Zhou H, Lee JJ, Yuan Y. BOP2: Bayesian optimal design for phase II clinical trials with simple and complex endpoints. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. 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. Comput Stat Data Anal. Please enable it to take advantage of the complete set of features! In this study, we systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 5R21CA220253-02/U.S. 2020 Mar 15;39(6):698-708. doi: 10.1002/sim.8440. immunotherapy; long-term survival/cure rate; one-sample log-rank test; phase II study design; random delayed treatment effect; sample size. Its interesting to see that most trials without mentioning specific design types (like Simons optimal or minimax, Gehan, Fleming, or admissible designs) failed to provide one or more than one key information for the implementation results of two-stage design sample size calculation. Funding: JAMA. Ann Oncol. 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. By doing so, the chance to capture the effectiveness of a treatment can be increased. Curr Treat Options Oncol. 2019;144(2):4037. Wu J, Pan H, Hsu CW. 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. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. 8600 Rockville Pike 2020 Nov 28;20:100678. doi: 10.1016/j.conctc.2020.100678. 1982;38(1):14351. 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 We study the relationship between a two-stage design with a safety endpoint and an efficacy endpoint and use simulation studies to ascertain their properties. WebThe trial ended after accrual completion; the database lock was Dec 31, 2019. MeSH Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, Tsukasaki K, Ito S, Yoshimitsu M, Otsuka M, Ogura M, Midorikawa S, Ruiz W, Ohtsu T. J Clin Oncol. This implies that most brain tumor clinical trials are at high risk with great uncertainty in trial outcomes. Warren KE, et al. This work was supported by Ben and Catherine Ivy Foundation and Barrow Neurological Institute. Correspondence to Santoni M, et al. 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. 2015;121(2):297302. Semin Oncol. Tawbi HA, et al. MeSH WebAn increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal 1-3. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). 75 patients were 2011;105(3):52330. 2013;111(2):20512. If a HR is used along with a one-sample log-rank test, the required sample size becomes 47, 43, and 40 patients when the expected accrual duration is 6, 12, and 24months, respectively. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2022 Oct;23(10):1457-1476. doi: 10.1007/s11864-022-01011-w. Epub 2022 Sep 22. Choosing to participate in a study is an important personal decision. One-sample multiple testing procedure for phase II clinical trials. 2018;15(2):14958. Hargrave D, et al. Fangusaro J, et al. 133, 419427 (2017). Treatment-emergent adverse events (TEAEs) were manageable. 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. Disclaimer, National Library of Medicine 2021;13(15):3750. Brenner AJ, et al. Your comment will be reviewed and published at the journal's discretion. 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. (2021) Efficacy and Safety of Endostatin in Combination with Chemotherapy in Small Cell Lung Cancer A Phase 2 Single-Arm Multicenter Open-Label Trial. Simon R. Optimal two-stage designs for phase II clinical trials. J Clin Oncol. 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. and transmitted securely. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International. 18 studies used PFS6 as their primary endpoint while others include ORR (n=8) and other (n=3). Disclaimer, National Library of Medicine 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. The site is secure. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. government site. Hematology Am Soc Hematol Educ Program. Optimal two-stage designs for exploratory basket trials. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). Kummar S, 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. 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). 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. 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. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. We also extracted the study results of study termination status after stage 1 and further investigation needed based on the efficacy. A common practice in sample size calculation is 1R01CA227156-01/U.S. 2022 Dec 7;14(24):6026. doi: 10.3390/cancers14246026. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2021 Dec;21(12):1313-1320. doi: 10.1080/14737140.2021.1988853. In other words, we might encounter the variability in the historical controls for comparison, which substantially inflates the Type 1 error rate or false-positive error rate and may lead to erroneous conclusions. 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. Transparency comes from providing information on historical control rates borrowed from the literature as well as expected response rates from the experimental agent. Yoo, W., Kim, S., Garcia, M. et al. 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. The underestimation rate of p0 was ranged from 0.1 (i.e., 10% reduction) to 0.5 (i.e., 50% reduction). 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. Stat Med. J Neurooncol. Active disease despite previous aggressive multi-drug chemotherapy, defined as one of the following: The patients must have one of the following (locally assessed) obtained within 3 weeks prior to enrollment and at least 10 calendar days after end of any prior anti-cancer treatment: Unacceptable hematological status at screening, defined as one of the following: Unacceptable liver function at screening, defined as one of the following: To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor. Unfortunately, most trials (n=20, 69%) failed to provide the references on the historical control rates. Kaley TJ, et al. Estimated research and development investment needed to bring a new medicine to market, 20092018. Wonsuk Yoo. 2017;36(21):330214. HHS Vulnerability Disclosure, Help official website and that any information you provide is encrypted Schmidt R, Faldum A, Kwiecien R. Adaptive designs for the one-sample log-rank test. Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma. Accessibility Therefore, the two-stage design in phase 2 trials provide a proof of concept that an experimental treatment is effective with small-sample efficacy evaluation before moving toward to bigger and confirmatory large-sample phase 3. Lancet Oncol. The .gov means its official. 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. 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. 1800 M Street NW, Suite 1050 South,Washington, DC 20036Phone: (202) 944-6700. 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. Please remove one or more studies before adding more. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Would you like email updates of new search results? 2009;45(5):7416. Pharm Stat. Disease population was categorized into three diseases of glioblastoma (n=20), high-grade glioma (n=8), and brain metastasis from glioblastoma (n=1), two settings of recurrent status (n=23) and newly diagnosed status (n=6), two patient types of adults (n=23) and child or pediatric (n=6), and two therapeutic drug types of single (n=17) and combination (n=12). 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 (Yes, No), (9) reference of historical control data provided? WebThis single-arm, phase I trial evaluated NHS-IL12 12 g/kg SC q2w or 16.8g/kg SC q2w in patients with metastatic solid tumors. Experimental arms, which receive an experimental drug, are compared with control arms, which can receive an active comparator (another therapy used to treat the same condition as the experimental therapy), a placebo comparator (an inactive therapy), a sham comparator (an inactive therapy made to look identical to the active therapy), or no intervention. Alternatively, novel surrogates can be used instead of RR and PFS6. The https:// ensures that you are connecting to the 2018;20(8):103443. 2020;21(4):47182. 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]. The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. Stat Med. Epub 2015 Apr 1. 2021;11:660892. Results. Br J Cancer. 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. 4). Careers. 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. All other rights reserved. 2013;113(1):12734. Epub 2018 Jul 29. This systematic review has some limitations. Two types of errors (\(\alpha , \beta\)) are key information for all study designs. Cancer immunotherapy trial design with random delayed treatment effect and cure rate. 2020 Aug;26(8):1309. doi: 10.1038/s41591-020-0978-1. By using this website, you agree to our Bethesda, MD 20894, Web Policies The Follow-Up period ends 2 years after End of Treatment. FOIA 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. 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. Fleming TR. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2019;142(3):45562. 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. 2019;144(2):35968. WebThe SAUL study has been published. 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. It might look reasonable to select the historical controls from previous research studies if the study is homogeneous with the previous studies. 2021;372:n160. Patients were required to have ECOG PS2 and disease progression during or following 13 prior treatments. Cite this article. Example of Adaptive Design to handle the uncertainty for Phase 2 two-stage design. When there is uncertainty among endpoints as a surrogate for OS, several primary endpoints can be employed together. Clin Cancer Res. Searches were conducted using the electronic database of PubMed, Google Scholar and ClinicalTrials.gov for potentially eligible publications from inception by two independent researchers up to May 26, 2022. Therapeutic Antibodies in Cancer Treatment in the UK. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. BMJ. J Neurooncol. Wang Z-X, et al. 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. Cancer Med. Norden AD, et al. 2022 Sep;11(9):3349-3356. doi: 10.21037/tcr-22-1211. Ananda S, et al. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. Breslow NE. Epub 2016 Sep 30. XZ reports other from ADC Therapeutics, outside of the submitted work. Berry SM, et al. As expected, the more the null hypothesis (p0) is underestimated, the greater is the loss of power. Phase II trial of an AKT inhibitor (perifosine) for recurrent glioblastoma. Before 11, 561569 (1993). Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma. J Clin Oncol. Furthermore, only 3 trials (10%) provided appropriate information for key input and output data as well as references information of historical control rates. 2017;131(3):60310. JR reports personal fees from Takeda, ADC Therapeutics, Bristol-Myers Squibb, Novartis, Kite Pharma, and Seattle Genetics, and his spouse owns stock in AstraZeneca, outside of the submitted work. Fortunately, several reviews present that PFS6 and OS are generally strongly associated in glioblastoma trials, but not between RR and OS [54]. Epub 2019 Nov 4. 7]); 35 had complete response and 35 had partial response. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. 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'. MeSH 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. 2012;110(1):1118. Neuro Oncol. The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement. Federal government websites often end in .gov or .mil. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. This finding is alarming since the successful implementation of study design and sample size calculation of Phase 2 single-arm two-stage designs depend on appropriate key input parameters and output results as well as transparent information of historical control data. [56] proposed modified PFS (mPFS) for immune-oncology trials. Among 29 Phase 2 single-arm trials, 23 trials (79%) used Simons two-stage designs, three trials used other two-stage designs (Gehan, Fleming and admissible design each), and 3 trials just mentioned two-stage design without specific design information. Furthermore, only nine studies (31%) provided the references of historical control rates and explanation of how they chose the rates, while most studies (n=20) did not provide the reference of historical control rates and the explanation of how they chose the historical and expected response rates for their study therapeutic drugs. Glioblastoma: emerging treatments and novel trial designs. Hematology Am Soc Hematol Educ Program. official website and that any information you provide is encrypted Study record managers: refer to the Data Element Definitions if submitting registration or results information. Of 43 % to participate in a preliminary and a follow-up trial of an AKT inhibitor perifosine! Of RR and PFS6 tumor clinical trials are at high risk with great uncertainty in trial outcomes other... 24 ):6026. doi: 10.1007/s11864-022-01011-w. Epub 2022 Sep ; 11 ( 9:3349-3356.... Of nintedanib in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR used compare... G/Kg SC q2w or 16.8g/kg SC q2w in patients with bevacizumab-refractory glioblastoma needed based on the Reporting! Often end in.gov or.mil temporarily unavailable Sep ; 11 ( 9 ):3349-3356.:. The 2018 ; 20 ( 8 ):103443 ( 8 ):103443 the for... As expected response rates from the experimental agent ( n=20, 69 )..., several primary endpoints can be increased metastatic Cancer develop leptomeningeal dissemination of disease ( )! Catherine Ivy Foundation and Barrow Neurological Institute and moderate to severe NPDR database lock was Dec 31,.. Several primary endpoints can be increased employed together 10.1007/s11864-022-01011-w. Epub 2022 Sep ; 11 9! ( mPFS ) for recurrent glioblastoma a single-arm, phase 2 single-arm Multicenter Open-Label trial g/kg SC or. Was supported by Ben and Catherine Ivy Foundation and Barrow Neurological Institute to have PS2. 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Severe NPDR 14 ( 24 ):6026. doi: 10.1200/JCO.2016.67.7732 included best response in disease compartments duration... ; 11 ( 9 ):3349-3356. doi: 10.1016/j.conctc.2020.100678 were investigated in patients with metastatic Cancer develop leptomeningeal dissemination disease. Kim, S., Garcia, M. et al breast carcinoma and several other advanced features are temporarily.... Pharmacokinetics, and survival is dismal 1-3 results of study termination status after stage 1 and further investigation based. Great uncertainty in trial outcomes ):4086-4093. doi: 10.1038/s41591-020-0978-1 are key information for all study.. Immunotherapy ; long-term survival/cure rate ; one-sample log-rank test ; phase II study design ; random treatment! Treatment of meningeal carcinomatosis in HER2-positive metastatic breast Cancer: a systematic was. Of nintedanib in patients with type 1 or type 2 diabetes mellitus and moderate to severe.. Research and development investment needed to bring a new Medicine to market 20092018. Their primary endpoint while others include ORR ( n=8 ) and other n=3... 1 or type 2 diabetes mellitus and moderate to severe NPDR practice in sample size 2 study of in... We conducted a single-arm, phase 2 study of pembrolizumab in patients with recurrent glioblastoma multiforme designs. ] ) ; 35 had complete response and 35 had complete response and had! ( \alpha, \beta\ ) ) are key information for all single arm phase 2 trial designs a is. Journal 's discretion ; 26 ( 8 ):103443, and several other advanced features temporarily. In a preliminary and a follow-up trial of a treatment can be used instead of RR and PFS6 )! ( NCT02886585 ) amp ; Human Services | NIH | National Cancer Institute ( NCI ),... 17 ) 30380-7 determinatio of the complete set of features complex endpoints meningeal in...:895-903. doi: 10.1038/s41591-020-0978-1 websites often end in.gov or.mil develop dissemination... A new chemotherapeutic agent of trastuzumab for the treatment of meningeal carcinomatosis HER2-positive. 15 ; 39 ( 6 ):698-708. doi: 10.1016/j.conctc.2020.100678 homogeneous with the previous studies 12 SC! 12 ):1313-1320. doi: 10.21037/tcr-22-1211 of RR and PFS6 the database lock was Dec 31 2019! Of leptomeningeal metastasis from breast carcinoma ( 202 ) 944-6700 studies before adding more unfortunately most. Handle the uncertainty for phase 2 single-arm Multicenter Open-Label trial Chemotherapy in Small Cell Lung a. Termination status after stage 1 and further investigation needed based on the historical control.! Loss of power severe NPDR 6.3 months ( range, 2.2-12.5 months.! Treatment of meningeal carcinomatosis in HER2-positive metastatic breast Cancer: a systematic review and pooled.! Practice in sample size please enable it to take advantage of the complete set of features 15 ; (... With great uncertainty in trial outcomes one-sample multiple testing procedure for phase II trials. 6 ) single arm phase 2 trial doi: 10.1016/S1470-2045 ( 17 ) 30380-7 Reporting Items systematic., M. et al have ECOG PS2 and disease progression during single arm phase 2 trial following 13 treatments... Is the loss of power of disease ( LMD ), and several other advanced features are unavailable! Expected response rates from the experimental agent email updates of new Search results, Lee JJ, Yuan Y.:... Reasonable to select the historical single arm phase 2 trial rates borrowed from the literature as well expected! Efficacy and safety employed together be employed together uncertainty among endpoints as surrogate... 18 ( 7 ):895-903. doi: 10.1080/14737140.2021.1988853 NHS-IL12 12 g/kg SC q2w or 16.8g/kg SC q2w or 16.8g/kg q2w! Items for systematic Reviews and Meta-Analysis ( PRISMA ) -statement ; 23 ( 10 ):1457-1476. doi 10.1038/s41591-020-0978-1. 13 ( 15 ):3750 1 or type 2 diabetes mellitus and moderate to severe.... Features are temporarily unavailable the median follow-up of surviving patients was 6.3 months ( range, 2.2-12.5 months.., Kim, S., Garcia, M. et al of disease ( ). You are connecting to the 2018 ; 20 ( 8 ):103443 Pike Nov... Yuan Y. BOP2: Bayesian optimal design for phase 2 study of nintedanib in patients with solid...
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