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. For instance, Silvani et al. 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. Nat Rev Cancer. Unable to load your collection due to an error, Unable to load your delegates due to an error. Cancer Med. 2020;323(9):84453. Epub 2016 Sep 30. We can see that four and twelve studies utilized Simons minimax and optimal designs respectively, in Table 1. GBM: glioblastoma, PFS6: progression-free survival at 6months, Key info: key input parameters for two-stage design, Right SS: did two-stage sample size calculation be appropriately implanted? Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe. Stat Med. 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. 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. 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 ($${p}_{0}, {p}_{1}$$). BSK reports grants from ADC Therapeutics, during the conduct of the study; and personal fees from Seattle Genetics and Genentech, outside of the submitted work. The choice of type I and type II errors is highly important since researchers need to assure that potentially effective therapy is not abandoned and at the same time the insignificant studies with very small marginal effects should not be advanced to subsequent phase III studies. 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. Spatial Two-stage Designs for Phase II Clinical Trials. Kim S, Wong WK. Banerjee A, Tsiatis AA. doi: 10.1016/S2352-3026(21)00311-2. Oncol Lett. Comput Stat Data Anal. 2011;2(1):1322. 2022 Dec 6;15:1481-1501. doi: 10.2147/OTT.S326632. Accessibility Now our interest turns to how we can choose type I and II error rates for clinical trials? TACE-HAIC Plus Lenvatinib for Patients With Unresectable HCC: an Open-label, Single-arm, Phase 2 Trial (Thalen) The safety and scientific validity of this study Trials involving several arms, or randomized Le Rhun, E. et al. Pembrolizumab is safe and feasible and displays promising activity in patients with LMD. J Neurooncol. Simon R, et al. 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. 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. IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). 2013;24(4):11129. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. Sort by Weight Alphabetically Medicine and Dentistry Patient This implies that most brain tumor clinical trials are at high risk with great uncertainty in trial outcomes. Experimental: Naxitamab and GM-CSF in combination with irinotecan and temozolomide, 12 Months and older (Child, Adult, Older Adult). This site needs JavaScript to work properly. 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. Hargrave D, et al. CC-S reports grants from ADC Therapeutics, during the conduct of the study; and grants from Rhizen Pharmaceuticals, and personal fees from Servier, Novartis, Genenta Science, ADC Therapeutics, Roche, Boehringer Ingelheim, Sanofi, Karyopharm, Bristol-Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, and AstraZeneca, outside of the submitted work. PubMedGoogle Scholar. 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. Some clinical trial designs, such as the lung cancer master protocol design, allow for several experimental drugs to be tested simultaneously. Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. J Neurooncol. 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. A total of 29 articles were included into the review of Phase 2 two-stage trials in glioblastoma. Admissible two-stage designs for phase II cancer clinical trials. Eur J Clin Pharmacol. 2014;33(12):2004-2016. 2022 Sep;11(9):3349-3356. doi: 10.21037/tcr-22-1211. Due to duplicates (n=10), 71 articles were eligible to assess. Childs Nerv Syst. Clin Trials. Furthermore, only 3 trials (10%) provided appropriate information for key input and output data as well as references information of historical control rates. 2019;10(14):321423. 2010;28(11):193641. WA reports grants from Nurix Therapeutics, and personal fees from ADC Therapeutics, Nurix, and Kymera, outside of the submitted work. Optimized image-based surrogate endpoints in targeted therapies for glioblastoma: a systematic review and meta-analysis of phase iii randomized controlled trials. Epub 2020 Sep 1. 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. Disclaimer, National Library of Medicine Single-arm studies have been traditionally used in Phase II oncology clinical trials. 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? Le Rhun E, Devos P, Houillier C, Cartalat S, Chinot O, Di Stefano AL, Lepage C, Reyns N, Dubois F, Weller M. Romiplostim for temozolomide-induced thrombocytopenia in glioblastoma: The PLATUM trial. 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). WebZhao, Y., Zhang, X., Jin, C.X., 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. J Neurooncol. Second, given the limited number of available single-arm two-stage trials, the results in these studies are subject to specific degree of selection criteria. Zhou H, et al. Figure1 shows flow diagram (PRIMA) of the literature search and study selection process. WebMethods: We did a multicentre (28 hospital sites in the USA, UK, Italy, and Switzerland), open-label, single-arm, phase 2 trial (LOTIS-2) in patients aged 18 years or older with OPTIM-ARTSAn adaptive phase II open platform trial design with application to a metastatic melanoma study. Intrathecal administration of trastuzumab for the treatment of meningeal carcinomatosis in HER2-positive metastatic breast cancer: a systematic review and pooled analysis. J Clin Neurosci. Int Stat Rev/Revue Int de Stat. 2012;48(2):25362. Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: a phase II study. Chamberlain MC, Johnston SK. 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. WebThe trial ended after accrual completion; the database lock was Dec 31, 2019. 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. 2022. Schmidt R, Kwiecien R, Faldum A, Berthold F, Hero B, Ligges S. Sample size calculation for the one-sample log-rank test. Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, Andr F; International Breast Cancer Study Group and the Breast International Group. Sci Rep. 2021;11(1):2306. The site is secure. The patients will receive irinotecan 50 mg/m2/day IV and temozolomide 100 mg/m2/day orally (both on Days 1-5) in combination with naxitamab 2.25 mg/kg/day IV (Days 2, 4, 8 and 10) (total 9 mg/kg per cycle), and GM-CSF 250 ug/m2/day sc, (Days 6-10). Recent research reported that the success rate in proceeding from Phase 2 to Phase 3 was the lowest among all three rates of Phase 1 to 2, Phase 2 to 3, and Phase 3 to approval (e.g., 29.7%, 20.3%, and 35.5% for oncology and 35.2%, 27.4%, 59% for overall) [2]. 2021;13(15):3750. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Glioblastoma clinical trials: current landscape and opportunities for improvement. Patients will receive naxitamab + GM-CSF + irinotecan/temozolomide. However, there are circumstances where the minimax designs are preferrable than the optimal design. 2021 Feb 8;16(2):e0246448. 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 sharing sensitive information, make sure youre on a federal 2020;20(1):126. Their composite endpoint model provides efficiency while still maintaining the clinical relevance of OS. A recent systematic review shows that both RR and PFS6 are suitable surrogate endpoints for OS, but their surrogacy varies according to therapy line or type and study size [53]. Designing phase 0 cancer clinical trials. 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. P30 CA022453/CA/NCI NIH HHS/United States, R01 GM107639/GM/NIGMS NIH HHS/United States. In these cases, researchers must use endpoints like response ratethat can demonstrate clinical impact in the absence of direct comparison data. 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. 2013;113(1):12734. Stat Med. 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. 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. doi: 10.1371/journal.pone.0246448. Ostrom QT, et al. Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. 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. Article FOIA Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. 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