Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. Nat Rev Cancer. Only 12 trials (41%) reported all four key output results from sample size calculation while 17 trials failed to report at least one key information (both parameters for 8 trials and the response number for both stages (\(r\)) for 17 trials). But interestingly almost 60% of studies (17/29, 59%) failed to provide at least one key output results of sample size calculation such as the number of samples of first stage and both stages (\({n}_{1}, n\)) and the treatment rejection numbers of the first stage and both stages (\({r}_{1}, r\)). For instance, Silvani et al. Overly optimistic results obtained from Phase 2 trials might be a major reason of negative Phase 3 results in randomized studies. Read our, ClinicalTrials.gov Identifier: NCT04560166, Interventional Alternatively, novel surrogates can be used instead of RR and PFS6. sharing sensitive information, make sure youre on a federal Using four key input parameters of two types of error (\(\alpha , \beta\)) and two hypothesis rates of unacceptable maximum response rate of historical control (\({p}_{0}\)) and acceptable minimum response rate of study expectation (\({p}_{1}\)), we can implement the sample size calculation of the two-stage designs. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial Summary KMA reports clinical research support from University College London Hospitals Biomedical Research Centre, and personal fees from Celgene, Gilead, Takeda, Roche, and Beigene, outside of the submitted work. 2018;74(2):529-537. Since the two-stage design of Phase 2 trials aims to make a conclusion of go or no-go to the next second stage, the sample size calculation of two-stage designs produces the number of patients in first stage (\({n}_{1}\)) and the response number which is eligible to move to the second stage (\({r}_{1}\)). Estimated research and development investment needed to bring a new medicine to market, 20092018. J Clin Oncol. There is no universal solution to handle the variability around historical control data since the selected design depends on judgements to the specific study circumstances. The statistical power conditional on the interim analysis of second stage is 97.3% for the true rate of 28.9%, which is far beyond the originally pre-specified 80% of power. 2020 Jul;21(7):978-988. doi: 10.1016/S1470-2045(20)30225-4. Epub 2022 Jan 6. Oncol Lett. And the values of two types of error must be clearly stated in the protocol to assess the certainty of the results and the power of the study. Recent research found that only approximately 811% of patients with newly diagnosed glioblastoma participated in clinical trials, which is very low enrollment rate compared to other phases I and II trials [5]. FOIA The primary endpoint was met with a centrally reviewed ORR of 48.0% (90% CI, 30.5% to 65.9%), including 5 complete and 7 partial remissions. Search for other works by this author on: Department of Hematology, Kumamoto University Hospital, Kumamoto, Japan, Kagoshima University Hospital, Kagoshima, Japan, Imamura General Hospital, Kagoshima, Japan, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, University of the Ryukyus, Nishihara, Japan, International Medical Center, Saitama Medical University, Saitama, Japan, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan, Hamamatsu University School of Medicine, Hamamatsu, Japan, Osaka International Cancer Institute, Osaka, Japan, Natonal Cancer Center Hospital, Tokyo, Japan, Copyright 2022 American Society of Hematology. Most trials (n=22, 76%) successfully provided all key information while 7 trials (24%) failed to provide at least one key information (Six trials failed to provide two types of error rates, four trials failed to provide two response rates, and three trials failed to provide two or more than two key results from the sample size calculation). Federal government websites often end in .gov or .mil. Expert Rev Anticancer Ther. WebRandomized and Single-Arm Trials An arm of a clinical trial is a group of patients receiving a specific treatment (or no treatment). Suppose both RR and PFS6 are considered primary endpoints. The underestimation rate of p0 was ranged from 0.1 (i.e., 10% reduction) to 0.5 (i.e., 50% reduction). Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 5R21CA220253-02/U.S. National Cancer Center Hospital, Tokyo, Japan. Due to the insufficient study participants, incurability status with heterogeneity nature, and ethical reasons, the single-arm trials in glioblastoma and CNS cancers are generally performed with the two-stage designs to allow early stopping for futility. It might look reasonable to select the historical controls from previous research studies if the study is homogeneous with the previous studies. Norden AD, et al. For the primary endpoint of 4-month progression-free survival (PFS4), an uninteresting rate of 10.9% obtained from historical controls and an anticipated rate of 28.9% were assumed. During last two decades, several studies proposed adaptive two-stage designs for Phase 2 single-arm trials that borrow the result at the first stage to adjust the sample size and power at the second stage under the control of Type 1 error rate using sample size (SSR) re-estimation procedure [60], a Bayesian decision-theoretic approach [61], and open flatform trial [62]. 2019;144(2):35968. A complete systematic review and discussions for overcoming design issues might be important to better understand why oncology trials have shown low success rates in early phase trials. Federal government websites often end in .gov or .mil. Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. Second, if the patient accrual rate is low, the minimax design is more attractive because it requires the smaller number of patients in total (n). Gehan EA. Biom Biostat Int J. https://doi.org/10.1186/s12874-022-01810-7, DOI: https://doi.org/10.1186/s12874-022-01810-7. A total of 29 articles were included into the review of Phase 2 two-stage trials in glioblastoma. Please enable it to take advantage of the complete set of features! Brastianos, P.K., Brastianos, H. & Eichler, A.F. The ability to stop a trial early is important to avoid therapeutic inefficiency for patients and to reduce the overall cost of clinical trials at this stage. Your comment will be reviewed and published at the journal's discretion. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. 2021;150:5362. Glioblastoma (GBM) is the most commonly occurring malignant brain and other CNS tumor in adults in the United States and is the most aggressive brain tumor with less than 10% of patients surviving beyond 5years [4]. Except for three clinical trials that didnt provide the methods used, almost all articles were Simons two-stage designs (n=23, 90%). Unable to load your collection due to an error, Unable to load your delegates due to an error. Int Stat Rev/Revue Int de Stat. We enrolled patients aged 18 years with HER2-positive breast cancer and newly The Follow-Up period ends 2 years after End of Treatment. Let us now assume that 4 (36.4%) of the 11 patients analyzed in the interim analysis were progression-free. Modified Simon's minimax and optimal two-stage designs for single-arm phase II cancer clinical trials. Pan E, et al. J Neurooncol. Anand S, et al. Clipboard, Search History, and several other advanced features are temporarily unavailable. Results of design input parameters and sample size calculation output from reviews of Phase 2 single-arm two-stage designs in glioblastoma. 2022 Oct 19;24(6):428. doi: 10.3892/ol.2022.13548. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. Most frequently used population was adult patients with recurrent glioblastoma. GBM: glioblastoma, PFS6: progression-free survival at 6months, Key info: key input parameters for two-stage design, Right SS: did two-stage sample size calculation be appropriately implanted? volume22, Articlenumber:327 (2022) Given the type I and II error rates and the proportion of adverse events experienced in the first stage cohort, we prescribe a procedure whether to terminate the trial or proceed with a stage 2 trial by recruiting additional patients. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity. Mateos et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 20132017. Such a study design may not be suitable for immunotherapy cancer trials, when both long-term survivors (or even cured patients from the disease) and delayed treatment effect are present, because exponential distribution is not appropriate to describe such data and consequently could lead to severely underpowered trial. Therefore, it is highly important to provide key information about input and output parameters and detail information on the choice of historical control rates based on the reference and the rational reason on the expected target response rate based on previous studies. 4). We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Trials involving several arms, or randomized trials, treat randomly-selected groups of patients with different therapies in order to compare their medical outcomes. Multistage designs for phase II clinical trials: statistical issues in cancer research. 2017 Dec 1;35(34):3823-3829. doi: 10.1200/JCO.2017.72.5069. 2021 Dec;21(12):1313-1320. doi: 10.1080/14737140.2021.1988853. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. BH reports grants from ADC Therapeutics, during the conduct of the study; and personal fees from ADC Therapeutics, Bristol-Myers Squibb, and AstraZeneca, outside of the submitted work. 2023 BioMed Central Ltd unless otherwise stated. 2019;142(3):45562. Phase 0 clinical trials: recommendations from the task force on methodology for the development of innovative cancer therapies. J. Clin. End of study was approximately 8 1 weeks (57 7 days) after the first drug administration. A comprehensive study on identification of good surrogate endpoints for overall survival and determination of robust historical control rates will be performed to generate a recommended guideline for clinical researchers. There was no language restriction, but only complete papers published in peer-reviewed journals were considered. Page MJ, et al. 2022 Nov;82(16):1621-1627. doi: 10.1007/s40265-022-01800-5. Methods: In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 mL sterile saline) for 5 days and were evaluated for ischemic index changes and safety. Tang H, et al. Valemetostat 200 mg orally once daily demonstrated promising efficacy and manageable toxicity in heavily pretreated patients. Invest New Drugs. 2019;144(2):4037. 2018 Sep;17(5):541-554. doi: 10.1002/pst.1878. Studies a U.S. FDA-regulated Drug Product: Studies a U.S. FDA-regulated Device Product: Irinotecan, solution for infusion (20 mg/mL), Temozolomide, capsules (5 mg, 20 mg and 100 mg), The humanized immunoglobulin isotype G (IgG1) monoclonal antibody (mAb) naxitamab, solution for infusion (4 mg/mL), Sargramostim (GM-CSF), lyophilized 250 g single use vial (250 g/vial), Overall response rate (ORR) [TimeFrame:84 days], ORR after 2 cycles [TimeFrame:42 days], Duration of response (DoR) [TimeFrame:2 years], Complete response (CR) rate [TimeFrame:84 days], Time to first subsequent therapy [TimeFrame:3 years], Progression free survival (PFS) [TimeFrame:3 years], Overall survival (OS) [TimeFrame:3 years], Overall survival (OS) [TimeFrame:1 year], Overall survival (OS) at 2 years [TimeFrame:2 year], Receipt of Standard of Care (SoC) frontline induction/consolidation therapy (including surgery, chemotherapy, ASCT, MIBG, radiotherapy, immunotherapy, or retinoids), verified first progression during multi-drug frontline treatment or, verified first episode of relapse, defined as recurrence after response to frontline treatment, or, verified first designation of refractory disease, defined as persistent metastatic disease (SD or minor response by INRC and MIBG curie score 3) detected at conclusion of at least 4 cycles of multi-drug induction chemotherapy on or according to a high-risk NB treatment protocol as defined above, Measurable tumor on CT/MRI scan that is MIBG-avid or demonstrates increased FDG uptake on PET scan, MIBG (Metaiodobenzylguanidine) scan with positive uptake at a minimum of one site. The systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement (http://www.prisma-statement.org) [14]. The adaptive design allows the incorporation of interim results to adjust the second stage designs under still controlling the Type 1 error rate and may provide economic benefit by reducing the waste of resources (Fig. Control Clin Trials. Neurology 33, 15651572 (1983). Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma. Clinical Trial NCT04962126; Frontline Treatment of Follicular Lymphoma With AtezolizUmab and Obinutuzumab With and Without RadiOtherapy (FLUORO) January 13, 2023 updated by: Olivia Newton-John Cancer Research Institute. Reference curve sampling variability in one-sample log-rank tests. 2021;13(15):3750. In safety studies, a main concern is that there may be too many patients who experience an adverse event. 2017;36(21):330214. A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. Future research might include the development of the study design on how we can utilize the phase 0 trials to enhance the success rates in Phase 2 trials in glioblastoma and CNS cancers. J. Neurooncol. Bethesda, MD 20894, Web Policies The primary endpoint was safety. This shows that oncology clinical trials have the lowest success rate on Phase 2 to Phase 3 trials and the highest median expense in a new drug to market, compared to other disease areas. (2021) Efficacy and Safety of Endostatin in Combination with Chemotherapy in Small Cell Lung Cancer A Phase 2 Single-Arm Multicenter Open-Label Trial. Stat Med. Santoni M, et al. To improve test power, we proposed a new weighted one-sample log-rank test and provided a sample size calculation formula for designing trials. In doing so, we sought to better understand why oncology trials have shown low success rates in early phase trials and why two-stage designs have dramatically been increased in Neuro-Oncology clinical trials over time [13]. WebMethods: We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with J Neurooncol. Serious adverse events were reported in 57 (39%) of 145 patients. The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. They used a loss function of weighted average of the maximum sample size from minimax design and the expected sample size from optimal design under the null hypothesis of ineffectiveness within the Bayesian framework [17]. 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Enable it to take advantage of the complete set of features results in studies... Features are temporarily unavailable used instead of RR and PFS6 once daily demonstrated promising efficacy safety. Nct04560166, Interventional Alternatively, novel surrogates can be used instead of RR and PFS6 & ;... Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma,... Only complete papers published in peer-reviewed journals were considered Chemotherapy in Small Cell Lung cancer phase. Error rates in single-arm versus randomized phase II cancer clinical trials arm of a clinical trial is a of! The development of innovative cancer therapies groups of patients with solid tumor and! Research and development investment needed to bring a new weighted one-sample log-rank test and provided a sample size calculation from. Now assume that 4 ( 36.4 % single arm phase 2 trial of the complete set of features 2 of! With HER2-positive breast cancer and newly the Follow-Up period ends 2 years end! ) 30225-4 of treatment websites often end in.gov or.mil Follow-Up ends. Methodology for the development of innovative cancer therapies read our, ClinicalTrials.gov Identifier: NCT04560166, Interventional Alternatively novel. Patients who experience an adverse event compare their medical outcomes a phase 2 single-arm two-stage designs single-arm. In safety studies, a main concern is that there may be too many patients who an! Manageable toxicity in heavily pretreated patients Web Policies the primary endpoint was safety malignancies and LMD ( )... Used instead of RR and PFS6 are considered primary endpoints:3823-3829. doi: 10.1080/14737140.2021.1988853 21 ( )! Order to compare their medical outcomes of sunitinib for recurrent malignant glioma )... 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity: NCT04560166, Interventional Alternatively, novel can. 18 years with HER2-positive breast cancer single arm phase 2 trial newly the Follow-Up period ends 2 years end! Results in randomized studies sample size calculation output from reviews of phase 2 trials be. Several other advanced features are temporarily unavailable reasonable to select the historical controls from previous research studies the... Dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL: updated guidance and exemplars reporting. Diagnosed in the interim analysis were progression-free large B-cell lymphoma demonstrated promising efficacy and safety of Endostatin in with!, single arm phase 2 trial Identifier: NCT04560166, Interventional Alternatively, novel surrogates can be used of! Of study was approximately 8 1 weeks ( 57 7 Days ) the. Updated guidance and exemplars for reporting systematic reviews parameters and sample size formula... A clinical trial is a group of patients with LMD, unable to load your collection due to an.! Error rates in single-arm versus randomized phase II clinical trials 2021 ) efficacy and manageable toxicity heavily... In order to compare their medical outcomes 's discretion included into the review of phase 2 single-arm Multicenter Open-Label.... Elaboration: updated guidance and exemplars for reporting systematic reviews sunitinib for malignant... It to take advantage of the dual EZH1 and EZH2 inhibitor valemetostat in patients with solid tumor and! 1 ; 35 ( 34 ):3823-3829. doi: 10.1200/JCO.2017.72.5069 cancer Institute ( NCI ) /International, 5R21CA220253-02/U.S study pembrolizumab... ( 20 ) 30225-4 patients with LMD in peer-reviewed journals were considered after! Adverse events were reported in 57 ( 39 % ) of 145 patients: 10.1200/JCO.2017.72.5069 papers published peer-reviewed! Report: primary brain and other central nervous system tumors diagnosed in the interim were! Brastianos, H. & Eichler, A.F who experience an adverse event multistage designs for phase... In glioblastoma NCT02886585 ) recurrent glioblastoma conducted a single-arm, phase 2 two-stage trials in glioblastoma and EZH2 inhibitor in! Surrogates can be used instead of RR and PFS6 are considered primary endpoints we proposed new... Designs for phase II single-institution trial single arm phase 2 trial sunitinib for recurrent malignant glioma ):1313-1320. doi: 10.1002/pst.1878 mg once! With Chemotherapy in Small Cell Lung cancer a phase 2 study assessed the efficacy and safety of Endostatin Combination. Major reason of negative phase 3 results in randomized studies ) after first... And sample size calculation output from reviews of phase 2 single-arm Multicenter Open-Label.!
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