NIHRDataInsights/HRCSData huggingface dataset:
Title: CRUK/11/047: COAST (Cisplatin Ototoxicity attenuated by ASpirin Trial): A phase II randomised controlled trial of aspirin in the preventative role of cisplatin induced ototoxicity.
Funder: Cancer Research UK

Abstract: Background:Approximately 18,500 patients receive cisplatin on an annual basis within the UK. 50% of patients receiving high dose cisplatin (200mg/m2 total dose) have a significant reduction in their hearing following treatment (ototoxicity) and the resulting deafness results in a considerable reduction in quality of life. In some patients hearing can be restored by hearing aids, others have such severe hearing loss that they cannot benefit from the hearing aids, and are considered for cochlear implantation. Both hearing aids and cochlear implantation have important short and long term costs to the NHS. &amp;lt;br/&amp;gt;There is evidence in the literature, in an animal model, that aspirin can minimise the hearing loss associated with cisplatin. There is also compelling evidence from a human trial with 200 patients that aspirin prevented hearing loss associated with gentamicin. Both gentamicin and cisplatin are thought to damage the inner-ear with the same mechanism of action. Aims and objectives 1) To gather initial information on whether aspirin reduces hearing loss/ototoxicity for patients receiving cisplatin chemotherapy. 2) To determine whether it is feasible to conduct a Phase III randomised controlled trial of aspirin for the same patient population. 3) To quantify the extent of hearing loss in patients receiving cisplatin via the use of otoacoustic emissions (OAE). Method&amp;lt;br/&amp;gt;Design: A two arm randomised Phase II trial. Setting: Southampton University Hospital NHS Trust and The Royal Marsden Hospital, London Population: Patients undergoing cisplatin treatment (intended cumulative dose equal to or greater than 200mg/m2) for malignancy. ;Sample size: 88 patients (44 in each arm) Intervention: Aspirin – 975mg tds and Esomeprazole – 20mg od for 4 days with each cisplatin dose. Control: Standard management. Primary outcome will be the objective difference in hearing before and after treatment, using the pure tone audiogram (PTA) test at frequencies of 6 and 8kHz. Secondary outcomes: Common Toxicity Criteria (CTC) – a clinician assessed level of hearing loss.• OAE profile, before and after treatment.;• Assess safety profile (gastro-intestinal and renal toxicity)


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS
Title: The role of fumarate-mediated 2-oxoglutarate-dependent oxygenase inhibition in hereditary renal cancer.
Funder: Cancer Research UK

Abstract: Background_x000D_ The identification of mutations in genes of known metabolic function, but previously unsuspected links to cancer, has renewed interest in Warburg’s hypothesis that dysregulated energy metabolism may be oncogenic. One such gene encodes the Krebs cycle enzyme Fumarate hydratase (FH), mutated in hereditary leiomyomatosis and renal cell cancer (HLRCC). Affected individuals develop benign cutaneous and uterine leiomyomas, renal cysts, aggressive type II papillary and collecting duct renal cell carcinomas (RCC). Although FH has a critical role in cellular energy metabolism, the mechanisms of tumourigenesis remain undefined. We have generated animal and cellular models and have described how loss of FH enzymatic activity leads to an accumulation of intracellular fumarate, which may act as an onco-metabolite. Fumarate is a potent inhibitor of a class of enzymes that require oxygen, non-haem Fe(II), and 2-oxoglutarate (2OG) for activity. These 2OG oxygenases catalyse diverse biochemical oxidations that potentially impact on oncogenic pathways including protein hydroxylation, histone demethylation and nucleic acid hydroxylation. _x000D_ _x000D_ Aims_x000D_ Recently, we demonstrated inhibition of prolyl hydroxylation and upregulation of hypoxia-inducible-factor-alpha (HIFa) in FH-deficient cells. However, further experiments in a mouse model of FH-disease have indicated that upregulation of HIF is not the cause of FH-associated neoplasia. Therefore, we hypothesise that fumarate inhibits other 2OG oxygenases; specifically histone demethylase (HDM) and TET enzymes that catalyse histone demethylation and hydroxylation of 5-methlycytosine respectively. Mutational inactivation of HDM and TET enzymes have been described in human cancers, making them attractive candidates for HLRCC oncogenesis. We propose to test this hypothesis by biochemical analysis of the inhibitory potential of fumarate on these enzymes and genetic and biochemical manipulation of fumarate levels in models of FH deficiency. _x000D_ _x000D_ Methods_x000D_ We will analyse histone and DNA methylation in FH-deficient cell lines and in cells treated with fumarate (inhibitor) or 2OG (substrate). HDMs will be assayed directly using cell-free in vitro assays and transient expression assays in FH wild type and knockout cells. For the assay of TET activity and function, isogenic cell lines will be infected with constructs bearing the TET1 catalytic domain or catalytically inactive mutants and assayed for effects on hydroxyl-methylcytosine and methylcytosine content of DNA._x000D_ _x000D_ How the results of this research will be used_x000D_ The identification of candidate 2OG oxygenases for HLRCC oncogenesis will support the development of targeted therapies for HLRCC and might inform the biology of a broadening array of inherited tumour syndromes and somatic tumours associated with mutations in metabolic enzymes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: How does Rif1 control DNA replication initiation?
Funder: Cancer Research UK

Abstract: BACKGROUND & CANCER RELEVANCE: The Rif1 chromosome stability protein is implicated in the development of breast and colorectal cancers. Rif1 is conserved, but previous evidence suggests it has different functions in yeast and human cells—with yeast Rif1 regulating telomere length, and human Rif1 involved in facilitating chromosome replication, especially within damaged DNA. _x000D_ We have discovered that yeast Rif1 regulates the initiation of DNA replication, representing a new function for Rif1 that could be conserved through evolution. Rif1 affects replication initiation by the Cdc7-Dbf4 kinase complex (also called DDK for Dbf4-Dependent Kinase). DDK is under active development as a target for chemotherapy, so it is crucial that we understand how replication initiation by DDK is regulated. The goal of this research is to understand the mechanism by which Rif1 affects DDK-mediated replication initiation, and to establish whether this role for Rif1 is conserved in human cells. _x000D_ _x000D_ AIMS & METHODS: We discovered that yeast cells lacking Rif1 no longer exhibit the normal requirement for DDK to initiate DNA replication. Our research plan is to elucidate the mechanism by which Rif1 affects replication initiation and to test its conservation, using a three-part strategy:- _x000D_ _x000D_ 1. Preliminary results suggest that Rif1 interacts physically with Dbf4. We will therefore test the possibility that Rif1 binds directly to DDK and controls its kinase activity to regulate replication initiation. We will also test if Rif1 regulates the action of DDK in the DNA damage response pathway. _x000D_ _x000D_ 2. Both Rif1 and Dbf4 are chromatin-associated proteins. We will establish whether Rif1 controls DDK-mediated replication initiation by altering chromatin context. In particular, we will test if Rif1 modulates the accessibility of replication origins to DDK recruitment and replication initiation._x000D_ _x000D_ 3. Having established how yeast Rif1 affects replication initiation by DDK, we will test whether the molecular mechanism(s) identified are conserved in normal and transformed human cells._x000D_ _x000D_ OUTCOME & USE OF RESEARCH: It has become clear that Rif1 has roles in chromosome stability extending beyond its originally identified function at telomeres. This work will elucidate the molecular function of Rif1, illuminating its role in carcinogenesis and potentially enabling development of new cancer diagnostic or treatment strategies based on manipulation of Rif1 or DDK function. Our results suggest that Rif1 acts as a physiological inhibitor of DDK activity, which is of particular importance for the ongoing development of chemotherapeutic drugs that inhibit DDK-mediated replication initiation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK11/019: vit-0910: International randomized phase ii trial of the combinations of vincristine and irinotecan with or without temozolomide (vi or vit) in patients with refractory or relapsed Rhabdomyosarcoma
Funder: Cancer Research UK

Abstract: Background: Rhabdomyosarcoma is the commonest soft tissue sarcoma in children and occurs throughout adult life. While many patients with localised RMS do well, outcomes remain poor in metastatic and refractory disease and some situations of localised recurrence and new treatment strategies are needed. The combination of irinotecan with vincristine is active in RMS but at present irinotecan is not routinely used in first-line therapy in Europe. Temozolomide potentiates the action of irinotecan and is commonly used with irinotecan for the treatment of relapsed or refractory Ewings sarcoma. We wish to investigate its role in Rms Aims:The primary aim is to evaluate the efficacy of the combination of temozolomide with vincristine and irinotecan (VIT) in children and adult patients with refractory or relapsed rhabdomyosarcoma as assessed by confirmed objective tumor response. Secondary aims are i) to evaluate the safety, tolerability and efficacy of VIT and vincristine with irinotecan (VI) alone as assessed by: duration of response, time to tumor progression, time to treatment failure, overall survival and adverse event profile and to ii) correlate pharmacogenetic profiles from 384 SNP including UGT1A1, ABCB1, MGMT and from a specific genetic analysis for response and toxicity of VIT and VI alone. Methods:This is an open-label, multicentre, randomized phase II trial. 80 patients aged 6 months to 50 years with relapsed or refractory RMS who have failed standard treatment, have measurable disease and fulfil all other eligibility criteria, will be randomised to receive vincristine 1.5 mg/m2 iv on Days 1 and 8, irinotecan 50 mg/m2 iv on Days 1-5 with or without oral temozolomide 125 mg/m2 on Days 1-5 of each 21 day cycle. The temozolomide dose will be escalated to 150mg/m2 in subsequent courses provided patients do not experience toxicity grade 3. Response will be assessed by CT or MRI after the second cycle of treatment and after every 2 subsequent cycles. A 2-stage Simon design will be employed for the VIT arm (p0=0.20, p1 = 0.40, ?=0.10 and ?=0.10). Patients may receive up to 12 cycles of therapy in the absence of disease progression. Output: This study will show whether the VIT combination is sufficiently active to take forward into phase III trials in Rms It will also give an estimate of whether VI or VIT is the more appropriate arm to take forward in phase II trials in relapsed/refractory disease, for example with the addition of targeted agents.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/045: A randomised phase II trial to assess the feasibility and safety of the combination of docetaxel plus Ra-223 in the first line chemotherapy treatment of men with bony metastatic castrate resistant prostate cancer
Funder: Cancer Research UK

Abstract: Background: Docetaxel (+ prednisolone) remains a standard therapy for metastatic Hormone (or castrate) Refractory Prostate Cancer (HRPC or CRPC) having been shown to improve survival and palliate symptoms Combination of docetaxel with radio-isotopes is attractive as these agents are generally very well tolerated. Our current phase II/III trial, Trapeze, combining docetaxel with Sr89 is set to complete recruitment Q1 2012 with first definitive analysis planned Q1 2013. To date, no trials_x000D_ combining docetaxel with any drug have shown benefit over docetaxel alone, which therefore remains the standard of care for chemotherapy for CRPC._x000D_ Ra-223 (Alpharadin) is a bone seeking radio-isotope with impressive activity and safety in phase I and II trials. A randomised phase II trial comparing four monthly injections of Ra223 with best supportive care showed an increase in time to progression from 8 to 26 weeks and overall survival from 46 to 65 weeks. A confirmatory phase III is in follow up. Myelosuppression is minimal with this agent as the short track length of alpha-irradiation causes less damage to uninvolved bone marrow than the beta-emissions of Sr89. A phase I dose finding study combining Ra-223 with docetaxel in_x000D_ the second line setting is underway in the USA. We are now seeking to obtain feasibility and safety data for the combination of docetaxel plus Ra-223 as a first line combination in preparation for a possible future phase III trial building on the results of_x000D_ the Trapeze trial. The trial will be timed to open on completion of the Trapeze phase III recruitment and will aim to utilise the same network of investigators._x000D_ Aims and Objectives: To evaluate the tolerability and activity of combining docetaxel with Ra-223 in the first line chemotherapy of patients with bone metastatic castrate refractory prostate cancer._x000D_ Methods: Randomised phase II trial. Primary endpoints: tolerability (defined as the proportion of patients with no grade 3 or 4 toxic events) and efficacy (defined as the proportion of patients who are clinically progression free (composite of pain, PSA, clinical) at 12 months). Secondary objectives include feasibility measured by impact of Ra-223 on docetaxel delivery, number of Ra-223 treatments received, PSA response rate, 12-month survival rates, bone markers._x000D_ How the results will be used:_x000D_ As combining active agents is usually better than sequential use in oncology, it seems logical to evaluate the two drugs together with a target endpoint of an improvement in overall survival in this poor prognosis


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/025: IRIS: A Phase II study to assess the safety and efficacy of the steroid sulfatase inhibitor Irosustat in combination with aromatase inhibition in ER positive locally advanced or metastatic breast cancer patients.
Funder: Cancer Research UK

Abstract: Background Endocrine therapy is a key modality in the management of breast cancer but resistance limits its use. Therefore, there is a need for new agents and treatment strategies. Steroid sulfatase (STS) is the second pathway involved in oestrogen biosynthesis, and it has been implicated in endocrine resistance. STS is the enzyme responsible for the hydrolysis of steroid sulfates to their unconjugated, biologically active forms, converting estrone sulphate (E1S) to estrone (E1), and dehydroepiandrosterone sulfate (DHEAS) to DHEA. 17ß-hydroxysteroid dehydrogenase type 1 (17ß- HSD1) in turn converts E1 to estradiol and DHEA to androstenediol (Adiol). Androstenediol, although an androgen, has potent oestrogenic effects, and can stimulate the growth of hormonedependent breast cancer cells in vitro and in vivo. STS expression is greater in malignant than in normal breast tissue, with higher levels associated with a poorer prognosis. An up regulation of STS has been reported in breast tumours following neoadjuvant AI treatment, indicating that this may represent a compensatory response to depletion of intra-tumoural oestrogen. In addition, serum DHEAS has been shown to be significantly higher in postmenopausal women progressing on AI therapy, as compared to responders. As AIs do not block androstenediol formation from DHEA, this suggests that androstenediol production from DHEAS may be a mechanism for developing resistance. Given these data there is a rationale for targeting and blocking STS in ER positive breast cancer. Irosustat is an irreversible sulfatase inhibitor. Phase I studies have shown it to be well tolerated and to suppress STS activity to 98% and 99% of baseline in the peripheral blood lymphocytes and breast tumour. In these studies of heavily pre-treated patients a number of disease stabilisations were documented but no responses. Aims To evaluate the efficacy of Irosustat in combination with existing AI therapy by measuring clinical benefit rate i.e. complete response, partial response and stable disease for at least 6 months. Methods ER positive locally advanced/metastatic breast cancer patients that have progressed during first line endocrine therapy with an AI, where either an objective response or stabilisation of disease for at least 6 months has been documented, will be recruited. Irosustat will be added to the AI on which the breast cancer has progressed. How the results of this research will be used This study, if positive, will lead to a full randomised phase III trial comparing AI versus AI plus Irosustat with the primary end point of progression free survival.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Distinguishing physical and biological determinants of radiotherapy toxicity (Vox Tox).
Funder: Cancer Research UK

Abstract: Background This programme focuses on reducing toxicity from radiotherapy (RT). This would have benefits for patients and society. Additionally, individualised reduction of toxicity risk will allow dose escalation, and combination with chemotherapy. Since a strong radiotherapy dose-response relationship exists for many tumours, this will improve cancer cure rates. Aims 1. To quantify the differences between planned dose and the dose actually delivered during the whole course of radiotherapy, and to link these data to differences between expected and observed toxicity. 2. To determine the relative contributions to individual variation in toxicity from underlying biological factors or physical dose variation. 3. Develop a suite of integrated software tools for dose review during the treatment course, with the objective of individualising treatment, based on predicted toxicity. Methods We will analyse the discrepancy between RT doses which are planned, and those actually delivered, based on daily CT data acquired within our clinical programme of high precision image-guided radiotherapy. In Cambridge we have a unique archive of daily volumetric imaging of patients treated on our TomoTherapy units. We will develop systems to map the location of each point (voxel) within the patient outline, and then to re-compute the dose at that point each day during treatment. We will apply techniques from image processing, materials modelling, tumour & tissue modelling and radiation biology to construct models of cumulative dose during treatment that cannot be achieved using current techniques. To do this we will bring together a cross-disciplinary group of clinicians and clinically-orientated scientists from the University Department of Oncology, the NHS Oncology Centre, the Cavendish (Physics) Laboratory, the University Engineering Department and the CR UK Cambridge Research Institute. How will the results be used The results will be used to improve radiotherapy based on individualised toxicity. More accurate data on the relative contributions to individual variation from underlying biological factors or physical dose variation will feed in to studies of genetic determinants of individual variation in toxicity (radiogenomics). The development of an integrated suite of software tools for dose review during the treatment course will allow individual toxicity prediction and provide capability to re-plan treatment including toxicity as an optimisation parameter. Together, these tools will allow individualised treatment with reduced toxicity. The tools may be commercialisable.


Research activity codes: 6.4 SURGERY;6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Physical and biological optimisation of radiotherapy in head and neck cancer
Funder: Cancer Research UK

Abstract: Background: Locally advanced head and neck cancer is the ideal setting for integrating physical and biological approaches to optimising radiotherapy. Advances in the physical basis of radiotherapy delivery and better biological characterisation of locally advanced head and neck cancer offer the prospect of optimising treatment outcomes for these patients. _x000D_ Aims: In this proposal, we outline three research themes with the common goal of integrating physical targeting and biological response modification to develop personalised treatment approaches for different risk categories of head and neck cancer. _x000D_ Methods: In the first theme, we will assess the role of functional magnetic resonance imaging (MRI) in planning radiotherapy for locally advanced disease. We will evaluate parameters defined on dynamic contrast-enhanced MRI and diffusion-weighted MRI as predictive biomarkers of poor outcome in preclinical in vivo and patient studies. Subsequently, we will develop and test new radiotherapy delivery optimisation techniques to escalate radiation dose delivery to biological target volumes defined by functional imaging. The second theme will focus on targeted agents that modulate the radiation-induced DNA damage response to exploit differences between cancer and normal tissues. Intermediate-/poor-risk tumours (tobacco/alcohol use, T3/T4, node-positive, non-oropharyngeal, HPV/p16INK4a negative, p53 mutant) are inherently genetically unstable with defective G1/S checkpoint control and dependence on G2/M checkpoint function for DNA repair. Such tumours will be considered for treatment intensification by adding modulators of the radiation-induced DNA damage response to standard radiotherapy or chemoradiotherapy. Low-risk locally advanced head and neck cancers (HPV/p16INK4a positive, p53 wild-type, oropharyngeal) tumours lack an effective G1 checkpoint and rely on S/G2 arrest to repair DNA damage. These tumours will be considered for treatment de-intensification by replacing concomitant cisplatin-based chemoradiotherapy with radiotherapy combined with a modulator of the radiation-induced DNA damage response. The first two themes focus on improving outcomes in head and neck cancer through imaging-based, optimised physical delivery and biological response modulation. These goals require a detailed understanding of the radiation dose-constraints of early- and late-reacting normal tissues. Without such information, we cannot accurately plan optimised, dose-escalated RT or optimally combine it with biological response modifiers. Therefore, the third theme will focus on continuing development of models to predict normal tissue toxicity as a means of maximising the therapeutic index in locally advanced head and neck cancer._x000D_ Implementation of Research Results: We anticipate translational of all 3 research themes into early-phase clinical trials in patients with head and neck cancer.


Research activity codes: 5.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS