Ann Oncol. Optimal two-stage design of single arm Phase II clinical trials based on median event time test. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab. 2019;10(14):321423. Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 1R01CA244975-01/U.S. Epub 2022 Apr 1. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Single-arm or non-randomized trials,in which everyone enrolled in a trial receives the experimental therapy, are common in Phase 1 and 2 testing. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. J. Clin. An official website of the United States government. Furthermore, a couple of trials did not provide explanation and description about the results of sample size calculation (no shown here). Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy. Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis. J Neurooncol. Neuro Oncol. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). Thus, the key input parameters (\(\alpha , \beta , {p}_{0}, {p}_{1}\)) and output results (\({n}_{1}, n, {r}_{1}, r\)) were investigated to assess the appropriate usage and report of the two-stage phase 2 trials. 2012;106(3):6439. 2021;11:660892. Kaley TJ, et al. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Expert Rev Anticancer Ther. BMC Med Res Methodol 22, 327 (2022). Flow diagram (PRIMA) of the literature search and study selection process. 2015;17(7):9928. Most trials (90%) used Simons two-stage designs. 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. WebRandomized and Single-Arm Trials An arm of a clinical trial is a group of patients receiving a specific treatment (or no treatment). Federal government websites often end in .gov or .mil. 2004;23(4):5619. We show that Simon's two-stage designs for efficacy studies can be similarly used to design a two-stage safety study by modifying some of the design parameters. Copyright 2021 Elsevier Ltd. All rights reserved. Clipboard, Search History, and several other advanced features are temporarily unavailable. sharing sensitive information, make sure youre on a federal Dhakal A, Van Swearingen AED, O'Regan R, Anders CK. 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. statement and Onco Targets Ther. 2013;113(1):12734. In the final analysis, the null hypothesis is rejected if more than 6 of the total number of 33 patients are progression-free after 4months. We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 The underestimation rate of p0 was ranged from 0.1 (i.e., 10% reduction) to 0.5 (i.e., 50% reduction). 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. J Neurooncol. Among 23 Simons two-stage designs, 12 trials used Simons optimal designs, 4 trials used Simons minimax designs, and 7 trials just mentions Simons two-stage designs without specific design types of the two, Optimal and Minimax. While Phase 3 trials are frequently randomized in order to provide more precise data on safety and effectiveness outcomes, a Phase 3 trial might use a single arm if a small target population makes conducting a randomized trial impractical. Chamberlain MC, Johnston SK. 1R01CA227156-01/U.S. Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study. Fleming TR. Cookies policy. Epub 2020 Sep 1. 2011;18(11):14448. If equal to or more than 2 of these patients are progression-free after 4months, the trial continues with additional 22 patients. 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. We restricted the phase II clinical trials in glioblastoma to those published in 2011 or later. The site is secure. For good study design with phase II trials, investigators should maintain low level of type I and II errors. eCollection 2022 Dec. Transl Cancer Res. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. 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. 2011;105(3):52330. Funding: Modified Simon's minimax and optimal two-stage designs for single-arm phase II cancer clinical trials. Wu X, Wu C, Liu F, Zhou H, Chen C. A generalized framework of optimal two-stage designs for exploratory basket trials. 2021 Feb 8;16(2):e0246448. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. Oncoimmunol. Nonetheless Simons two designs (minmax and optimal) are the two most frequently used two-stage design in phase II single-arm oncology trials. Spatial two-stage designs for phase ii clinical trials. 2019 Jan 28;19(1):22. doi: 10.1186/s12874-019-0659-2. 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]. Disclaimer, National Library of Medicine PMC In this systematic review, only 9 Phase 2 two-stage trials provided the information of where their historical control rate came from and how they selected the rate among various control rates in literatures. Treatment-emergent adverse events (TEAEs) were manageable. sharing sensitive information, make sure youre on a federal Phase 0 clinical trials in oncology new drug development. We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 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 (\({r}_{1}, r\)). HHS Vulnerability Disclosure, Help WebMethods: 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 WebPhase II Two-Stage Single-Arm Clinical Trials for Testing Toxicity Levels Simon's two-stage designs are frequently used in phase II single-arm trials for efficacy studies. Study record managers: refer to the Data Element Definitions if submitting registration or results information. 2022 Nov;82(16):1621-1627. doi: 10.1007/s40265-022-01800-5. Keywords: 8600 Rockville Pike Interpretation: PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. 2013;10(5):72034. In the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. Designing phase 0 cancer clinical trials. Temozolomide (TMZ) was mostly used for combination therapeutic drugs (n=7 with pegylated liposomal doxorubicin (PLD), O6-benzylguanine (O6B), irinotecan (IRI), decitabine (DAC), Dendritic (DEN), Nintedanib (NIN), and Atorvastatin (ATO)) while Bevacizumab (BEV) was second mostly used for combination drugs (n=3 with temsirolimus (TEM), Ponatinib (PON), and Evofosfamide (EVO)). The https:// ensures that you are connecting to the Furthermore, all trials except one trial did not explain how they chose the acceptable response rate. Wonsuk Yoo. Please remove one or more studies before adding more. 2021;13(15):3750. Cancers (Basel). Treatment-emergent adverse events (TEAEs) were manageable. The author(s) read and approved the final manuscript. 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 Novak 2 , Erika Lerch 5 , Galle Rhyner Agocs 6 , 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]. Neurology 33, 15651572 (1983). To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. 2012;11(3):2419. Phase II study of Dovitinib in recurrent glioblastoma. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. In this manner, the two-stage designs allow stopping of a futile trial early. Thus, PFS6 should be considered the primary endpoint over RR whenever possible. Odronextamab, a human CD20CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. 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. Oncotarget. 2014;1(2):345. [56] proposed modified PFS (mPFS) for immune-oncology trials. You have reached the maximum number of saved studies (100). 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. 2021 May 6;134(11):1299-1309. doi: 10.1097/CM9.0000000000001463. There was no language restriction, but only complete papers published in peer-reviewed journals were considered. Comput Stat Data Anal. We evaluated the efficacy and safety of valemetostat, a potent EZH1 and EZH2 inhibitor, in treating relapsed/refractory (R/R) ATL. Table 1 shows the summary of the included studies for Phase 2 single-arm two-stage clinical trials in glioblastoma. doi: 10.1016/S2352-3026(21)00311-2. In Phase 2 trials, RR and PFS6 are used as popular surrogate endpoints for OS. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. Some clinical trial designs, such as the lung cancer master protocol design, allow for several experimental drugs to be tested simultaneously. The https:// ensures that you are connecting to the FOIA PLoS One. Epub 2022 Jan 21. 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 (\({p}_{0}, {p}_{1}\)). All other rights reserved. Multistage designs for phase II clinical trials: statistical issues in cancer research. For the trial, 70 children aged 618 years old with peanut allergies received 12-hour boiled peanuts for 12 weeks, 2-hour boiled peanuts for 20 weeks, and roasted peanuts for 20 weeks, to a target maintenance dose of 12 roasted peanuts daily. 2015;17(8):110613. Curr Treat Options Oncol. A total of 29 articles were included into the review of Phase 2 two-stage trials in glioblastoma. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. 2019;37(15_suppl):1820618206. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 5R21CA220253-02/U.S. The sample size calculation for the two-stage designs is determined based on the historical control rate and difference between the two rates (\({p}_{0}, {p}_{1}\)). 2020;323(9):84453. 2019;8(13):598894. 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). Simon R, et al. 2018;7(4):e1412901. Pharm Stat. This site needs JavaScript to work properly. Please enable it to take advantage of the complete set of features! Article The Follow-Up period ends 2 years after End of Treatment. The site is secure. 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. Clin Cancer Res. More than half studies used single therapeutic drug (n=17, 59%) rather than combined therapeutic treatment (n=12, 41%). Phase 0 clinical trials: recommendations from the task force on methodology for the development of innovative cancer therapies. Particularly, a recent research of the phase 2 basket trials has extended the two-stage design for multiple heterogeneous indications, which is an important tool to identify the effective drug through a generalized framework of an optimal basket design. 2006;25(19):338295. Epub 2017 May 24. Phase 2 study of Pomalidomide (CC-4047) monotherapy for children and young adults with recurrent or progressive primary brain tumors. 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 (\({r}_{1}\)). Are low success rates and high medium expense of Phase 2 oncology trials associated with inappropriate implementation of two-stage design Phase 2 single-arm trials? Patients will receive naxitamab + GM-CSF + irinotecan/temozolomide. 2019;142(3):45562. Alternatively, novel surrogates can be used instead of RR and PFS6. 1975;43(1):45-57. Results of design input parameters and sample size calculation output from reviews of Phase 2 single-arm two-stage designs in glioblastoma. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. Bethesda, MD 20894, Web Policies A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. TEAEs that occurred in 20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. 2017;131(3):60310. Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). To illustrate the effect of underestimated historical control on the study power, we carried out a simulation study as follows. Zagouri F, Sergentanis TN, Bartsch R, Berghoff AS, Chrysikos D, de Azambuja E, Dimopoulos MA, Preusser M. Breast Cancer Res Treat. CAS government site. Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon's design. sharing sensitive information, make sure youre on a federal 2022 Feb 20;41(4):786-797. doi: 10.1002/sim.9258. Eur J Cancer. government site. After excluding 42 articles due to randomized trials (n=7), single-stage designs (n=5), abstracts (n=3), and inadequate information (n=27), we had 29 studies included in review. 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. Bethesda, MD 20894, Web Policies Before Clin Cancer Res. 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. 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 Disclaimer, National Library of Medicine Mol Interv. An Open-Label, Single-Arm, Phase 2 Trial of Valemetostat in Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma - ScienceDirect Available online 27 2022 Dec;17(6):524-532. doi: 10.1159/000526431. 1. 2020;20(1):126. Expert Rev Anticancer Ther. J Neurooncol. Using the cumulative binomial probability distribution, we could find the probability that the number of progression-free patients are three or more in the second stage was 0.4357. 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 Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma. Br J Cancer. 2012;48(2):25362. Phase II and biomarker study of programmed cell death protein 1 inhibitor nivolumab and metronomic cyclophosphamide in paediatric relapsed/refractory solid tumours: Arm G of AcSe-ESMART, a trial of the European innovative therapies for children with cancer consortium. Table 1 is the summary of the included studies [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. Valemetostat 200 mg orally once daily demonstrated promising efficacy and manageable toxicity in heavily pretreated patients. Springer Nature. 2022 Dec 26;56:101779. doi: 10.1016/j.eclinm.2022.101779. 2022. This study has the time limitation focusing on the last decade (20112021) because the two-stage designs in glioblastoma had increased dramatically since 2011. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. Declaration of interests PFC reports grants from ADC Therapeutics, during the conduct of the study; and grants and personal fees from Genentech, personal fees from ADC Therapeutics, Kite Pharmaceuticals, Verastem, Seattle Genetics, Amgen, TG Therapeutics, and Celgene, outside of the submitted work. Together they form a unique fingerprint. Neuro Oncol. 2022 Oct;23(10):1457-1476. doi: 10.1007/s11864-022-01011-w. Epub 2022 Sep 22. Evaluating efficacy and safety of loncastuximab tesirine injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma. The two types of errors (\(\alpha , \beta\)) and unacceptable and acceptable response rates (\({p}_{0}, {p}_{1}\)) are key input information for successful sample size calculation of two-stage design. 8600 Rockville Pike Now our interest turns to how we can choose type I and II error rates for clinical trials? The discrete conditional error based adaptive design method requires to recalculate the probability of rejection region using the results from the first stage. Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, Piperdi B, Mehnert JM. 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. Schmidt R, Kwiecien R, Faldum A, Berthold F, Hero B, Ligges S. Sample size calculation for the one-sample log-rank test. Publisher Correction: Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. Oncol. Annals of Palliative Medicine, 10, 3277-3285. 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'. Epub 2020 Jun 5. J Clin Oncol. 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. There has been the need for new two-stage designs that allow flexible modification of design parameters under the control of the Type 1 error, which is called adaptive design methods to perform arbitrary design modification under the control of the Type 1 error rate. Stat Med. 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. 2021 Jan;20(1):117-128. doi: 10.1002/pst.2060. Eltarhoni K, Kamel F, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). 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. J Immunother Cancer. Wang Z-X, et al. 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]. WebThe trial ended after accrual completion; the database lock was Dec 31, 2019. doi: 10.1371/journal.pone.0271094. 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? Example of Adaptive Design to handle the uncertainty for Phase 2 two-stage design. 75 patients were One decade ago, a new adaptive design method was proposed to allow an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the Type 1 error rate [63]. Salvage therapy with single agent bendamustine for recurrent glioblastoma. In safety studies, a main concern is that there may be too many patients who experience an adverse event. Brenner AJ, et al. (2004) developed an admissible two-stage design that compromises Simons optimal and minimax designs. BMC Medical Research Methodology We extracted disease type and setting, population, therapeutic drug, primary endpoint, input parameters and sample size results from two-stage designs, and historical control reference, and study termination status. Oncol Lett. KH, JF, SH, and YQ report personal fees from ADC Therapeutics, during the conduct of the study. We would like to thank the editors and anonymous reviewers for all valuable comments and suggestions, which helped us to improve the quality of the manuscript. 18 studies used PFS6 as their primary endpoint while others include ORR (n=8) and other (n=3). When the sample size is limited, one can use the Bayesian optimal design for phase II clinical trials, in which the power will be maximized given the fixed sample size and choice of type I error rate [51]. PubMedGoogle Scholar. Stat Med. Careers. By doing so, the chance to capture the effectiveness of a treatment can be increased. The outcomes of simulation are depicted in Fig. Adaptive two-stage designs for single-arm phase IIA cancer clinical trials. Thus, the maximum unacceptable response rates for historical controls should be considered throughout literature examination and/or previous research experience to screen out the inefficacious treatments [47, 48]. Overly optimistic results obtained from Phase 2 trials might be a major reason of negative Phase 3 results in randomized studies. 11, 561569 (1993). WebA phase II single-arm trial of memantine for prevention of cognitive decline during chemotherapy in patients with early breast cancer: Feasibility, tolerability, acceptability, and preliminary effects. Unable to load your collection due to an error, Unable to load your delegates due to an error. Disclaimer, National Library of Medicine 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.
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