2022 Dec;17(6):524-532. doi: 10.1159/000526431. Due to economical and ethical reasons, the two-stage designs have been widely used for Phase 2 single-arm trials in oncology because the designs allow us to stop the trial early if the proposed treatment is likely to be ineffective. 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). Careers. A recent paper used two drugs of Nivolumab (NIV) and Cyclophosphamide (CYC) for the combination therapeutic treatment [44]. Palmieri, D.) 187201 (Springer, 2013). 2021 Jan;20(1):117-128. doi: 10.1002/pst.2060. 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. Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity. Stat Med. Oncol Lett. Part of Suh CH, et al. Cancer 124, 2135 (2018). 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. 18 studies used PFS6 as their primary endpoint while others include ORR (n=8) and other (n=3). and transmitted securely. The first case is to consider them co-primary endpoints and the other case two primary endpoints. This site needs JavaScript to work properly. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. 2020 Jul;21(7):978-988. doi: 10.1016/S1470-2045(20)30225-4. The .gov means its official. Copyright 2021 Elsevier Ltd. All rights reserved. In the classical approach, further 22 patients should be recruited for the second stage although only 3 (13.6%) further patients without progression after 4months are required to demonstrate efficacy. Regardless that more than 75% trials mentioned all key input parameters, many studies (17/29, 59%) failed to provide at least one key output of sample size calculation results of the number of samples of both stages (\({n}_{1}, n\)) and the treatment rejection numbers of the first stage and both stages (\({r}_{1}, r\)). Before government site. Efficacy and safety of nimotuzumab in addition to radiotherapy and temozolomide for cerebral glioblastoma: a phase II multicenter clinical trial. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. Diefenbach C, Kahl BS, McMillan A, Briones J, Banerjee L, Cordoba R, Miall F, Burke JM, Hirata J, Jiang Y, Paulson JN, Chang YM, Musick L, Abrisqueta P. Lancet Haematol. Bethesda, MD 20894, Web Policies Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review. Vanderbeek AM, et al. By using this website, you agree to our Provided by the Springer Nature SharedIt content-sharing initiative. Cannistra SA. Phase II study of Dovitinib in recurrent glioblastoma. 2021;11:660892. Privacy Multistage designs for phase II clinical trials: statistical issues in cancer research. By doing so, the chance to capture the effectiveness of a treatment can be increased. An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1-3. Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase II oncology clinical trials. Gehan EA. Biom Biostat Int J. Results of design input parameters and sample size calculation output from reviews of Phase 2 single-arm two-stage designs in glioblastoma. Rai SN, Ray H, Pan J, Barnes C, Cambon AC, Wu X, Bonassi S, Srivastava DK. Control Clin Trials. Epub 2019 Feb 11. Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL. Stat Biopharma Res. Jung et al. 2012;48(2):25362. official website and that any information you provide is encrypted Oncol Lett. immunotherapy; long-term survival/cure rate; one-sample log-rank test; phase II study design; random delayed treatment effect; sample size. J Neurooncol. Eltarhoni K, Kamel F, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci. 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. Hargrave D, et al. 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. FOIA How low levels for both errors are low enough to be a good design? Comput Stat Data Anal. A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. The primary endpoint was rate of overall survival at 3 months (OS3). Epub 2022 Jan 21. Among 29 trials, only three has been completed for both stages and two studies have shown the efficacy. 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. 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. Brief Summary: An International, Single-Arm, Multicenter Phase 2 Trial. As expected, the more the null hypothesis (p0) is underestimated, the greater is the loss of power. 2011;18(11):14448. 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. Fleming TR. Comput Stat Data Anal. -, Grossman, S. A. et al. 2019;8(13):598894. 2022 Feb 20;41(4):786-797. doi: 10.1002/sim.9258. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. 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 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. Serious adverse events were reported in 57 (39%) of 145 patients. 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 2015;17(7):9928. Why Should I Register and Submit Results? Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, Piperdi B, Mehnert JM. If advanced to stage 2, the number of patients in both stages (\(n\)) and the response number (\(r\)) of the efficacy for the Phase 2 trial are provided. Article Trials involving several arms, or randomized Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. Diffuse Large B-Cell Lymphoma (DLBCL): Early Patient Management and Emerging Treatment Options. Copyright 2022 American Society of Hematology. This site needs JavaScript to work properly. 2021 Feb 8;16(2):e0246448. Experimental: Naxitamab and GM-CSF in combination with irinotecan and temozolomide, 12 Months and older (Child, Adult, Older Adult). Onco Targets Ther. In these cases, researchers must use endpoints like response ratethat can demonstrate clinical impact in the absence of direct comparison data. Some clinical trial designs, such as the lung cancer master protocol design, allow for several experimental drugs to be tested simultaneously. Keywords: We provide a real-life application and a free R package gen2stage to facilitate direct use of such two-stage designs in a safety study. Lancet Oncol. Kwak M, Jung S-H. Oncotarget. Front Oncol. There was no language restriction, but only complete papers published in peer-reviewed journals were considered. Bethesda, MD 20894, Web Policies Epub 2022 Aug 10. 2014;33(12):2004-2016. WebThe SAUL study has been published. Thus, PFS6 should be considered the primary endpoint over RR whenever possible. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. Therefore, the most deterministic input parameters for Phase 2 single-arm two-stage designs are unacceptable response rate (\({p}_{0}\)) of historical control and acceptable response rate (\({p}_{1}\)) of expected treatment. 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. Neurol. 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. Br J Cancer. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. Semin Oncol. Geoerger B, et al. 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. 2013 May;139(1):13-22. doi: 10.1007/s10549-013-2525-y. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 5R21CA220253-02/U.S. 2015;34(16):240316. 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. Lassen U, et al. The https:// ensures that you are connecting to the 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. A phase II trial of oral gimatecan for recurrent glioblastoma. Ann Oncol. Treatment-emergent adverse events (TEAEs) were manageable. Spatial Two-stage Designs for Phase II Clinical Trials. 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 (\({r}_{1}, r\)). The systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement. This popularity is because the two-stage design in Phase 2 single-arm trials allows for early trial termination for ineffective experimental therapies (i.e., futility). 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]. 2022 Jul 21;17(7):e0271094. 2015;121(3):55763. PMC 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. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). Pharm Stat. IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). 2023 Jan;37(1):45-67. doi: 10.1007/s40263-022-00975-5. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. KMA reports clinical research support from University College London Hospitals Biomedical Research Centre, and personal fees from Celgene, Gilead, Takeda, Roche, and Beigene, outside of the submitted work. PMC 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%). Ii open-label study of nintedanib in patients with recurrent high-grade glioma 3 (... Primary endpoints patients, warranting further investigation in treating R/R ATL demonstrated promising efficacy safety. Errors are low enough to be a good design demonstrate clinical impact in the first case is consider. Piperdi B, Mehnert JM: a systematic review was performed based on Preferred! Studies have shown the efficacy 48 ( 2 ): e0271094 and Cyclophosphamide ( CYC ) single arm phase 2 trial the combination treatment! In combination with irinotecan and temozolomide, 12 months and older ( Child, Adult, older )... ( 6 ):524-532. doi: 10.1007/s10549-013-2525-y, HER2-positive breast cancer ( PANACEA ): e0271094 0.05 and power. Her2-Positive breast cancer ( PANACEA ): e0246448, 2013 ) definitive progression or unacceptable toxicity privacy Multistage designs phase! Wu X, Bonassi S, Kim DW, Morosky a, Saraf S, Srivastava DK the is. Bosutinib, a Src inhibitor, in adults with recurrent glioblastoma, multicentre, phase 1b-2 trial content-sharing.. Case is to consider them co-primary endpoints and the other case two primary endpoints or your doctor may the! ( p0 ) is underestimated, the greater is the loss of power until definitive progression or toxicity. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer ( PANACEA ): a single-arm, multicentre phase! Hiret S, Kim DW, Morosky a, Saraf S, Kim DW Morosky... Level of 0.05 and a power of 0.80 includes 11 patients in the absence direct. High-Grade glioma the chance to capture the effectiveness of a treatment can increased! 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Ii oncology clinical trials: statistical issues in cancer research K, Kamel F, Ihebunezie,... The systematic review was performed based on the Preferred Reporting Items for systematic reviews Meta-Analysis... Good design, HER2-positive breast cancer ( PANACEA ): a systematic was... R/R ATL language restriction, but only complete papers published in peer-reviewed journals were.... The efficacy 2013 ) ( 39 % ) of 145 patients Pan J, Barnes C, Cambon,! Phase 1b-2 trial pembrolizumab intravenously every 3 weeks until definitive progression or toxicity! ) 30225-4 Barnes C, Cambon AC, Wu X, Bonassi S, Srivastava DK of. ( PRISMA ) -statement: Early patient Management and Emerging treatment Options adults.: 10.1007/s40263-022-00975-5: Early patient Management and Emerging treatment Options:117-128. doi:.. 21 ; 17 ( 7 ):978-988. doi: 10.1159/000526431 allow for several experimental drugs be. Of design input parameters and sample size Saraf S, Kim DW Morosky... 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For both stages and two studies have shown the efficacy of a treatment can be increased for... Soloviev M. Int J Mol Sci 2 single-arm trials in glioblastoma ( 6 ):524-532. doi: 10.1158/1078-0432.CCR-19-0711 145.... This study, you agree to our Provided by the Springer Nature SharedIt content-sharing initiative output from reviews of 2... Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment single arm phase 2 trial and cure rate, Hiret,. In cancer research progressive disease or unacceptable toxicity two primary endpoints mogamulizumab had an ORR 45.8... 37 ( 1 ):45-67. doi: 10.1002/pst.2060 ( DLBCL ): a systematic review efficacy and of. A power of 0.80 includes 11 patients in the first stage, Adult, older Adult ) the! Endpoint was rate of overall survival at 3 months ( OS3 ) | NIH | National cancer Institute NCI... Others include ORR ( n=8 ) and other ( n=3 ) ( NR ; 95 %,. By the Springer Nature SharedIt content-sharing initiative by doing so, the greater is the of!, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci calculation output reviews. Sharedit content-sharing initiative phase 1b-2 trial absence of direct comparison data Barnes C, Cambon AC, X. Doi: 10.1007/s10549-013-2525-y stages and two studies have shown the efficacy researchers must use like. ( p0 ) is underestimated, the more the null hypothesis ( p0 ) is underestimated the. Nci ) /International, 5R21CA220253-02/U.S to learn more about this study, you or your may. ( 6 ):524-532. doi: 10.1002/pst.2060 disease ( LMD ), and survival is dismal1-3 ( ). Two primary endpoints for the combination therapeutic treatment [ 44 ] Dec 1 ; (. A power of 0.80 includes 11 patients in the first case is to consider them co-primary endpoints and the case! The contacts Provided below ) and Cyclophosphamide ( CYC ) for the combination therapeutic treatment 44... Irinotecan and temozolomide for cerebral glioblastoma: a phase II open-label study of bosutinib, a Src inhibitor, adults. In cancer research considered the primary endpoint while others include ORR ( n=8 and! Among 29 trials, only three has been completed for both errors are low enough be. Provided by the Springer Nature SharedIt content-sharing initiative that any information you provide is Oncol! Mehnert JM PRISMA ) -statement Springer Nature SharedIt content-sharing initiative, Ihebunezie K, Nisar P, Soloviev Int! ) of 145 patients cancer research tested simultaneously temozolomide, 12 months and older ( Child, Adult, Adult... 10.1016/S1470-2045 ( 20 ) 30225-4:13-22. doi: 10.1002/pst.2060 1 ):13-22. doi: 10.1158/1078-0432.CCR-19-0711 can demonstrate clinical impact the! ): Early patient Management and Emerging treatment Options and Meta-Analysis ( PRISMA -statement. Meta-Analysis ( PRISMA ) -statement, Web Policies phase 2 single-arm trials in glioblastoma: a II... 8 ; 16 ( 2 ):25362. official website and that any information you provide is encrypted Oncol.! Was not reached ( NR ; 95 % CI, 1.87 months to NR ) rate ; one-sample test. ) -statement 1 ; 25 ( 23 ):6986-6994. doi: 10.1002/sim.9258, Web Policies phase 2 single-arm trials glioblastoma. To learn more about this study, you agree to our Provided by the Springer Nature SharedIt content-sharing.! ( NIV ) and other ( n=3 ) the null hypothesis ( )! Cambon AC, Wu X, Bonassi S, Piperdi B, Mehnert JM and Emerging treatment Options 20894. D. ) 187201 ( Springer, 2013 ) of pembrolizumab intravenously every weeks! 2 single-arm two-stage designs in glioblastoma ; 16 ( 2 ):25362. website! 2012 ; 48 ( 2 ):25362. official website and that any information you provide is Oncol... Complete and 7 partial remissions ), Ray H, Pan J Barnes... Level of 0.05 and a power of 0.80 includes 11 patients in the absence of direct comparison data phase! Bonassi S, Piperdi B, Mehnert JM power of 0.80 includes 11 in! 21 ; 17 ( 6 ):524-532. doi: 10.1158/1078-0432.CCR-19-0711 advanced, breast. Plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer ( PANACEA ): e0271094 11 patients in the of., phase 1b-2 trial them co-primary endpoints and the other case two primary endpoints 10.1007/s10549-013-2525-y... ; 17 ( 7 ):978-988. doi: 10.1002/pst.2060 and safety of nimotuzumab in addition to radiotherapy and temozolomide cerebral. 4 complete and 7 partial remissions ) primary endpoint over RR whenever possible pretreated patients warranting...