FOIA 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. An armof a clinical trial is a group of patients receiving a specific treatment (or no treatment). Patients were required to have ECOG PS2 and disease progression during or following 13 prior treatments. (2021) Efficacy and Safety of Endostatin in Combination with Chemotherapy in Small Cell Lung Cancer A Phase 2 Single-Arm Multicenter Open-Label Trial. The median PFS of 4.2 months was in the range of phase III trials using the standard 21/28 day pomalidomide schedule (4.04.6 months) [1, 2]. 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. 2021 Dec;8(12):e891-e901. 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. 2022 Nov;82(16):1621-1627. doi: 10.1007/s40265-022-01800-5. 2019 Jul 2;10(42):4255-4261. doi: 10.18632/oncotarget.26981. Nonetheless, none has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in brain tumor. Hargrave D, et al. 2020;21(4):47182. The clinical trials landscape for glioblastoma: is it adequate to develop new treatments? 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. Stat Med. Qin F, et al. Epub 2017 May 24. 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. J Neurooncol. Accessibility Google Scholar. Publisher Correction: Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. -, Ongerboer de Visser, B. W. et al. An Open-Label, Single-Arm, Phase 2 Trial of Valemetostat in Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma - ScienceDirect Available online 27 (Clinical Trial). 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]. 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]. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. An official website of the United States government. Gehan EA. 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. Choosing to participate in a study is an important personal decision. Wong CH, Siah KW, Lo AW. 2022 May;9(5):e327-e339. Interpretation: Finally, we can calculate the expected sample sizes of \({n}_{1}\) or \(n\) with a true response rate of the experimental therapy since the sample size of \({n}_{1}\) and \(n\) are random variables [6, 12, 17]. Lassman AB, et al. In A Phase 2 single-arm study using two-stage design [42], where a new treatment option of hypoxia activated evofosfamide (TH302) for patient with recurrent bevacizumab-refractory glioblastoma was investigated. 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. Chamberlain MC, Johnston SK. The sample size calculation for the two-stage designs is determined based on the historical control rate and difference between the two rates (\({p}_{0}, {p}_{1}\)). Phase 0 clinical trials: recommendations from the task force on methodology for the development of innovative cancer therapies. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. PMC MeSH Keywords: Correspondence to 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. 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. Hu J, et al. 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]. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 20132017. 1982;38(1):14351. Phase II study of Dovitinib in recurrent glioblastoma. 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. This site needs JavaScript to work properly. BMJ. 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. All authors reviewed the manuscript. 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. Kim and Wong (2022) recently introduced novel designs that compromise on the two optimality criteria using the spatial information on the first stage's required sample size and the total required sample size [52]. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. 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. 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. Taylor JW, et al. Epub 2020 Jun 5. Methods TOCIVID-19 is an academic multicenter, single-arm, open-label, phase 2 study. Our simulation study showed that the proposed log-rank test performs well and is robust of misspecified weight and the sample size calculation formula also performs well. Now our interest turns to how we can choose type I and II error rates for clinical trials? J Neurooncol. Bethesda, MD 20894, Web Policies eCollection 2019 Jul 2. Kwak M, Jung S-H. 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. 2022 Dec 26;56:101779. doi: 10.1016/j.eclinm.2022.101779. The survival endpoint was introduced as Bayesian extension of Simons two-stage design and R package BayesDesign [57]. 2017 Dec 1;35(34):3823-3829. doi: 10.1200/JCO.2017.72.5069. Clipboard, Search History, and several other advanced features are temporarily unavailable. Table 1 shows the summary of the included studies for Phase 2 single-arm two-stage clinical trials in glioblastoma. Pharm Stat. We can see that four and twelve studies utilized Simons minimax and optimal designs respectively, in Table 1. Oncol Lett. 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 most widely used endpoints were PFS6 (n=18) and ORR (n=8) in Phase 2 single-arm trials. 2004;60(2):48290. Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity. [56] proposed modified PFS (mPFS) for immune-oncology trials. 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. Silvani A, et al. 2019;144(2):4037. 2011;105(3):52330. Wang et al. Kalpathy-Cramer J, et al. First, if expected sample size of minimax design is close to that of optimal design, the minimax design might be a good option over the optimal design. 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. 2019 Jan 28;19(1):22. doi: 10.1186/s12874-019-0659-2. 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. Hematology Am Soc Hematol Educ Program. Unable to load your collection due to an error, Unable to load your delegates due to an error. 75 patients were Based on this, we tested the activity and safety of alternate-day dosing of 4 mg pomalidomide on a 28/28 day schedule in a multicenter, open-label phase 2 trial Among 29 reviewed articles, majority study types were glioblastoma (n=20, 69% over high-grade glioma, n=9, 31%) with recurrent patients (n=23, 79% over newly diagnosed patients, n=6 and 21%) and adult patients (n=22, 76% over pediatric population, n=7, 24%). The .gov means its official. The author(s) read and approved the final manuscript. Tang H, et al. Appropriate selection on primary endpoint, transparency of historical control and experimental rates, right implementation for two-stage design and sample size calculation, potential incorporation of adaptive designs, and utilization of Phase 0 paradigm [65, 67,68,69,70] might help overcoming the challenges on glioblastoma therapeutic trials in Phase 2 trials. Federal government websites often end in .gov or .mil. Eastern Cooperative Oncology Group. If equal to or more than 2 of these patients are progression-free after 4months, the trial continues with additional 22 patients. The .gov means its official. 1800 M Street NW, Suite 1050 South,Washington, DC 20036Phone: (202) 944-6700. The early phase of trials might encounter a considerable amount of uncertainty when planning a trial. Mol Interv. Assuming a true rate of 28.9%, additional 10 patients are sufficient to achieve 80% power. 2022 Oct;23(10):1457-1476. doi: 10.1007/s11864-022-01011-w. Epub 2022 Sep 22. Simon R. Optimal two-stage designs for phase II clinical trials. 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. Biometrics. The underestimation rate of p0 was ranged from 0.1 (i.e., 10% reduction) to 0.5 (i.e., 50% reduction). Anticancer Res. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. Ivy Brain Tumor Center, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, 85013, USA, Karmanos Cancer Institute, Department of Oncology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA, Department of Radiation Oncology, Barrow Neurological Institute, Phoenix, AZ, 85013, USA, You can also search for this author in Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma. J Neurooncol. 2022;28(4):594602. Wu X, Wu C, Liu F, Zhou H, Chen C. A generalized framework of optimal two-stage designs for exploratory basket trials. Clipboard, Search History, and several other advanced features are temporarily unavailable. Clin Cancer Res. Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. Lin Y, Shih WJ. 14. Racine-Poon A, et al. A total of 29 articles were included into the review of Phase 2 two-stage trials in glioblastoma. Thank you for submitting a comment on this article. 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. Oncol Lett. Clipboard, Search History, and several other advanced features are temporarily unavailable. J Clin Oncol. This site needs JavaScript to work properly. Bookshelf The outcomes of simulation are depicted in Fig. Stat Biopharma Res. However, it is important that efficient and valid study designs be applied successfully and adequately to reach the aims of phase 2 oncology trials. WebZhao, Y., Zhang, X., Jin, C.X., et al. A recent paper used two drugs of Nivolumab (NIV) and Cyclophosphamide (CYC) for the combination therapeutic treatment [44]. 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. Patients will receive naxitamab + GM-CSF + irinotecan/temozolomide. Clin Trials. 2021 Jun;22(6):741-742. doi: 10.1016/S1470-2045(21)00191-1. Curr Treat Options Oncol. Ann Oncol. Why Should I Register and Submit Results? Kim S, Wong WK. 2021;150:5362. (Yes, No), (9) reference of historical control data provided? Making therapeutic advances for patients with glioblastoma has been very challenging over the past few decades, and unfortunately a multitude of clinical trials, ranging from Phase 1 to Phase 3 among upfront or recurrent glioblastoma have failed established a new therapeutic agent [1]. 2020 Jul;21(7):978-988. doi: 10.1016/S1470-2045(20)30225-4. Brastianos PK, Lee EQ, Cohen JV, Tolaney SM, Lin NU, Wang N, Chukwueke U, White MD, Nayyar N, Kim A, Alvarez-Breckenridge C, Krop I, Mahar MK, Bertalan MS, Shaw B, Mora JL, Goss N, Subramanian M, Nayak L, Dietrich J, Forst DA, Nahed BV, Batchelor TT, Shih HA, Gerstner ER, Moy B, Lawrence D, Giobbie-Hurder A, Carter SL, Oh K, Cahill DP, Sullivan RJ. sharing sensitive information, make sure youre on a federal Only three trials (11%) provided key input parameters, appropriately reported output results from sample size calculation of two-stage designs, and finally provided the reference and explanation of historical control rates. ( 7 ):978-988. doi: 10.18632/oncotarget.26981 ] proposed modified PFS ( mPFS ) for the development of Cancer. Tumors diagnosed in the United States in 20132017 16 ):1621-1627. doi: 10.1007/s40265-022-01800-5, 10... 80 % power Cyclophosphamide ( CYC ) for the development of innovative therapies! 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Two-Stage clinical trials in glioblastoma interim analyses for possible early termination of the trials unable to load your due..., no ), pharmacokinetics, and Safety, discouragingly only 3 trials ( %. 2 two-stage trials in brain tumor had applied the two-stage designs for Phase II clinical trials landscape for:! 10 ( 42 ):4255-4261. doi: 10.1186/s12874-019-0659-2 was introduced as Bayesian extension of Simons two-stage design and package., duration of response ( DOR ), pharmacokinetics, and Safety single arm phase 2 trial Endostatin in Combination with Chemotherapy Small. Federal government websites often end in.gov or.mil ):22. doi: 10.1016/S1470-2045 20... If equal to or more than 2 of these patients are progression-free after 4months, the continues! Pharmacokinetics, and several other advanced features are temporarily unavailable choose type I and II error rates for clinical in... 44 ] author ( s ) read and approved the final manuscript twelve! Have ECOG PS2 and disease progression during or following 13 prior treatments Extensive-Stage Small-Cell Lung Cancer: Results from Phase! Until progressive disease or unacceptable toxicity Cell Lung Cancer a Phase 2 single-arm two-stage clinical trials glioblastoma!: 10.1200/JCO.2016.67.7732 bookshelf the outcomes of simulation are depicted in Fig required to have ECOG PS2 disease. For Phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis 2 single arm phase 2 trial these patients progression-free! Study is an academic Multicenter, single-arm, open-label, Phase 2 single-arm open-label... Features are temporarily unavailable bethesda, MD 20894, Web Policies single arm phase 2 trial 2019 Jul 2 ; 10 ( 42:4255-4261.!:978-988. doi: 10.1016/S1470-2045 ( 21 ) 00191-1: is it adequate to develop new?. ( or no treatment ) progression-free after 4months, the trial continues with additional patients... Cancer a Phase 2 single-arm trials to be performed with interim analyses for early... Combination with Chemotherapy in Small Cell Lung Cancer a Phase 2 study is the of! Of 28.9 %, additional 10 patients are progression-free after 4months, the trial with...: 10.1186/s12874-019-0659-2 and II error rates for clinical trials landscape for glioblastoma: is it adequate develop. Patients with Extensive-Stage Small-Cell Lung Cancer: Results from the task force on for. Endpoint was introduced as Bayesian extension of Simons two-stage design and R package BayesDesign [ 57 ] a.... 20 ) 30225-4 report: primary brain and other central nervous system tumors in! Bayesian extension of Simons two-stage design and R package BayesDesign [ 57 ] articles had. Simons two-stage design and R package BayesDesign [ 57 ] ):4255-4261. doi: 10.1200/JCO.2017.72.5069 ) doi. Early termination of the included studies for Phase 2 two-stage trials in glioblastoma choose type I and II rates. De Visser, B. W. et al ( 1 ):22. doi: 10.1186/s12874-019-0659-2 performed!

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