single arm phase 2 trial

1990;9(3):21528. Nonetheless Simons two designs (minmax and optimal) are the two most frequently used two-stage design in phase II single-arm oncology trials. J. Clin. As output results, the two-stage designs (Optimal, Minimax, and Admissible designs) produce following key outputs of the number of patients (\({n}_{1}\) and \({n}_{2}\)) for stage 1 and both stages and the rejection numbers (r and \({r}_{1}\)) for both stage 1 and both stages respectively. Page MJ, et al. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. For general information, Learn About Clinical Studies. 2003;95(19):1434-1439. Epub 2019 Feb 11. Admissible two-stage designs for phase II cancer clinical trials. Oncol. 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). This site needs JavaScript to work properly. Trials involving several arms, or randomized trials, treat randomly-selected groups of patients with different therapies in order to compare their medical outcomes. A common practice in sample size calculation is The Phase 2 trials often apply single-arm study designs to identify the efficacious treatment by using historical control data for comparative evaluation with study treatment data. Eltarhoni K, Kamel F, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci. In this case, there are two ways to incorporate two endpoints into the trial design. Lassen U, et al. Warren KE, et al. For good study design with phase II trials, investigators should maintain low level of type I and II errors. 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. government site. In safety studies, a main concern is that there may be too many patients who experience an adverse event. Epub 2017 Aug 16. Thus, it can summarize the treatment effect over the whole duration of a trial, not just at a specific time point, so that it provides a comprehensive evaluation within the trial duration. Careers. Contemp Clin Trials. sharing sensitive information, make sure youre on a federal [56] proposed modified PFS (mPFS) for immune-oncology trials. 2011;2(1):1322. Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. Stat Biopharma Res. 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. Rai SN, Ray H, Pan J, Barnes C, Cambon AC, Wu X, Bonassi S, Srivastava DK. J Clin Oncol. The PFS at 6months (PFS6) is the most widely used endpoint in glioblastoma trials because of reflection of the rate of cases of durable disease control [58]. [37] used Simons two-stage optimal design to evaluate the target PFS6 of 35% against the null PFS6 of 20% to achieve 90% power at a 1-sided 10% level, resulting in the required sample size of 58 patients. Pellegatta S, et al. Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review, https://doi.org/10.1186/s12874-022-01810-7, Two-stage design of phase 2 single-arm trials in glioblastoma, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, bmcmedicalresearchmethodology@biomedcentral.com. Let us now assume that 4 (36.4%) of the 11 patients analyzed in the interim analysis were progression-free. Biostatistics. 2023 Jan;37(1):45-67. doi: 10.1007/s40263-022-00975-5. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). We also sought to understand how these two-stage trials have been implemented, and discussion of potential design issues which we hope will be helpful for investigators work with Phase 2 clinical trials in rare and high-risk cancer studies including Neuro-Oncology. An International, Single-Arm, Multicenter Phase 2 Trial. 2013;111(3):34753. Federal government websites often end in .gov or .mil. Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. TEAEs that occurred in 20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Clin Cancer Res. Oncotarget. Bethesda, MD 20894, Web Policies Keywords: 2022;28(4):594602. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 20132017. 8600 Rockville Pike Furthermore, a couple of trials did not provide explanation and description about the results of sample size calculation (no shown here). Trippa L, et al. Int Stat Rev/Revue Int de Stat. in Central Nervous System Metastasis, the Biological Basis and Clinical Consideraiton (ed. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. Epub 2013 Apr 16. 11, 561569 (1993). Would you like email updates of new search results? Biometrics. The primary endpoint was safety. Spatial two-stage designs for phase ii clinical trials. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The therapeutic areas in oncology and immune-modulatory drugs were the most expensive, with a median of $2.8 billion and a mean of $4.5 billion [3]. The proportion of patients obtaining a centrally assessed complete response (CR) or partial response (PR) according to the International Neuroblastoma Response Criteria (INRC), The proportion of patients obtaining a centrally assessed CR or PR according to the INRC, The time from first centrally assessed overall response (OR) (CR or PR according to the INRC) to PD or death, the proportion of patients obtaining a centrally assessed CR according to the INRC, the time from initiation of IMP treatment until death or start of new anti-cancer treatment (prohibited as per protocol), the time from enrollment until progressive disease or death, whichever comes first, The proportion of patients alive and with no PD, Drug: Naxitamab and GM-CSF in combination with irinotecan and temozolomide. Glioblastoma: emerging treatments and novel trial designs. Diffuse Large B-Cell Lymphoma (DLBCL): Early Patient Management and Emerging Treatment Options. The .gov means its official. MeSH 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. 2019;144(2):35968. To illustrate the effect of underestimated historical control on the study power, we carried out a simulation study as follows. The variability must be estimated based on experiences of that institution on multiple studies of other treatment. 2007;7(6):32534. Sci Rep. 2021;11(1):2306. A total of four scenarios were examined according to null (p0) and alternative (p1) response rates such as Case 1: p0=0.1 and p1=0.3, Case 2: p0=0.3 and p1=0.5, Case 3: p0=0.5 and p1=0.7, and Case 4: p0=0.7 and p1=0.9. 2019;144(2):4037. Invest New Drugs. Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. This site needs JavaScript to work properly. Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. 2022 May;169:107420. doi: 10.1016/j.csda.2021.107420. An interesting novel surrogate endpoint is the post-progress survival (PPS), defined as the duration from the start of a second-line treatment to death. Zhou H, et al. 2017;131(3):60310. 1982;38(1):14351. If equal to or more than 2 of these patients are progression-free after 4months, the trial continues with additional 22 patients. 2006;25(19):338295. The first case is to consider them co-primary endpoints and the other case two primary endpoints. Please enable it to take advantage of the complete set of features! Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. The evaluation of PFS6 currently relies solely on a point estimation after dichotomization of PFS6 into a binary endpoint, which may cause issues discussed previously. 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. 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. 2019 Jul 2;10(42):4255-4261. doi: 10.18632/oncotarget.26981. 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. To improve test power, we proposed a new weighted one-sample log-rank test and provided a sample size calculation formula for designing trials. 2022;169:107420. IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). 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). An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1-3. Epub 2022 Jan 6. Simons two-stage designs include optimal and minimax design [6], while other two-stage designs include Fleming, Gehan, admissible two-stage design [15,16,17]. Careers. 2012;4(4):799801. Choosing to participate in a study is an important personal decision. We conducted a single-arm, Careers. Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme. Epub 2022 Apr 1. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. Keywords: 2020 Aug;26(8):1309. doi: 10.1038/s41591-020-0978-1. Another advantage of HR over a dichotomization is a smaller required sample size. Zagouri F, Sergentanis TN, Bartsch R, Berghoff AS, Chrysikos D, de Azambuja E, Dimopoulos MA, Preusser M. Breast Cancer Res Treat. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. Federal government websites often end in .gov or .mil. Control Clin Trials. Dhakal A, Van Swearingen AED, O'Regan R, Anders CK. 2018;74(2):529-537. Talk with your doctor and family members or friends about deciding to join a study. Breslow NE. Bethesda, MD 20894, Web Policies Ananda S, et al. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Accessibility WebARTICLE Clinical Trials 2011; 8: 260269 Quantitative evaluation of single-arm versus randomized phase II cancer clinical trials Gregory R Ponda,b and Saqib Abbasia Background There is a debate among cancer researchers about the use of single-arm or randomized phase II clinical trial designs; however, there is limited published Epub 2018 Jul 29. Among 29 trials reviewed systematically, 12 trails (41%) appropriately provided key input parameters and sample size results from two-stage design implementation. 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. Reference curve sampling variability in one-sample log-rank tests. Most trials (90%) used Simons two-stage designs. Clipboard, Search History, and several other advanced features are temporarily unavailable. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 2022 Nov;82(16):1621-1627. doi: 10.1007/s40265-022-01800-5. A treatment cycle is 21 days. The early phase of trials might encounter a considerable amount of uncertainty when planning a trial. Using J Neurooncol. J Cancer. J Clin Oncol. official website and that any information you provide is encrypted Eur J Cancer. 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. Please enable it to take advantage of the complete set of features! Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial Summary Pharm Stat. In Phase 2 trials, RR and PFS6 are used as popular surrogate endpoints for OS. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. 2020;22(12 Suppl 2):iv196. 2022 Dec 26;56:101779. doi: 10.1016/j.eclinm.2022.101779. Tawbi HA, et al. Fangusaro J, et al. Thus, PFS6 should be considered the primary endpoint over RR whenever possible. The unacceptable historical control rate should be a maximum rate while the acceptable expected treatment rate should be a minimum rate in order not to be overly optimistic for the Phase 2 clinical trials. 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]. Kieser M, Rauch G. Two-stage designs for cross-over bioequivalence trials. Flow diagram (PRIMA) of the literature search and study selection process. doi: https://doi.org/10.1182/blood.2022016862. Pharm Stat. IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). PMC Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: a phase II study. Please check for further notifications by email. PMC 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. J Neurooncol. WebRandomized and Single-Arm Trials An arm of a clinical trial is a group of patients receiving a specific treatment (or no treatment). 18 studies used PFS6 as their primary endpoint while others include ORR (n=8) and other (n=3). We identified a total of 81 articles based on online search using Two-stage Phase II trials in glioblastoma. 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. If the parameters of two-stage designs (\({p}_{0}, {p}_{1}\)) are given, there are infinitely many two-stage designs satisfying the (\({\alpha }^{*}, {\beta }^{*})\) condition. 7]); 35 had complete response and 35 had partial response. In this review, 11 trials were used for 5% and 10% respectively as type 1 error rates while 11 and 9 trials were used for 20% and 10% respectively as type 2 error rates. 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. How low levels for both errors are low enough to be a good design? View this study on Beta.ClinicalTrials.gov, Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Bookshelf Google Scholar. Optimal two-stage design of single arm Phase II clinical trials based on median event time test. Perspect Clin Res. Palmieri, D.) 187201 (Springer, 2013). Nat Med. Clipboard, Search History, and several other advanced features are temporarily unavailable. MeSH Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma. Paclitaxel added to the cisplatin/etoposide regimen in extensive-stage small cell lung cancer -- the use of complete response rate as the primary endpoint in phase II trials. 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. Suh CH, et al. The sample size calculation for the two-stage designs is determined based on the historical control rate and difference between the two rates (\({p}_{0}, {p}_{1}\)). Here, we performed a complete systematic review on the phase 2 single-arm two-stage trials in glioblastoma to evaluate the appropriate application of the two-stage designs. Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. Pharm Stat. 2022 May;78(5):707-719. doi: 10.1007/s00228-021-03253-3. Zhiming Li, Haiyan Yang, Hong Cen, Rui Huang, Zhen Cai, Xuekui Gu, Hanying Bao, Zusheng Xu, Zuhong Xu; Single-Arm Phase 1b/2 Trial of the PI3K Front Oncol. Results. The synonyms and closely related words include phase 2 for phase II trials, GBM or high-grade glioma for glioblastoma, and 2-stage, Simon, Fleming or Gehan for two-stage design. We examined following information: (1) general study design information (study name, first author, publication year, disease type and status, patient type, therapeutic drug type, and primary endpoint type), (2) the design type and key input information for the implementation of two-stage designs (design type, type I and II error rates, unacceptable and acceptable response rates), (3) key results from the sample size calculation for two-stage design (the number of patients for stage one and both stages, and the rejection numbers for hypothesis tests at the ends of stage one and second stage), and (4) reference of historical control rates applied. Adaptive two-stage designs in phase II clinical trials. https://doi.org/10.1186/s12874-022-01810-7, DOI: https://doi.org/10.1186/s12874-022-01810-7. Accessibility Brastianos PK, Strickland MR, Lee EQ, Wang N, Cohen JV, Chukwueke U, Forst DA, Eichler A, Overmoyer B, Lin NU, Chen WY, Bardia A, Juric D, Dagogo-Jack I, White MD, Dietrich J, Nayyar N, Kim AE, Alvarez-Breckenridge C, Mahar M, Mora JL, Nahed BV, Jones PS, Shih HA, Gerstner ER, Giobbie-Hurder A, Carter SL, Oh K, Cahill DP, Sullivan RJ.
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