Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We ...describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.
STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate 'activity' stages (focus: failure-free survival), and a final 'efficacy' stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims.
(1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies.
The STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner.
ISRCTN78818544, NCT00268476. First patient into trial: 17 October 2005. First patient into abiraterone comparison: 15 November 2011.
Treatment intensification to maximize disease control and reduced intensity approaches to minimize the risk of late sequelae have been evaluated in newly diagnosed Hodgkin lymphoma. The influence of ...these interventions on the risk of secondary malignant neoplasms, progression-free survival and overall survival is reported in the meta-analysis herein, based on individual patient data from 9498 patients treated within 16 randomized controlled trials for newly diagnosed Hodgkin lymphoma between 1984 and 2007. Secondary malignant neoplasms were meta-analyzed using Peto's method as time-to-event outcomes. For progression-free and overall survival, hazard ratios derived from each trial using Cox regression were combined by inverse-variance weighting. Five study questions (combined-modality treatment
chemotherapy alone; more extended
involved-field radiotherapy; radiation at higher doses
radiation at 20 Gy; more
fewer cycles of the same chemotherapy protocol; standard-dose chemotherapy
intensified chemotherapy) were investigated. After a median follow-up of 7.4 years, dose-intensified chemotherapy resulted in better progression-free survival rates (
=0.007) as compared with standard-dose chemotherapy, but was associated with an increased risk of therapy-related acute myeloid leukemia/myelodysplastic syndromes (
=0.0028). No progression-free or overall survival differences were observed between combined-modality treatment and chemotherapy alone, but more secondary malignant neoplasms were seen after combined-modality treatment (
=0.010). For the remaining three study questions, outcomes and secondary malignancy rates did not differ significantly between treatment strategies. The results of this meta-analysis help to weigh up efficacy and secondary malignancy risk for the choice of first-line treatment for Hodgkin lymphoma patients. However, final conclusions regarding secondary solid tumors require longer follow-up.
BackgroundFor medical conditions with numerous interventions worthy of investigation, there are many advantages of a multi-arm multi-stage (MAMS) platform trial approach. However, there is currently ...limited knowledge on uptake of the MAMS design, especially in the late-phase setting. We sought to examine uptake and characteristics of late-phase MAMS platform trials, to enable better planning for teams considering future use of this approach.DesignWe examined uptake of registered, late-phase MAMS platforms in the EU clinical trials register, Australian New Zealand Clinical Trials Registry, International Standard Randomised Controlled Trial Number registry, Pan African Clinical Trials Registry, WHO International Clinical Trial Registry Platform and databases: PubMed, Medline, Cochrane Library, Global Health Library and EMBASE. Searching was performed and review data frozen on 1 April 2021. MAMS platforms were defined as requiring two or more comparison arms, with two or more trial stages, with an interim analysis allowing for stopping of recruitment to arms and typically the ability to add new intervention arms.Results62 late-phase clinical trials using an MAMS approach were included. Overall, the number of late-phase trials using the MAMS design has been increasing since 2001 and been accelerated by COVID-19. The majority of current MAMS platforms were either targeting infectious diseases (52%) or cancers (29%) and all identified trials were for treatment interventions. 89% (55/62) of MAMS platforms were evaluating medications, with 45% (28/62) of the MAMS platforms having at least one or more repurposed medication as a comparison arm.ConclusionsHistorically, late-phase trials have adhered to long-established standard (two-arm) designs. However, the number of late-phase MAMS platform trials is increasing, across a range of different disease areas. This study highlights the potential scope of MAMS platform trials and may assist research teams considering use of this approach in the late-phase randomised clinical trial setting.PROSPERO registration numberCRD42019153910.
Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or ...metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices.
A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints.
Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2;
= .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5;
< .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0;
= .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6;
< .001).
Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.
Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the ...evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion.
EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios HRs) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an
≥ 0.7.
Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the
was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS.
EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.
We provide the strongest evidence to date that local failure is an independent prognosticator of outcomes in high- and intermediate-risk prostate cancer patients treated with definitive radiation ...therapy. Distant metastasis predominantly develops from a clinical relapse-free state; however, a second wave of distant metastasis occurs subsequent to local failure, albeit less commonly.
The prognostic importance of local failure after definitive radiotherapy (RT) in National Comprehensive Cancer Network intermediate- and high-risk prostate cancer (PCa) patients remains unclear.
To evaluate the prognostic impact of local failure and the kinetics of distant metastasis following RT.
A pooled analysis was performed on individual patient data of 12 533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard (PH) models were developed to evaluate the relationship between overall survival (OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local failure as a time-dependent covariate. Markov PH models were developed to evaluate the impact of specific transition states.
The median follow-up was 11 yr. There were 795 (13%) local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451 (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metastases developed from a clinically relapse-free state (cRF state). Local failure was significantly associated with OS (hazard ratio HR 1.17, 95% confidence interval CI 1.06–1.30), PCSS (HR 2.02, 95% CI 1.75–2.33), and DMFS (HR 1.94, 95% CI 1.75–2.15, p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with DMFS (HR 1.57, 95% CI 1.36–1.81) but not with OS in intermediate-risk patients. Patients without local failure had a significantly lower HR of transitioning to a PCa-specific death state than those who had local failure (HR 0.32, 95% CI 0.21–0.50, p < 0.001). At later time points, more distant metastases emerged after a local failure event for both groups.
Local failure is an independent prognosticator of OS, PCSS, and DMFS in high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly developed from the cRF state, underscoring the importance of addressing occult microscopic disease. However a “second wave” of distant metastases occurs subsequent to local failure events, and optimization of local control may reduce the risk of distant metastasis.
Among men receiving definitive radiation therapy for high- and intermediate-risk prostate cancer, about 10% experience local recurrence, and they are at significantly increased risks of further disease progression. About 80% of patients who develop distant metastasis do not have a detectable local recurrence preceding it.
Purpose To investigate the role of symptom clusters in the analysis and utilisation of patient reported outcome measures (PROMs) for data modelling and clinical practice. To compare symptom clusters ...with scales, and to explore their value in PROMs interpretation and symptom management. Methods A dataset called RT01 (ISCRTN47772397) of 843 prostate cancer patients was used. PROMs were reported with the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI). Symptom clusters were explored with hierarchical cluster analysis (HCA) and average linkage method (correlation > 0.6). The reliability of the Urinary Function Scale was evaluated with Cronbach's Alpha. The strength of the relationship between the items was investigated with Spearman's correlation. Predictive accuracy of the clusters was compared to the scales by receiver operating characteristic (ROC) analysis. Presence of urinary symptoms at 3 years measured with the late effects on normal tissue: subjective, objective, management tool (LENT/SOM) was an endpoint. Results Two symptom clusters were identified (urinary cluster and sexual cluster). The grouping of symptom clusters was different than UCLA-PCI Scales. Two items of the urinary function scales ("number of pads" and "urinary leak interfering with sex") were excluded from the urinary cluster. The correlation with the other items in the scale ranged from 0.20 to 0.21 and 0.31 to 0.39, respectively. Cronbach's Alpha showed low correlation of those items with the Urinary Function Scale (0.14-0.36 and 0.33-0.44, respectively). All urinary function scale items were subject to a ceiling effect. Clusters had better predictive accuracy, AUC = 0.70-0.65, while scales AUC = 0.67-0.61. Conclusion This study adds to the knowledge on how cluster analysis can be applied for the interpretation and utilisation of PROMs. We conclude that multiple-item scales should be evaluated and that symptom clusters provide a study-specific approach for modelling and interpretation of PROMs.
There is limited research and literature on the data management challenges encountered in multi-arm, multi-stage platform and umbrella protocols. These trial designs allow both (1) seamless addition ...of new research comparisons and (2) early stopping of accrual to individual comparisons that do not show sufficient activity. FOCUS4 (colorectal cancer) and STAMPEDE (prostate cancer), run from the Medical Research Council Clinical Trials Unit (CTU) at UCL, are two leading UK examples of clinical trials implementing adaptive platform protocol designs. To date, STAMPEDE has added five new research comparisons, closed two research comparisons following pre-planned interim analysis (lack of benefit), adapted the control arm following results from STAMPEDE and other relevant trials, and completed recruitment to six research comparisons. FOCUS4 has closed one research comparison following pre-planned interim analysis (lack of benefit) and added one new research comparison, with a number of further comparisons in the pipeline. We share our experiences from the operational aspects of running these adaptive trials, focusing on data management.
We held discussion groups with STAMPEDE and FOCUS4 CTU data management staff to identify data management challenges specific to adaptive platform protocols. We collated data on a number of case report form (CRF) changes, database amendments and database growth since each trial began.
We found similar adaptive protocol-specific challenges in both trials. Adding comparisons to and removing them from open trials provides extra layers of complexity to CRF and database development. At the start of an adaptive trial, CRFs and databases must be designed to be flexible and scalable in order to cope with the continuous changes, ensuring future data requirements are considered where possible. When adding or stopping a comparison, the challenge is to incorporate new data requirements while ensuring data collection within ongoing comparisons is unaffected. Some changes may apply to all comparisons; others may be comparison-specific or applicable only to patients recruited during a specific time period. We discuss the advantages and disadvantages of the different approaches to CRF and database design we implemented in these trials, particularly in relation to use and maintenance of generic versus comparison-specific CRFs and databases. The work required to add or remove a comparison, including the development and testing of changes, updating of documentation, and training of sites, must be undertaken alongside data management of ongoing comparisons. Adequate resource is required for these competing data management tasks, especially in trials with long follow-up. A plan is needed for regular and pre-analysis data cleaning for multiple comparisons that could recruit at different rates and periods of time. Data-cleaning activities may need to be split and prioritised, especially if analyses for different comparisons overlap in time.
Adaptive trials offer an efficient model to run randomised controlled trials, but setting up and conducting the data management activities in these trials can be operationally challenging. Trialists and funders must plan for scalability in data collection and the resource required to cope with additional competing data management tasks.
There are limited research and literature on the trial management challenges encountered in running adaptive platform trials. This trial design allows both (1) the seamless addition of new research ...comparisons when compelling clinical and scientific research questions emerge, and (2) early stopping of accrual to individual comparisons that do not show sufficient activity without affecting other active comparisons. Adaptive platform design trials also offer many potential benefits over traditional trials, from faster time to accrual to contemporaneously recruiting multiple research comparisons, added flexibility to focus on more promising research comparisons via pre-planned interim analyses and potentially shorter time to primary results. We share here our experiences from a trial management perspective, highlighting the challenges and successes.
We evaluated the operational aspects of making changes to these adaptive platform trials and identified both common and trial-specific challenges. The operational steps and challenges linked to both the addition of new research comparisons and stopping recruitment following pre-planned interim analysis were considered in our evaluation.
Specific operational challenges in these adaptive platform protocols, additional to those in traditional two-arm trials, were identified. Key lessons are presented describing some of the solutions and considerations over conducting these trials. Careful consideration on the practicality of the protocol structure (modular versus single protocol), the longevity and continuity of trial oversight committees, and having clear clinical and scientific criteria for the addition of new research comparisons were identified as some of the most common challenges.
Understanding the operational complexities associated with running adaptive platform protocols is paramount for their conduct, adaptive platform trials offer an efficient model to run randomised controlled trials and we are continuing to work to reduce further the effort required from an operational perspective.
FOCUS4: ISRCTN Registry, ISRCTN90061546 . Registered on 16 October 2013.
ISRCTN Registry, ISRCTN78818544 . Registered on 2 February 2004.
Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), ...using a multigroup, multistage trial design.
We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer).
A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval CI, 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events).
Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).
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