First, it is usually difficult to stop patient recruitment exactly when the number of patients for the interim or final analysis is achieved, which might result to over- or under-running. MH reports grants from Takeda, Spectrum Pharmaceuticals, Astellas Pharma, and personal fees from Janssen, Incyte Corporation, ADC Therapeutics, Celgene, Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio, Sanofi Genzyme, BeiGene, and AstraZeneca, outside of the submitted work. Stat Med. Copyright 2021 Elsevier Ltd. All rights reserved. Comput Stat Data Anal. Eur J Clin Pharmacol. 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. 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. eCollection 2021. Before Suh CH, et al. Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma. Sci Rep. 2021;11(1):2306. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. 2022 May;9(5):e327-e339. Oncol Lett. Keywords: 2008;14(12):367582. The site is secure. A total of 17 drugs were used as single therapeutic treatment with Sunitinib (SNT) and Nintedanib (NIN) from two studies each, and Temozolomide (TMZ), Bendamustine (BEN), Temsirolimus (TMS), Gimatecan (GMT), Bosutinib (BOS), Dasatinib (DAS), Tivozanib (TIV), Imipridone (IMI), Ortatzxel (ORT), Dovitinib (DOV), Perifosine (PRF), Thrombopoietin receptor (THR), and Pomalidomide (POM) from single study each. Privacy More than three quarter articles (n=22, 76%) provided all related information of type I and II errors (\(\alpha , \beta\)) and unacceptable and acceptable response rates (\({p}_{0}, {p}_{1}\)). 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). Single-arm studies have been traditionally used in Phase II oncology clinical trials. 2009;45(5):7416. J Neurooncol. Re-formulating Gehan's design as a flexible two-stage single-arm trial. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. Du XJ, et al. Contemp Clin Trials. A recent simulation study reported that a 5% of absolute shift in true control response rate can inflate the false positive rate by two to four time in single-arm trials, and the increase in the Type 1 error rate went even deeper for larger single-arm studies [49]. This multicenter phase 2 trial (NCT04102150; https://clinicaltrials.gov/ct2/show/NCT04102150; DS3201-A-J201) enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Why Should I Register and Submit Results? Cannistra SA. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. The rapid trials and ethical reasons generally lead the single-arm trials to be performed with interim analyses for possible early termination of the trials. 2021 May 6;134(11):1299-1309. doi: 10.1097/CM9.0000000000001463. Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon's design. 2018;15(2):14958. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. Optimal two-stage designs for exploratory basket trials. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study. 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]. Clin Cancer Res. Nat Rev Cancer. 2019 Mar;20(3):371-382. doi: 10.1016/S1470-2045(18)30812-X. 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. 2013 May;139(1):13-22. doi: 10.1007/s10549-013-2525-y. 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]. J. Neurooncol. 11, 561569 (1993). BSK reports grants from ADC Therapeutics, during the conduct of the study; and personal fees from Seattle Genetics and Genentech, outside of the submitted work. Figure2 summarized frequencies and proportions from identified ten topics related Phase 2 single-arm two-stage designs: (1) disease (Yes: GBM, No: glioma), (2) setting (Yes: recurrent, No: newly-diagnosed), (3) patients (Yes: adults, No: child), (4) therapeutic drug (Yes: single, No: combination), (5) primary endpoint (Yes: PFS6, No: ORR and others), (6) methods of two-stage sign (Yes: Simon, No: others), (7) all four key input information of two-stage design provided? J Immunother Cancer. 2012;110(1):1118. Several important topics related to the design issues will be followed to handle the design issues by increasing the precision of efficacy from targeted therapeutic trials of Phase 2 two-stage designs in brain tumor. FOIA Assuming a true rate of 28.9%, additional 10 patients are sufficient to achieve 80% power. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Simons optimal design for a one-sided significance level of 0.05 and a power of 0.80 includes 11 patients in the first stage. Simon R. Optimal two-stage designs for phase II clinical trials. 2021;11:660892. FOIA Estimated research and development investment needed to bring a new medicine to market, 20092018. Federal government websites often end in .gov or .mil. Cancers (Basel). Results. CAS Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol. 2011;103(3):491501. Cancer immunotherapy trial design with long-term survivors. Rai SN, Ray H, Pan J, Barnes C, Cambon AC, Wu X, Bonassi S, Srivastava DK. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. 2018 Sep;17(5):541-554. doi: 10.1002/pst.1878. WebDive into the research topics of 'MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial'. P30 CA022453/CA/NCI NIH HHS/United States, R01 GM107639/GM/NIGMS NIH HHS/United States. A phase II trial of oral gimatecan for recurrent glioblastoma. Cancer Med. Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. 2022 Dec 9;2022(1):146-154. doi: 10.1182/hematology.2022000332. Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. J Neurooncol. J Neurooncol. 2022 Dec 7;14(24):6026. doi: 10.3390/cancers14246026. Wang Z-X, et al. official website and that any information you provide is encrypted Friends of Cancer Research is a 501 (C)(3) non-profit organization.Our tax ID number is 52-1983273. 2005;23(28):7199206. 2013;24(4):11129. The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). Oncotarget. Such an unexpected situation cannot be appropriately handled with the current system of two-stage designs because current designs require to prespecify the design information like sample size for each stage and stopping rules in the study protocol. -. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. Their composite endpoint model provides efficiency while still maintaining the clinical relevance of OS. Google Scholar. 2014;33(12):2004-2016. Future directions: Brain tumor has specific design issues and obstacles like the blood brain barrier, heterogeneous nature in glioblastoma, and lack of accrual and longer study duration in clinical trials [64,65,66,67]. A better way to avoid the potential issues is to use a hazard ratio (HR). 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. J Clin Oncol. If the therapy shows sufficient responses with the first stage data, the study will be continued for additional second stage with more patients to finalize the interim tests on the hypothesis that the therapy has sufficient biological activity to be able to advance for larger phase 3 randomized trials [6, 12]. WebSingle-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial Erstverffentlichung 2022 Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. Please enable it to take advantage of the complete set of features! A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. doi: 10.1016/S2352-3026(21)00311-2. However, we should acknowledge there exist heterogeneities when we borrow the historical control information from other published studies due to different population conditions and quality of supportive care. A phase II single-arm study of irinotecan in combination with temozolomide (TEMIRI) in children with newly diagnosed high grade glioma: a joint ITCC and SIOPE-brain tumour study. Trippa and colleges [55] introduced a novel composite endpoint model by combining PFS6 and OS for glioblastoma trials. Bookshelf The .gov means its official. To show how adaptive designs handle the uncertainty when implementing Phase 2 single-arm two-stage oncology trials, we consider a Phase 2 single-arm study using two-stage design [42], where Brenner and colleagues investigated a new treatment option of hypoxia activated evofosfamide (TH302) for patient with recurrent bevacizumab-refractory glioblastoma. Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. Pharm Stat. 1990;9(3):21528. 2022 Feb 20;41(4):786-797. doi: 10.1002/sim.9258. J Neurooncol. Single-arm phase II trial design under parametric cure models. Naxitamab and GM-CSF will be given for at least 8 cycles. Better understanding on the study drug information and targeted molecular information might help the understanding of why the two-stage trials had been terminated after the stage 1 and ineffective after successful completion of both stages. Right implementation for two-stage design and sample size calculation, transparency of historical control and experimental rates, appropriate selection on primary endpoint, potential incorporation of adaptive designs, and utilization of Phase 0 paradigm might help overcoming the challenges on glioblastoma therapeutic trials in Phase 2 trials. California Privacy Statement, Only around 41% of trials (n=12) appropriately provided the key input and output information for the study design and sample size calculation of two-stage designs phase 2 trials. The choice of type I and type II errors is highly important since researchers need to assure that potentially effective therapy is not abandoned and at the same time the insignificant studies with very small marginal effects should not be advanced to subsequent phase III studies. Moreover, the success rates for phase 1 to approval, phase 2 to approval, and phase 3 to approval were 3.4%, 6.7% and 35.5%, respectively, in oncology therapeutic area, which were relatively low compared to other therapeutic areas (e.g., 25.5%, 32.3%, and 62.2% of cardiovascular disease therapeutic area and 25.2%, 35.1%, and 75.3% of infectious disease therapeutic area) [3]. WebMethods We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 5R21CA220253-02/U.S. Federal government websites often end in .gov or .mil. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. The purpose of this study is to evaluate the efficacy and safety in patients with FGFR2-Rearranged unresectable or metastatic intrahepatic cholangiocarcinoma who failed prior therapy Arms and Interventions Arm: Experimental Drug ICP-192 Outcome Measures Breslow NE. Silvani A, et al. Neuro Oncol. eCollection 2022 Dec. Transl Cancer Res. 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]. Bookshelf Optimal two-stage design of single arm Phase II clinical trials based on median event time test. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1-3. Suppose a two-stage design with a type I error no larger than \({\alpha }^{*}\) and a power no smaller than (1- \({\beta }^{*}\)) for given (\({p}_{0}\), \({p}_{1}\)). KH, JF, SH, and YQ report personal fees from ADC Therapeutics, during the conduct of the study. Unlike a survival rate at a specific time point, a HR is not a point estimate and uses all the information in the entire survival curve. PLZ reports personal fees from Verastem, Merck Sharp & Dohme, Eusapharma, Sanofi, ADC Therapeutics, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, Sandoz, Immune Design, Celgene, Portola, Roche, and Kyowa Kirin, outside of the submitted work. 2022 Dec 6;15:1481-1501. doi: 10.2147/OTT.S326632. Finkelstein DM, Muzikansky A, Schoenfeld DA. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis. Int Stat Rev/Revue Int de Stat. 3). An official website of the United States government. Google Scholar. The outcomes of simulation are depicted in Fig. 8600 Rockville Pike Ananda S, et al. 2017;36(21):330214. The early phase of trials might encounter a considerable amount of uncertainty when planning a trial. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Bethesda, MD 20894, Web Policies We identified a total of 81 articles based on online search using Two-stage Phase II trials in glioblastoma. Keywords: Korean J Radiol. Eur J Cancer. A systematic review of surrogate endpoints (SEPs) for overall survival (OS) in metastatic colorectal cancer mCRC. Chamberlain MC, Johnston SK. Pasqualini C, et al. To avoid this temptation, which poses a potential risk to patients, investigators should practice transparency by citing historical data sources used in the study protocol. Brastianos, P.K., Brastianos, H. & Eichler, A.F. Epub 2020 Sep 1. MS reports grants from ADC Therapeutics, during the conduct of the study; and personal fees from Amgen and Celgene, outside of the submitted work. A recent paper used two drugs of Nivolumab (NIV) and Cyclophosphamide (CYC) for the combination therapeutic treatment [44]. 2004;60(2):48290. 2021;20(6):123548. The era of CD19-directed therapy in diffuse large B-cell lymphoma. 8600 Rockville Pike Wong CH, Siah KW, Lo AW. 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. Most studies (n=27, 93%) provided the number of patients in stage 1 and both stages, so many trials (n=17) failed to report one or more from both response numbers of stage 1 and both stages which are key information to determine the study continuation toward the second stage (\({r}_{1}\)) at the end of first stage and hypothesis testing of efficacy (\(r\)) at the end of second stage. in Central Nervous System Metastasis, the Biological Basis and Clinical Consideraiton (ed. 2019;37(15_suppl):1820618206. 2022. doi: 10.1371/journal.pone.0246448. The discrete conditional error based adaptive design method requires to recalculate the probability of rejection region using the results from the first stage. Thank you for submitting a comment on this article. Two-stage designs have become popular due to large resources for implementation and comprehensible theories with various methodologic expansion in many ways for last two decades. 2014;1(2):345. Exploration of modified progression-free survival as a novel surrogate endpoint for overall survival in immuno-oncology trials. Would you like email updates of new search results? Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma. Berry SM, et al. Murgo AJ, et al. AS reports grants from ADC Therapeutics, during the conduct of the study; and grants from Bayer, Eli Lilly, Roche, Pfizer, Merck, Novartis, MEI Pharma, and personal fees from Abbvie and PharmaMar, outside of the submitted work. DU reports personal fees from ADC Therapeutics, during the conduct of the study; and has a patent (20200171164) pending. Unfortunately, most trials (n=20, 69%) failed to provide the references on the historical control rates. 2021;13(3):28694. Before Admissible two-stage designs for phase II cancer clinical trials. MeSH -, Wang, N., Bertalan, M. S. & Brastianos, P. K. Leptomeningeal metastasis from systemic cancer: review and update on management. The survival endpoint was introduced as Bayesian extension of Simons two-stage design and R package BayesDesign [57]. Hu J, et al. The study met the primary endpoint, as 12 of 20 (OS3, 0.60; 90% confidence interval, 0.39-0.78) patients were alive at 3 months after enrollment. Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review. Glioblastoma clinical trials: current landscape and opportunities for improvement. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2022 Oct 19;24(6):428. doi: 10.3892/ol.2022.13548. 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. Childs Nerv Syst. Third, when expected sample sizes from both designs are close each other, the minimax design may be more appropriate than the optimal design because the minimax design produces the smaller total patients [6]. Anand S, et al. Warren KE, et al. Epub 2017 May 24. Ramchandren R, Johnson P, Ghosh N, Ruan J, Ardeshna KM, Johnson R, Verhoef G, Cunningham D, de Vos S, Kassam S, Fayad L, Radford J, Bailly S, Offner F, Morgan D, Munoz J, Ping J, Szafer-Glusman E, Eckert K, Neuenburg JK, Goy A. EClinicalMedicine. Alternatively, novel surrogates can be used instead of RR and PFS6. Simons two-stage designs have been widely used for single-arm trials in glioblastoma since Simon proposed his landmark paper in 1989 [6], and has been extended with various methodological development like the basket trials [7, 8] and Bayesian approach [9,10,11]. Epub 2020 Jun 5. Naxitamab and Granulocyte-Macrophage Colony Stimulating Factor in Combination With Irinotecan and Temozolomide in Patients With High-Risk Neuroblastoma With Primary Refractory Disease or in First Relapse. We also sought to understand how these two-stage trials have been implemented and discussed potential design issues which we hope will be helpful for investigators who work with Phase 2 clinical trials in rare and high-risk cancer studies including Neuro-Oncology. PMC Recent research reported that the success rate in proceeding from Phase 2 to Phase 3 was the lowest among all three rates of Phase 1 to 2, Phase 2 to 3, and Phase 3 to approval (e.g., 29.7%, 20.3%, and 35.5% for oncology and 35.2%, 27.4%, 59% for overall) [2]. Webmultiple myeloma: a multicenter, single-arm phase 2 trial Thilo Zander 1, Thomas Pabst 2, Smi Schr 3, Stefan Aebi 1,2, Ulrich Mey 4, Urban Novak2, Erika Lerch 5, Galle Rhyner Agocs 6, J Neurooncol. Therapeutic Antibodies in Cancer Treatment in the UK. Valemetostat 200 mg orally once daily demonstrated promising efficacy and manageable toxicity in heavily pretreated patients. In this phase 2 study, we demonstrated that treatment with single-agent PD-1 inhibitor was safe and associated with a 3-month OS of 60% in a heavily pre-treated The following data were extracted from the reviewed studies in Phase 2 single-arm two-stage trials in glioblastoma: (1) general study information like first author name, published year, disease type (glioblastoma or high-grade glioma), setting (recurrent or newly-diagnosed), population (adults or pediatric), drug therapeutic type (single or combination), primary endpoint (progression-free survival at six months (PFS6) or objective response rate (ORR) and others), (2) key information for two-stage design implementation like design type (Simons two-stage design or other two-stage design), type I and II error rates (\(\alpha , \beta\)), and unacceptable and acceptable response rates (\({p}_{0}, {p}_{1}\)), (3) results from sample size calculation data like the number of patients for stage 1 and both stages (\({n}_{1}, n\)), the treatment rejection numbers for the first stage and both stages (\({r}_{1}, r\)), and whether studies provided source of historical control rate data. Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. 2022 Dec;17(6):524-532. doi: 10.1159/000526431. Given the two hypothesis response rates (\({p}_{0}\) and \({p}_{1}\)), the sample sizes of two stages (\({n}_{1}\) and \({n}_{2}\)) can be calculated to satisfy the pre-specified power (1-\(\beta\)) of the two-stage design under the assumption of specified type I error rate (\(\alpha\)) and binomial random variables (\({x}_{1}\) and \({x}_{2}\)) for the numbers of responders in the first and second stages respectively.
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