Love, S.B.
Cafferty, F.
Snowdon, C.
Carty, K.
Savage, J.
Pallmann, P.
McParland, L.
Brown, L.
Masters, L.
Schiavone, F.
Hague, D.
Townsend, S.
Amos, C.
South, A.
Sturgeon, K.
Langley, R.
Maughan, T.
James, N.
Hall, E.
Kernaghan, S.
Bliss, J.
Turner, N.
Tutt, A.
Yap, C.
Firth, C.
Kong, A.
Mehanna, H.
Watts, C.
Hills, R.
Thomas, I.
Copland, M.
Bell, S.
Sebag-Montefiore, D.
Jones, R.
Parmar, M.K.
Sydes, M.R.
(2022). Practical guidance for running late-phase platform protocols for clinical trials: lessons from experienced UK clinical trials units. ,
Vol.23
(1),
p. 757.
show abstract
BACKGROUND: Late-phase platform protocols (including basket, umbrella, multi-arm multi-stage (MAMS), and master protocols) are generally agreed to be more efficient than traditional two-arm clinical trial designs but are not extensively used. We have gathered the experience of running a number of successful platform protocols together to present some operational recommendations. METHODS: Representatives of six UK clinical trials units with experience in running late-phase platform protocols attended a 1-day meeting structured to discuss various practical aspects of running these trials. We report and give guidance on operational aspects which are either harder to implement compared to a traditional late-phase trial or are specific to platform protocols. RESULTS: We present a list of practical recommendations for trialists intending to design and conduct late-phase platform protocols. Our recommendations cover the entire life cycle of a platform trial: from protocol development, obtaining funding, and trial set-up, to a wide range of operational and regulatory aspects such as staffing, oversight, data handling, and data management, to the reporting of results, with a particular focus on communication with trial participants and stakeholders as well as public and patient involvement. DISCUSSION: Platform protocols enable many questions to be answered efficiently to the benefit of patients. Our practical lessons from running platform trials will support trial teams in learning how to run these trials more effectively and efficiently..
Dearnaley, D.
Hinder, V.
Hijab, A.
Horan, G.
Srihari, N.
Rich, P.
Houston, J.G.
Henry, A.M.
Gibbs, S.
Venkitaraman, R.
Cruickshank, C.
Hassan, S.
Miners, A.
Mason, M.
Pedley, I.
Payne, H.
Brock, S.
Wade, R.
Robinson, A.
Din, O.
Lees, K.
Graham, J.
Worlding, J.
Murray, J.
Parker, C.
Griffin, C.
Sohaib, A.
Hall, E.
PROMPTS investigators,
(2022). Observation versus screening spinal MRI and pre-emptive treatment for spinal cord compression in patients with castration-resistant prostate cancer and spinal metastases in the UK (PROMPTS): an open-label, randomised, controlled, phase 3 trial. The lancet. oncology,
.
show abstract
Background
Early diagnosis of malignant spinal cord compression (SCC) is crucial because pretreatment neurological status is the major determinant of outcome. In metastatic castration-resistant prostate cancer, SCC is a clinically significant cause of disease-related morbidity and mortality. We investigated whether screening for SCC with spinal MRI, and pre-emptive treatment if radiological SCC (rSCC) was detected, reduced the incidence of clinical SCC (cSCC) in asymptomatic patients with metastatic castration-resistant prostate cancer and spinal metastasis.
Methods
We did a parallel-group, open-label, randomised, controlled, phase 3, superiority trial. Patients with metastatic castration-resistant prostate cancer were recruited from 45 National Health Service hospitals in the UK. Eligible patients were aged at least 18 years, with an Eastern Co-operative Oncology Group performance status of 0-2, asymptomatic spinal metastasis, no previous SCC, and no spinal MRI in the past 12 months. Participants were randomly assigned (1:1), using a minimisation algorithm with a random element (balancing factors were treatment centre, alkaline phosphatase [normal vs raised, with the upper limit of normal being defined at each participating laboratory], number of previous systemic treatments [first-line vs second-line or later], previous spinal treatment, and imaging of thorax and abdomen), to no MRI (control group) or screening spinal MRI (intervention group). Serious adverse events were monitored in the 24 h after screening MRI in the intervention group. Participants with screen-detected rSCC were offered pre-emptive treatment (radiotherapy or surgical decompression was recommended per treating physician's recommendation) and 6-monthly spinal MRI. All patients were followed up every 3 months, and then at month 30 and 36. The primary endpoint was time to and incidence of confirmed cSCC in the intention-to-treat population (defined as all patients randomly assigned), with the primary timepoint of interest being 1 year after randomisation. The study is registered with ISRCTN, ISRCTN74112318, and is now complete.
Findings
Between Feb 26, 2013, and April 25, 2017, 420 patients were randomly assigned to the control (n=210) or screening MRI (n=210) groups. Median age was 74 years (IQR 68 to 79), 222 (53%) of 420 patients had normal alkaline phosphatase, and median prostate-specific antigen concentration was 48 ng/mL (IQR 17 to 162). Screening MRI detected rSCC in 61 (31%) of 200 patients with assessable scans in the intervention group. As of data cutoff (April 23, 2020), at a median follow-up of 22 months (IQR 13 to 31), time to cSCC was not significantly improved with screening (hazard ratio 0·64 [95% CI 0·37 to 1·11]; Gray's test p=0·12). 1-year cSCC rates were 6·7% (95% CI 3·8-10·6; 14 of 210 patients) for the control group and 4·3% (2·1-7·7; nine of 210 patients) for the intervention group (difference -2·4% [95% CI -4·2 to 0·1]). Median time to cSCC was not reached in either group. No serious adverse events were reported within 24 h of screening.
Interpretation
Despite the substantial incidence of rSCC detected in the intervention group, the rate of cSCC in both groups was low at a median of 22 months of follow-up. Routine use of screening MRI and pre-emptive treatment to prevent cSCC is not warranted in patients with asymptomatic castration-resistant prostate cancer with spinal metastasis.
Funding
Cancer Research UK..
Brown, S.R.
Hinsley, S.
Hall, E.
Hurt, C.
Baird, R.D.
Forster, M.
Scarsbrook, A.F.
Adams, R.A.
(2022). A road map for designing phase I clinical trials of radiotherapy-novel agent combinations. ,
,
p. clincanres.4087.2021.
show abstract
Radiotherapy has proven efficacy in a wide range of cancers. There is growing interest in evaluating radiotherapy-novel agent combinations, and a drive to initiate this earlier in clinical development of the novel agent, where scientific rationale and pre-clinical evidence for a radiotherapy combination approach is high. Optimal design, delivery and interpretation of studies is essential. In particular, design of phase I studies to determine safety and dosing are critical to an efficient development strategy. There is significant interest in early phase research amongst scientific and clinical communities over recent years, at a time when scrutiny of trials methodology has significantly increased. To enhance trial design, optimize safety, and promote efficient trial conduct, this position paper reviews the current phase I trial design landscape. Key design characteristics extracted from 37 methodology papers were used to define a road map and design selection process for phase I radiotherapy-novel agent trials. Design selection is on the basis of single or dual therapy dose escalation, dose limiting toxicity categorisation, maximum tolerated dose determination, subgroup evaluation, software availability and design performance. Fifteen of 37 designs were identified as being immediately accessible and relevant to radiotherapy-novel agent phase I trials. Applied examples of using the road map are presented. Developing these studies is intensive, highlighting the need for funding and statistical input early in trial development to ensure appropriate design and implementation from the outset. Application of this road map will improve design of phase I radiotherapy-novel agent combination trials, enabling a more efficient development pathway..
Hall, E.
Hussain, S.A.
Porta, N.
Lewis, R.
Crundwell, M.
Jenkins, P.
Rawlings, C.
Tremlett, J.
Sreenivasan, T.
Wallace, J.
Syndikus, I.
Sheehan, D.
Lydon, A.
Huddart, R.
James, N.
BC2001 Investigators,
(2022). Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. ,
,
pp. S0302-2838(22)02265.
show abstract
BACKGROUND: BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88). There are limited data on long-term recurrence risk. OBJECTIVE: To determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). INTERVENTION: Radiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Locoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer-specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. RESULTS AND LIMITATIONS: Chemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43-0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36-0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60-1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58-1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69-1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59-1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9-21%) with chemoradiotherapy versus 22% (95% CI 16-31%) with radiotherapy alone (HR 0.54, [95% CI 0.31-0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. CONCLUSIONS: Long-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. PATIENT SUMMARY: We looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr..
Mateo, J.
Porta, N.
Bianchini, D.
McGovern, U.
Elliott, T.
Jones, R.
Syndikus, I.
Ralph, C.
Jain, S.
Varughese, M.
Parikh, O.
Crabb, S.
Robinson, A.
McLaren, D.
Birtle, A.
Tanguay, J.
Miranda, S.
Figueiredo, I.
Seed, G.
Bertan, C.
Flohr, P.
Ebbs, B.
Rescigno, P.
Fowler, G.
Ferreira, A.
Riisnaes, R.
Pereira, R.
Curcean, A.
Chandler, R.
Clarke, M.
Gurel, B.
Crespo, M.
Nava Rodrigues, D.
Sandhu, S.
Espinasse, A.
Chatfield, P.
Tunariu, N.
Yuan, W.
Hall, E.
Carreira, S.
de Bono, J.S.
(2020). Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. The lancet. oncology,
Vol.21
(1),
pp. 162-174.
show abstract
Background Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer.Methods In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing.Findings 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort.Interpretation Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice.Funding Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres..
Birtle, A.
Johnson, M.
Chester, J.
Jones, R.
Dolling, D.
Bryan, R.T.
Harris, C.
Winterbottom, A.
Blacker, A.
Catto, J.W.
Chakraborti, P.
Donovan, J.L.
Elliott, P.A.
French, A.
Jagdev, S.
Jenkins, B.
Keeley, F.X.
Kockelbergh, R.
Powles, T.
Wagstaff, J.
Wilson, C.
Todd, R.
Lewis, R.
Hall, E.
(2020). Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. The lancet,
Vol.395
(10232),
pp. 1268-1277.
Dearnaley, D.
Syndikus, I.
Mossop, H.
Khoo, V.
Birtle, A.
Bloomfield, D.
Graham, J.
Kirkbride, P.
Logue, J.
Malik, Z.
Money-Kyrle, J.
O'Sullivan, J.M.
Panades, M.
Parker, C.
Patterson, H.
Scrase, C.
Staffurth, J.
Stockdale, A.
Tremlett, J.
Bidmead, M.
Mayles, H.
Naismith, O.
South, C.
Gao, A.
Cruickshank, C.
Hassan, S.
Pugh, J.
Griffin, C.
Hall, E.
CHHiP Investigators,
(2016). Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. The lancet. oncology,
Vol.17
(8),
pp. 1047-1060.
show abstract
Background Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up.Methods CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923.Findings Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported.Interpretation Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer.Funding Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network..
Hall, E.
Tree, A.
van As, N.
Intensity Modulated Radiotherapy Versus Stereotactic Body Radiotherapy for Prostate Cancer (PACE-B): 2 year Toxicity Results From a Randomised Open-label Phase III Non-inferiority Trial. ,
.
Hall, E.
Randomized Trial of PHOTOdynamic-Surgery in Non-Muscle Invasive Bladder Cancer. ,
.
Nutting, C.M.
Griffin, C.L.
Sanghera, P.
Foran, B.
Beasley, M.
Bernstein, D.
Cosgrove, V.
Fisher, S.
West, C.M.
Sibtain, A.
Palaniappan, N.
Urbano, T.G.
Sen, M.
Soe, W.
Rizwanullah, M.
Wood, K.
Ramkumar, S.
Junor, E.
Cook, A.
Roques, T.
Scrase, C.
Bhide, S.A.
Gujral, D.
Harrington, K.J.
Mehanna, H.
Miah, A.
Emson, M.
Gardiner, D.
Morden, J.P.
Hall, E.
Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial. European journal of cancer,
Vol.153,
pp. 242-256.
Hall, E.
Parr, H.
Porta, N.
Joint Models for Dynamic Prediction in Localised Prostate Cancer: A Literature Review. ,
.