molecularly targeted agents licensed in this disease. As we continue to move into the genomic era of cancer therapy, it is clear that optimal therapy is going to depend on molecular stratification and that the stratification itself is going to need to contend with tumor heterogeneity. In this article, we discuss molecular stratification and tumor heterogeneity in the context of high-grade serous ovarian cancer. The development of bevacizumab and olaparib has provided contrasting examples of stratification in molecularly targeted agents. Bevacizumab is licensed as an unselected agent, currently without molecular (or indeed histological) stratification. However, emerging data may be able to help us refine which patients may benefit the most from this agent (and which may not require it). Any such refinement can be expected to increase the median benefit in the selected population and reinforce the cost:benefit advantage. Conversely, olaparib is licensed as a highly selected agent, currently by genomic or somatic BRCA1/BRCA2 mutation in high-grade serous cancer. However, emerging data may be able to help us expand its role into tumors with other homologous recombination deficits (while also determining if all BRCA1/BRCA2 mutations respond equally). For both agents, however, cancers progress even on continuous therapy and targeting the resistant clones that have emerged from tumor heterogeneity will be key to extending benefit for these patients.
- Published
- 2015
45. FAK-PD1: a phase I/IIa trial of FAK (defactinib) & PD-1 (pembrolizumab) inhibition
- Author
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Dorothy Currie, Alan Serrels, Christian H. Ottensmeier, T.R.J. Evans, Victoria Coyle, Dean A. Fennell, S. Dillon, James Paul, Fiona Thomson, and Stefan Symeonides
- Subjects
Oncology ,business.industry ,Defactinib ,Phase (matter) ,Cancer research ,Medicine ,Hematology ,Pembrolizumab ,business - Published
- 2017
46. Cabozantinib in metastatic renal cell carcinoma (mRCC): Real world experience from the UK
- Author
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Balaji Venugopal, Alfonso Gomez de Liano, Thomas Powles, Naveen S. Vasudev, Luma Khasti, Kate Fife, S. Rudman, Stefan Symeonides, Claire Pettinger, and Ekaterini Boleti
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Cabozantinib ,medicine.medical_treatment ,VEGF receptors ,urologic and male genital diseases ,Targeted therapy ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,medicine ,In patient ,Everolimus ,biology ,business.industry ,medicine.disease ,030104 developmental biology ,Survival benefit ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,business ,medicine.drug - Abstract
e16578Background: The randomised phase III METEOR trial showed survival benefit of cabozantinib over everolimus in patients with mRCC who progressed after VEGF targeted therapy. We report real worl...
- Published
- 2018
47. Prevalence, associations, and adequacy of treatment of major depression in patients with cancer: a cross-sectional analysis of routinely collected clinical data
- Author
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Ravi Ramessur, Michael Sharpe, Stefan Symeonides, Paul Martin, Jane Walker, Christian Holm Hansen, and Gordon D Murray
- Subjects
616.8 Nervous & mental disorders ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Cross-sectional study ,Cancer ,medicine.disease ,Hospital Anxiety and Depression Scale ,Cancer registry ,Psychiatry and Mental health ,Breast cancer ,Internal medicine ,medicine ,Lung cancer ,Psychiatry ,business ,RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,Depression (differential diagnoses) - Abstract
Summary Background Major depression is an important complication of cancer. However, reliable data are lacking for the prevalence of depression in patients with cancer in different primary sites, the association of depression with demographic and clinical variables within cancer groupings, and the proportion of depressed patients with cancer receiving potentially effective treatment for depression. We investigated these questions with data from a large representative clinical sample. Methods We analysed data from patients with breast, lung, colorectal, genitourinary, or gynaecological cancer who had participated in routine screening for depression in cancer clinics in Scotland, UK between May 12, 2008, and Aug 24, 2011. Depression screening was done in two stages (first, Hospital Anxiety and Depression Scale; then, major depression section of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition). Data for depression status were linked with demographic and clinical data obtained from the Scottish National Cancer Registry. Findings We analysed data for 21 151 patients. The prevalence of major depression was highest in patients with lung cancer (13·1%, 95% CI 11·9–14·2%), followed by gynaecological cancer (10·9%, 9·8–12·1), breast cancer (9·3%, 8·7–10·0), colorectal cancer (7·0%, 6·1–8·0), and genitourinary cancer (5·6%, 4·5–6·7). Within these cancer groupings, a diagnosis of major depression was more likely in patients who were younger, had worse social deprivation scores, and, for lung cancer and colorectal cancer, female patients. 1130 (73%) of 1538 patients with depression and complete patient-reported treatment data were not receiving potentially effective treatment. Interpretation Major depression is common in patients attending cancer clinics and most goes untreated. A pressing need exists to improve the management of major depression for patients attending specialist cancer services. Funding Cancer Research UK and Chief Scientist Office of the Scottish Government.
- Published
- 2014
48. Phase 1-2 study of TI-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies
- Author
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Pankaj Bhargava, Alice Bexon, T.R. Jeffry Evans, Antoine Italiano, Pamela T. Manning, Philippa Graham, Stefan Symeonides, Karr Robert W, David Hinds, Ferry A.L.M. Eskens, and Sanjay Chanda
- Subjects
0301 basic medicine ,Cancer Research ,business.industry ,CD47 ,Cancer ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Phase (matter) ,Signal-regulatory protein alpha ,Cancer research ,Medicine ,In patient ,business ,Surface protein - Abstract
TPS3109 Background: The cell surface protein CD47 is expressed or over-expressed on many tumor types. CD47 binds to signal regulatory protein alpha (SIRPα) on macrophages resulting in a “don’t eat me” signal that blocks host cell phagocytosis of the tumor cells, thus allowing them to escape removal by the innate immune system. Recent data indicate that anti-CD47 antibodies also contribute to an effective anti-tumor T cell response in immune-competent mice. Therefore, anti-CD47 antibodies are a new class of immune checkpoint inhibitors that modulate both the innate and adaptive immune systems. Ti-061 is a novel IgG4 humanized monoclonal antibody that specifically binds to CD47 with Kd values range from 100 – 500 pM. Ti-061 exhibits cross-species binding to cynomolgus monkey, mouse and rat CD47, enabling efficacy and toxicity testing across species. Ti-061 binds to CD47 on RBCs; however, it does not cause agglutination of RBCs in vitro from any of the species tested. Ti-061 exhibits anti-tumor activity in several in vivo mouse tumor models. This ongoing Phase 1-2 study will assess the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of Ti-061 alone and in combination with other anti-cancer agents in patients with advanced malignancies. Methods: Part A is an open-label, dose-escalation study of Ti-061 administered as a weekly 1-hour IV infusion at doses ranging from 1 to 20 mg/kg. Once the MTD/RP2D or “active dose” is determined, patients with specific solid tumors and high CD47 expression will be enrolled in 4 or more expansion cohorts. Up to 160 patients with histologically confirmed solid tumors, ECOG PS 0-1, adequate blood counts (Hb≥ 10 g/dL), organ function, and archival or fresh tumor tissue will be enrolled in Part A, and will be treated until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint is safety, which will be assessed using NCI-CTCAE v4.03. Secondary endpoints include PK, PD, objective response rate (ORR) and progression-free survival (PFS), which will be assessed using RECIST v1.1. The results of this study will support further development of Ti-061 in combination with checkpoint inhibitors (Part B) and other anti-cancer agents.
- Published
- 2017
49. Integrated collaborative care for comorbid major depression in patients with cancer (SMaRT Oncology-2): A multicentre randomised controlled effectiveness trial
- Author
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Paul Martin, Lucy Wall, Michael Sharpe, Christian Holm Hansen, Charlie Gourley, Stefan Symeonides, Jane Walker, Gordon D Murray, and David Weller
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Adult ,Male ,medicine.medical_specialty ,MEDLINE ,Collaborative Care ,law.invention ,Young Adult ,Randomized controlled trial ,Ambulatory care ,law ,Neoplasms ,Medicine ,Humans ,Young adult ,Aged ,Aged, 80 and over ,Patient Care Team ,Analysis of Variance ,Depressive Disorder, Major ,Intention-to-treat analysis ,business.industry ,Delivery of Health Care, Integrated ,General Medicine ,Odds ratio ,Middle Aged ,Patient Acceptance of Health Care ,Checklist ,Antidepressive Agents ,Neoadjuvant Therapy ,Psychotherapy ,Treatment Outcome ,Physical therapy ,Female ,business - Abstract
BACKGROUND: Medical conditions are often complicated by major depression, with consequent additional impairment of quality of life. We aimed to compare the effectiveness of an integrated treatment programme for major depression in patients with cancer (depression care for people with cancer) with usual care. METHODS: SMaRT Oncology-2 is a parallel-group, multicentre, randomised controlled effectiveness trial. We enrolled outpatients with major depression from three cancer centres and their associated clinics in Scotland, UK. Participants were randomly assigned in a 1:1 ratio to the depression care for people with cancer intervention or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. Depression care for people with cancer is a manualised, multicomponent collaborative care treatment that is delivered systematically by a team of cancer nurses and psychiatrists in collaboration with primary care physicians. Usual care is provided by primary care physicians. Outcome data were collected up until 48 weeks. The primary outcome was treatment response (≥50% reduction in Symptom Checklist Depression Scale [SCL-20] score, range 0-4) at 24 weeks. Trial statisticians and data collection staff were masked to treatment allocation, but participants could not be masked to the allocations. Analyses were by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN40568538. FINDINGS: 500 participants were enrolled between May 12, 2008, and May 13, 2011; 253 were randomly allocated to depression care for people with cancer and 247 to usual care. 143 (62%) of 231 participants in the depression care for people with cancer group and 40 (17%) of 231 in the usual care group responded to treatment: absolute difference 45% (95% CI 37-53), adjusted odds ratio 8·5 (95% CI 5·5-13·4), p
- Published
- 2014
50. Treatment of depression in people with lung cancer: a systematic review
- Author
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Gordon D Murray, Michael Sharpe, Christian Holm Hansen, Aarti Sawhney, Paul Martin, Stefan Symeonides, and Jane Walker
- Subjects
Pulmonary and Respiratory Medicine ,Cancer Research ,medicine.medical_specialty ,Palliative care ,Lung Neoplasms ,Population ,Psychological intervention ,Quality of life ,Medicine ,Humans ,Adverse effect ,Lung cancer ,education ,Intensive care medicine ,Depression (differential diagnoses) ,Randomized Controlled Trials as Topic ,education.field_of_study ,business.industry ,Depression ,Palliative Care ,Cancer ,medicine.disease ,Antidepressive Agents ,Psychotherapy ,Treatment Outcome ,Oncology ,Physical therapy ,Quality of Life ,business - Abstract
Lung cancer commonly occurs in older adults who live in deprived areas and have multiple medical comorbidities. As well as suffering severe physical deterioration they are aware of their poor prognosis. It is therefore unsurprising that people with lung cancer have a high rate of depression. Whilst there are effective treatments for depression in people who do not have cancer, it is uncertain which treatments, if any, are effective in depressed cancer patients; the special characteristics of the condition only increase that uncertainty for people with lung cancer.We therefore conducted a systematic review of relevant randomised controlled trials to determine which, if any, treatments have been found to be effective for depression in patients with lung cancer. Surprisingly, we found no completed trials of treatments in patients selected for having depression and no trials that had evaluated treatments known to be effective for depression in the general population. We did, however, find six trials of interventions intended to improve quality of life in unselected patients with lung cancer. These suggested that enhanced care is more effective in reducing depressive symptoms than standard care.Whilst it may be reasonable to treat depression in individuals with lung cancer with standard treatments until more specific evidence is available, clinicians should be aware that the effectiveness and potential adverse effects of these treatments remain unknown in this patient group. Evidence from randomised trials is urgently required. © 2012 Elsevier Ireland Ltd.
- Published
- 2012
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