single arm phase 2 trial

The sample size calculation for the two-stage designs is determined based on the historical control rate and difference between the two rates (\({p}_{0}, {p}_{1}\)). 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. Would you like email updates of new search results? MeSH 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. Optimal two-stage designs for exploratory basket trials. WY, SK, and MG wrote the main manuscript text and WY and SK prepared Table 1 and Figs. 2013;10(5):72034. FOIA Epub 2019 Nov 4. -, Grossman, S. A. et al. Epub 2022 Jan 6. doi: 10.1016/S2352-3026(21)00311-2. Blood 2022; blood.2022016862. J Neurooncol. 2021;13(3):28694. Would you like email updates of new search results? Franceschi E, Brandes AA. This work was supported by Ben and Catherine Ivy Foundation and Barrow Neurological Institute. Qin F, et al. Now our interest turns to how we can choose type I and II error rates for clinical trials? 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. Neuro Oncol. 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. Trials involving several arms, or randomized Please enable it to take advantage of the complete set of features! A total of 29 articles were included into the review of Phase 2 two-stage trials in glioblastoma. Bookshelf Optimal, minimax and admissible two-stage design for phase II oncology clinical trials. 2004;60(2):48290. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Eur J Cancer. Federal government websites often end in .gov or .mil. Comput Stat Data Anal. Alternatively, novel surrogates can be used instead of RR and PFS6. In this manner, the two-stage designs allow stopping of a futile trial early. The clinical trials landscape for glioblastoma: is it adequate to develop new treatments? Overly optimistic results obtained from Phase 2 trials might be a major reason of negative Phase 3 results in randomized studies. 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]. The primary endpoint was rate of overall survival at 3 months (OS3). 8600 Rockville Pike Publisher Correction: Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. PLoS One. For instance, in Case 3, the 10% and 50% reductions of p0 are 0.45 (=0.50.9) and 0.25 (=0.50.5). The response and survival of children with recurrent diffuse intrinsic pontine glioma based on phase II study of antineoplastons A10 and AS2-1 in patients with brainstem glioma. OPTIM-ARTSAn adaptive phase II open platform trial design with application to a metastatic melanoma study. 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. 2022 Dec 26;56:101779. doi: 10.1016/j.eclinm.2022.101779. Even though Simons two-stage designs have been popularly in oncology Phase 2 trials during last two decades, none, to our knowledge, has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in brain tumors. 2007;7(2):1319. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Front Oncol. Geoerger B, et al. The .gov means its official. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. and HCR: did the reference of historical control rate be provided?, all key input and output information as well as reference of historical control rates provided (Yes, No)?, and (11) did the trial be stopped (Yes, No)? The Follow-Up period ends 2 years after End of Treatment. https://doi.org/10.1186/s12874-022-01810-7, DOI: https://doi.org/10.1186/s12874-022-01810-7. 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]. The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. Pharm Stat. Neuro Oncol. Gehan EA. Phase 0 clinical trials in cancer drug development: from FDA guidance to clinical practice. Disclaimer, National Library of Medicine (Clinical Trial). 2021 Feb 8;16(2):e0246448. 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. Zhou H, Lee JJ, Yuan Y. BOP2: Bayesian optimal design for phase II clinical trials with simple and complex endpoints. The other three trials used two-stage designs like Inadmissible design, Fleming and Gehan designs. 2015;34(16):240316. government site. statement and Lassen U, et al. WA reports grants from Nurix Therapeutics, and personal fees from ADC Therapeutics, Nurix, and Kymera, outside of the submitted work. Bookshelf All rights reserved. official website and that any information you provide is encrypted This is an international, single-arm, multicenter phase 2 trial, in patients 12 months of age with high-risk NB with primary refractory disease or in first relapse. Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. 2015;17(8):110613. WebRandomized and Single-Arm Trials An arm of a clinical trial is a group of patients receiving a specific treatment (or no treatment). 2015;121(3):55763. Clipboard, Search History, and several other advanced features are temporarily unavailable. PubMedGoogle Scholar. eCollection 2022. 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 MeSH Perspect Clin Res. In the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. 2015;17(7):9928. Stat Med. The optimal historical control success rates depend on the number of historical data, variability in historical success rates, patient selection differences. Wu X, Wu C, Liu F, Zhou H, Chen C. A generalized framework of optimal two-stage designs for exploratory basket trials. For general information, Learn About Clinical Studies. 2012;4(4):799801. Accessibility 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. WebIn the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. Chamberlain MC, Johnston SK. Simon R, et al. Phase II clinical trials: issues and practices. 2014;33(12):2004-2016. Most trials (90%) used Simons two-stage designs. 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). The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). FOIA Epub 2021 Nov 15. 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. A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. 2021 May 6;134(11):1299-1309. doi: 10.1097/CM9.0000000000001463. J Neurooncol. XZ reports other from ADC Therapeutics, 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. Warren KE, et al. The outcomes of simulation are depicted in Fig. An official website of the United States government. Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials. Stat Med. safety; single-stage design; tolerability; toxicity; two-stage design. Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. 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. 4). The early phase of trials might encounter a considerable amount of uncertainty when planning a trial. J Clin Oncol. Accessibility Sharma M, et al. 1R01CA227156-01/U.S. Clipboard, Search History, and several other advanced features are temporarily unavailable. Some clinical trial designs, such as the lung cancer master protocol design, allow for several experimental drugs to be tested simultaneously. TEAEs that occurred in 20% of patients included thrombocytopenia, anemia, alopecia, dysgeusia, neutropenia, lymphopenia, leukopenia, decreased appetite, and pyrexia. Neyns B, et al. J Neurooncol. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. 2011;2(1):1322. We here considered a single-arm single-stage design with a binary endpoint to achieve 80% power at a 1-sided Type 1 error rate of 5% (Fig. Since the two-stage design of Phase 2 trials aims to make a conclusion of go or no-go to the next second stage, the sample size calculation of two-stage designs produces the number of patients in first stage (\({n}_{1}\)) and the response number which is eligible to move to the second stage (\({r}_{1}\)). 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. J Neurooncol. KH, JF, SH, and YQ report personal fees from ADC Therapeutics, during the conduct of the study. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. Neurosurg. Invest New Drugs. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. An official website of the United States government. Norden AD, 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. Glioblastoma clinical trials: current landscape and opportunities for improvement. Please check for further notifications by email. Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis. Epub 2021 May 11. Lee EQ, et al. Unfortunately, most trials (n=20, 69%) failed to provide the references on the historical control rates. Lancet Oncol. Most frequently used population was adult patients with recurrent glioblastoma. Refining Therapy in Patients with HER2-Positive Breast Cancer with Central Nervous System Metastasis. We systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). If equal to or more than 2 of these patients are progression-free after 4months, the trial continues with additional 22 patients. Estimated research and development investment needed to bring a new medicine to market, 20092018. Kummar S, et al. Cancer immunotherapy trial design with cure rate and delayed treatment effect. [56] proposed modified PFS (mPFS) for immune-oncology trials. 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. Evaluating efficacy and safety of loncastuximab tesirine injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma. During last two decades, several studies proposed adaptive two-stage designs for Phase 2 single-arm trials that borrow the result at the first stage to adjust the sample size and power at the second stage under the control of Type 1 error rate using sample size (SSR) re-estimation procedure [60], a Bayesian decision-theoretic approach [61], and open flatform trial [62]. An Open-Label, Single-Arm, Phase 2 Trial of Valemetostat in Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma - ScienceDirect Available online 27 Google Scholar. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. Ananda S, et al. California Privacy Statement, 8600 Rockville Pike 8600 Rockville Pike Bethesda, MD 20894, Web Policies (Yes, No), (9) reference of historical control data provided? 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. Given the type I and II error rates and the proportion of adverse events experienced in the first stage cohort, we prescribe a procedure whether to terminate the trial or proceed with a stage 2 trial by recruiting additional patients. Keywords: They used a loss function of weighted average of the maximum sample size from minimax design and the expected sample size from optimal design under the null hypothesis of ineffectiveness within the Bayesian framework [17]. Please remove one or more studies before adding more. Phase 0 clinical trials: recommendations from the task force on methodology for the development of innovative cancer therapies. Careers. Keywords: Most studies (n=27, 93%) provided the number of patients in stage 1 and both stages, so many trials (n=17) failed to report one or more from both response numbers of stage 1 and both stages which are key information to determine the study continuation toward the second stage (\({r}_{1}\)) at the end of first stage and hypothesis testing of efficacy (\(r\)) at the end of second stage. 2022 Dec;17(6):524-532. doi: 10.1159/000526431. Eur J Cancer. A Bayesian basket trial design using a calibrated Bayesian hierarchical model. Google Scholar. Wouters OJ, McKee M, Luyten J. Schmidt R, Kwiecien R, Faldum A, Berthold F, Hero B, Ligges S. Sample size calculation for the one-sample log-rank test. Privacy 2020 Mar 15;39(6):698-708. doi: 10.1002/sim.8440. And 7 trials were used with (1) 5% and 20% (2) 10% and 10% as their type 1 and 2 errors respectively. 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. 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. Phase II clinical trials with time-to-event endpoints: optimal two-stage designs with one-sample log-rank test. 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]. Modified Simon's minimax and optimal two-stage designs for single-arm phase II cancer clinical trials. Valemetostat 200 mg orally once daily demonstrated promising efficacy and manageable toxicity in heavily pretreated patients. By doing so, the chance to capture the effectiveness of a treatment can be increased. 11, 561569 (1993). IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). Cancer 124, 2135 (2018). Brenner AJ, et al. The site is secure. Leptomeningeal carcinomatosis. The underestimation rate of p0 was ranged from 0.1 (i.e., 10% reduction) to 0.5 (i.e., 50% reduction). Lassman AB, et al. 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. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Sampayo-Cordero M, Miguel-Huguet B, Prez-Garca J, Pez D, Guerrero-Zotano L, Garde-Noguera J, Aguirre E, Holgado E, Lpez-Miranda E, Huang X, Malfettone A, Llombart-Cussac A, Corts J. Contemp Clin Trials Commun. Silvani A, et al. 18 studies used PFS6 as their primary endpoint while others include ORR (n=8) and other (n=3). Oncoimmunol. 2020;22(12 Suppl 2):iv196. Murgo AJ, et al. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. 14. 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. 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. Comparison of error rates in single-arm versus randomized phase II cancer clinical trials. Please enable it to take advantage of the complete set of features! Using a 3+3 design, 13 patients with advanced cancer were enrolled and 12 were dose-limiting toxicity (DLT) evaluable. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews.