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MOTIVATION: Platform designs - master protocols that allow for new treatment arms to be added over time - have gained considerable attention in recent years. Between 2001 and 2019, 16 platform trials were initiated globally. The COVID-19 pandemic seems to have provided a new motivation for these designs. We conducted a rapid review to quantify and describe platform trials used in COVID-19. METHODS: We cross-referenced PubMed, ClinicalTrials.gov, and the Cytel COVID-19 Clinical Trials Tracker to identify platform trials, defined by their stated ability to add future arms. RESULTS: We identified 58 COVID-19 platform trials globally registered between January 2020 and May 2021. According to trial registries, 16 trials have added new therapies (median 3, IQR 4) and 11 have dropped arms (median 3, IQR 2.5). About 50% of trials publicly share their protocol, and 31 trials (53%) intend to share trial data. Forty-nine trials (84%) explicitly report adaptive features, and 21 trials (36%) state Bayesian methods. CONCLUSIONS: During the pandemic, there has been a surge in the number of platform trials compared to historical use. While transparency in statistical methods and clarity of data sharing policies needs improvement, platform trials appear particularly well-suited for rapid evidence generation. Trials secured funding quickly and many succeeded in adding new therapies in a short time period, thus demonstrating the potential for these trial designs to be implemented beyond the pandemic. The evidence gathered here may provide ample insight to further inform operational, statistical, and regulatory aspects of future platform trial conduct..

BACKGROUND: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability. METHODS: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented. FINDINGS: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36-48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3-4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia). INTERPRETATION: Ponatinib-FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers. FUNDING: Blood Cancer UK and Incyte..

BACKGROUND: Patient-reported adverse events may be a useful adjunct for assessing a drug's tolerability in dose-finding oncology trials (DFOT). We conducted surveys of international stakeholders and the National Cancer Research Institute (NCRI) Consumer Forum to understand attitudes about patient-reported outcome (PRO) use in DFOT. METHODS: A 35-question survey of clinicians, trial managers, statisticians, funders, and regulators of DFOT was distributed via professional bodies examining experience using PROs, benefits/barriers, and their potential role in defining tolerable doses. An 8-question survey of the NCRI Consumer Forum explored similar themes. RESULTS: International survey: 112 responses from 15 September-30 November 2020; 103 trialists [48 clinicians (42.9%), 38 statisticians (34.0%), 17 trial managers (15.2%)], 7 regulators (6.3%), 2 funders (1.8%)]. Most trialists had no experience designing (73, 70.9%), conducting (52, 50.5%), or reporting (88, 85.4%) PROs in DFOT. Most agreed that PROs could identify new toxicities (75, 67.0%) and provide data on the frequency (86, 76.8%) and duration (81, 72.3%) of toxicities. The top 3 barriers were lack of guidance regarding PRO selection (73/103, 70.9%), missing PRO data (71/103, 68.9%), and overburdening staff (68/103, 66.0%). NCRI survey: 57 responses on 21 March 2021. A total of 28 (49.1%) were willing to spend <15 min/day completing PROs. Most (55, 96.5%) preferred to complete PROs online. 61 (54.5%) trialists and 57 (100%) consumers agreed that patient-reported adverse events should be used to inform dose-escalation decisions. CONCLUSION: Stakeholders reported minimal experience using PROs in DFOT but broadly supported their use. Guidelines are needed to standardize PRO selection, analysis, and reporting in DFOT..

This paper reports guidelines for the content of statistical analysis plans for early phase clinical trials, ensuring specification of the minimum reporting analysis requirements, by detailing extensions (11 new items) and modifications (25 items) to existing guidance after a review by various stakeholders..

IMPORTANCE: Patient-reported outcomes (PROs) can inform health care decisions, regulatory decisions, and health care policy. They also can be used for audit/benchmarking and monitoring symptoms to provide timely care tailored to individual needs. However, several ethical issues have been raised in relation to PRO use. OBJECTIVE: To develop international, consensus-based, PRO-specific ethical guidelines for clinical research. EVIDENCE REVIEW: The PRO ethics guidelines were developed following the Enhancing the Quality and Transparency of Health Research (EQUATOR) Network's guideline development framework. This included a systematic review of the ethical implications of PROs in clinical research. The databases MEDLINE (Ovid), Embase, AMED, and CINAHL were searched from inception until March 2020. The keywords patient reported outcome* and ethic* were used to search the databases. Two reviewers independently conducted title and abstract screening before full-text screening to determine eligibility. The review was supplemented by the SPIRIT-PRO Extension recommendations for trial protocol. Subsequently, a 2-round international Delphi process (n = 96 participants; May and August 2021) and a consensus meeting (n = 25 international participants; October 2021) were held. Prior to voting, consensus meeting participants were provided with a summary of the Delphi process results and information on whether the items aligned with existing ethical guidance. FINDINGS: Twenty-three items were considered in the first round of the Delphi process: 6 relevant candidate items from the systematic review and 17 additional items drawn from the SPIRIT-PRO Extension. Ninety-six international participants voted on the relevant importance of each item for inclusion in ethical guidelines and 12 additional items were recommended for inclusion in round 2 of the Delphi (35 items in total). Fourteen items were recommended for inclusion at the consensus meeting (n = 25 participants). The final wording of the PRO ethical guidelines was agreed on by consensus meeting participants with input from 6 additional individuals. Included items focused on PRO-specific ethical issues relating to research rationale, objectives, eligibility requirements, PRO concepts and domains, PRO assessment schedules, sample size, PRO data monitoring, barriers to PRO completion, participant acceptability and burden, administration of PRO questionnaires for participants who are unable to self-report PRO data, input on PRO strategy by patient partners or members of the public, avoiding missing data, and dissemination plans. CONCLUSIONS AND RELEVANCE: The PRO ethics guidelines provide recommendations for ethical issues that should be addressed in PRO clinical research. Addressing ethical issues of PRO clinical research has the potential to ensure high-quality PRO data while minimizing participant risk, burden, and harm and protecting participant and researcher welfare..

BACKGROUND: Patient-reported adverse events (AEs) may be a useful adjunct to clinician-assessed AEs for assessing tolerability in early phase, dose-finding oncology trials (DFOTs). We reviewed DFOTs on ClinicalTrials.gov to describe trends in patient-reported outcome (PRO) use. METHODS: DFOTs commencing 01 January 2007 - 20 January 2020 with 'PROs' or 'quality of life' as an outcome were extracted and inclusion criteria confirmed. Study and PRO characteristics were extracted. Completed trials that reported PRO outcomes and published manuscripts on ClinicalTrials.gov were identified, and PRO reporting details were extracted. RESULTS: 5.3% (548/10 372) DFOTs included PROs as an outcome. 231 (42.2%) were eligible: adult (224, 97%), solid tumour (175, 75.8%), and seamless phase 1/2 (108, 46.8%). PRO endpoints were identified in more trials (2.3 increase/year, 95% CI: 1.6-2.9) from an increasing variety of countries (0.7/year) (95% CI: 0.4-0.9) over time. PROs were typically secondary endpoints (207, 89.6%). 15/77 (19.5%) completed trials reported results on the ClinicalTrials.gov results database, and of those eight included their PRO results. Eighteen trials had published manuscripts available on ClinicalTrials.gov. Three (16.7%) used PROs to confirm the maximum tolerated dose. No trials identified who completed the PROs or how PROs were collected. CONCLUSIONS: PRO use in DFOT has increased but remains limited. Future work should explore the role of PROs in DFOT and determine what guidelines are needed to standardise PRO use..

PURPOSE: Salvage options for patients who relapse after allogeneic stem-cell transplantation (allo-SCT) for acute myeloid leukemia (AML) and myelodysplasia (MDS) remain limited, and novel treatment strategies are required. Both lenalidomide (LEN) and azacitidine (AZA) possess significant antitumor activity effect in AML. Administration of LEN post-transplantation is associated with excessive rates of graft-versus-host disease (GVHD), but AZA has been shown to ameliorate GVHD in murine transplantation models. We therefore examined the tolerability and activity of combined LEN/AZA administration in post-transplantation relapse. PATIENTS AND METHODS: Twenty-nine patients who had relapsed after allo-SCT for AML (n = 24) or MDS (n = 5) were treated with sequential AZA (75 mg/m2 for 7 days) followed by escalating doses of LEN on days 10 to 30. Dose allocation and maximum tolerated dose (MTD) estimation were guided by a modified Bayesian continuous reassessment method (CRM). RESULTS: Sequential AZA and LEN therapy was well tolerated. The MTD of post-transplantation LEN, in combination with AZA, was determined as 25 mg daily. Three patients developed grade 2 to 4 GVHD. There was no GVHD-related mortality. Seven of 15 (47%) patients achieved a major clinical response after LEN/AZA therapy. CD8+ T cells demonstrated impaired interferon-γ/tumor necrosis factor-α production at relapse, which was not reversed during LEN/AZA administration. CONCLUSION: We conclude LEN can be administered safely post-allograft in conjunction with AZA, and this combination demonstrates clinical activity in relapsed AML/MDS without reversing biologic features of T-cell exhaustion. The use of a CRM model delivered improved efficiency in MTD assessment and provided additional flexibility. Combined LEN/AZA therapy represents a novel and active salvage therapy in patients who had relapsed post-allograft..

BACKGROUND: Adaptive designs are a wide class of methods focused on improving the power, efficiency and participant benefit of clinical trials. They do this through allowing information gathered during the trial to be used to make changes in a statistically robust manner - the changes could include which treatment arms patients are enrolled to (e.g. dropping non-promising treatment arms), the allocation ratios, the target sample size or the enrolment criteria of the trial. Generally, we are enthusiastic about adaptive designs and advocate their use in many clinical situations. However, they are not always advantageous. In some situations, they provide little efficiency advantage or are even detrimental to the quality of information provided by the trial. In our experience, factors that reduce the efficiency of adaptive designs are routinely downplayed or ignored in methodological papers, which may lead researchers into believing they are more beneficial than they actually are. MAIN TEXT: In this paper, we discuss situations where adaptive designs may not be as useful, including situations when the outcomes take a long time to observe, when dropping arms early may cause issues and when increased practical complexity eliminates theoretical efficiency gains. CONCLUSION: Adaptive designs often provide notable efficiency benefits. However, it is important for investigators to be aware that they do not always provide an advantage. There should always be careful consideration of the potential benefits and disadvantages of an adaptive design..

The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440-7. ©2017 AACR..