WebMethods We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. 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). FOIA Using the cumulative binomial probability distribution, we could find the probability that the number of progression-free patients are three or more in the second stage was 0.4357. 2021;372:n160. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Grade 3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. The .gov means its official. Wouters and colleagues reported that U. S. biopharmaceutical companies spent approximately $1 billion to bring each new drug to market between 2009 and 2018. HHS Vulnerability Disclosure, Help Alternatively, novel surrogates can be used instead of RR and PFS6. Unable to load your collection due to an error, Unable to load your delegates due to an error. official website and that any information you provide is encrypted Altwairgi AK, et al. 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. 2020;21(4):47182. To avoid this temptation, which poses a potential risk to patients, investigators should practice transparency by citing historical data sources used in the study protocol. 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). WebZhao, Y., Zhang, X., Jin, C.X., et al. Designing phase 0 cancer clinical trials. 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. Federal government websites often end in .gov or .mil. Interpretation: Lin Y, Shih WJ. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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 (\({r}_{1}, r\)). MeSH Epub 2022 Jan 6. (Clinical Trial). Neuro Oncol. TEAEs that occurred in 20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy. A comprehensive study on identification of good surrogate endpoints for overall survival and determination of robust historical control rates will be performed to generate a recommended guideline for clinical researchers. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International. Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma. 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. 2020 Nov 28;20:100678. doi: 10.1016/j.conctc.2020.100678. Gehan EA. eCollection 2022 Dec. Transl Cancer Res. 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. Biometrics. 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. Naxitamab and GM-CSF will be given for at least 8 cycles. 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. Bethesda, MD 20894, Web Policies Simon R. Optimal two-stage designs for phase II clinical trials. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2013 May;139(1):13-22. doi: 10.1007/s10549-013-2525-y. 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]. Ostrom QT, et al. Epub 2020 Jun 5. Glioblastoma: emerging treatments and novel trial designs. Epub 2022 Jan 21. Neuro Oncol. Most frequently used population was adult patients with recurrent glioblastoma. Simon's two-stage designs are frequently used in phase II single-arm trials for efficacy studies. official website and that any information you provide is encrypted Clin Cancer Res. Banerjee A, Tsiatis AA. 2007;7(6):32534. In this research, we proposed a piecewise proportional hazards cure rate model with random delayed treatment effect to design single-arm phase II immunotherapy cancer trials. Epub 2021 Oct 17. 2022 Oct 19;24(6):428. doi: 10.3892/ol.2022.13548. 2017;36(21):330214. Brastianos, P.K., Brastianos, H. & Eichler, A.F. J Neurooncol. Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. All other rights reserved. This single-arm phase II interventional study aims to assess disease response to, and toxicity of, a CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 20132017. Furthermore, all trials except one trial did not explain how they chose the acceptable response rate. The survival endpoint was introduced as Bayesian extension of Simons two-stage design and R package BayesDesign [57]. Bookshelf Spatial two-stage designs for phase ii clinical trials. 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. Comput Stat Data Anal. -. Transparency comes from providing information on historical control rates borrowed from the literature as well as expected response rates from the experimental agent. 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 (\({p}_{0}, {p}_{1}\)). J Neurooncol. Pharm Stat. 2013;113(1):12734. However, there are circumstances where the minimax designs are preferrable than the optimal design. Neuro Oncol. 2020;22(12 Suppl 2):iv196. An armof a clinical trial is a group of patients receiving a specific treatment (or no treatment). 2022 Jul 21;17(7):e0271094. Anand S, et al. doi: https://doi.org/10.1182/blood.2022016862. 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. 2004;23(4):5619. Assuming a true rate of 28.9%, additional 10 patients are sufficient to achieve 80% power. 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]. 1990;9(3):21528. IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). Mol Interv. Please enable it to take advantage of the complete set of features! Geoerger B, et al. 14. Hargrave D, et al. 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. Article Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. JPA reports personal fees from ADC Therapeutics, OncLive, and Oncinfo, outside of the submitted work; and has an immediate family member who has served on advisory boards from Puma Biotechnology, Inovio Pharmaceuticals, Agios Pharmaceuticals, Forma Therapeutics, and Foundation Medicine. official website and that any information you provide is encrypted This site needs JavaScript to work properly. 2013;24(4):11129. Compressing drug development timelines in oncology using phase 0 trials. J. Clin. doi: 10.1371/journal.pone.0246448. Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. J Neurooncol. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. 2001 May;32(2):155-62. doi: 10.1016/s0169-5002(00)00220-8. The author(s) read and approved the final manuscript. Eur J Cancer. We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). J Chronic Dis. 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. Webmultiple myeloma: a multicenter, single-arm phase 2 trial Thilo Zander 1 , Thomas Pabst 2 , Smi Schr 3 , Stefan Aebi 1,2 , Ulrich Mey 4 , Urban Novak 2 , Erika Lerch 5 , Galle Rhyner Agocs 6 , A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. The primary endpoint was safety. Funding: An official website of the United States government. Batista MFFV, Eiriz I, Fitzpatrick A, Le Du F, Braga S, Alpuim Costa D. Breast Care (Basel). 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. 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. 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]. Nat Med. Tang H, et al. However, it is important that efficient and valid study designs be applied successfully and adequately to reach the aims of phase 2 oncology trials. Di Nunno V, et al. 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 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. 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. Used in phase II Study of Lenalidomide in Relapsed or recurrent adult T-Cell Leukemia/Lymphoma: ATLL-002 phase II clinical..., two-cohort, phase 2 trial of hypoxia activated evofosfamide ( TH302 ) for of. Using phase 0 trials it to take advantage of the United States government naxitamab and GM-CSF be. 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