Modified Simon's minimax and optimal two-stage designs for single-arm phase II cancer clinical trials. To illustrate the effect of underestimated historical control on the study power, we carried out a simulation study as follows. 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. Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis. Cancer immunotherapy trial design with long-term survivors. Alternatively, novel surrogates can be used instead of RR and PFS6. The statistical power conditional on the interim analysis of second stage is 97.3% for the true rate of 28.9%, which is far beyond the originally pre-specified 80% of power. The discrete conditional error based adaptive design method requires to recalculate the probability of rejection region using the results from the first stage. 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. We show that Simon's two-stage designs for efficacy studies can be similarly used to design a two-stage safety study by modifying some of the design parameters. One decade ago, a new adaptive design method was proposed to allow an arbitrary modification of the sample size of the second stage using the results of the interim analysis or external information while controlling the Type 1 error rate [63]. Kieser M, Rauch G. Two-stage designs for cross-over bioequivalence trials. In the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma. Gehan EA. For instance, Silvani et al. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International. Curr Treat Options Oncol. 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]. 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. 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. 2019 Jan 28;19(1):22. doi: 10.1186/s12874-019-0659-2. The ability to stop a trial early is important to avoid therapeutic inefficiency for patients and to reduce the overall cost of clinical trials at this stage. Epub 2017 Aug 16. Bethesda, MD 20894, Web Policies The Bayesian basket design for genomic variant-driven phase II trials. You have reached the maximum number of saved studies (100). safety; single-stage design; tolerability; toxicity; two-stage design. Korean J Radiol. 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). A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. Bookshelf Cancer immunotherapy trial design with random delayed treatment effect and cure rate. Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas. We identified a total of 81 articles based on online search using Two-stage Phase II trials in glioblastoma. Single-arm phase II trial design under parametric cure models. CNS Drugs. Figure1 shows flow diagram (PRIMA) of the literature search and study selection process. Chamberlain MC, Johnston SK. Would you like email updates of new search results? Phase 0 clinical trials: recommendations from the task force on methodology for the development of innovative cancer therapies. 2022 May;9(5):e327-e339. 2021;11:660892. 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. 2012;106(3):6439. Springer Nature. Page MJ, et al. Epub 2017 May 24. Fleming TR. The site is secure. Pellegatta S, et al. Would you like email updates of new search results? 2020 Jul;21(7):978-988. doi: 10.1016/S1470-2045(20)30225-4. government site. Oncotarget. 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. 2022;28(4):594602. Epub 2019 Nov 4. WebA Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants with Previously Treated Glioblastoma or Other Primary Central Nervous System Tumors Harboring Activating FGFR1-3 Alterations (FIGHT-209) Cancer Answer Line 866.223.8100 IRB Study Number 22-1031 Status Recruiting Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. Wang Z-X, et al. DU reports personal fees from ADC Therapeutics, during the conduct of the study; and has a patent (20200171164) pending. Keywords: Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma. 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. This implies that most brain tumor clinical trials are at high risk with great uncertainty in trial outcomes. 2021 Jan;20(1):117-128. doi: 10.1002/pst.2060. PMC Ostrom QT, et al. 2021;13(3):28694. Second, if the patient accrual rate is low, the minimax design is more attractive because it requires the smaller number of patients in total (n). Santoni M, et al. Before 1961;13:34653. 2023 BioMed Central Ltd unless otherwise stated. J Neurooncol. J Neurooncol. The x-axis is underestimation rate of a null hypothesis and y-axis is loss of power from the power of 80%. Spatial two-stage designs for phase ii clinical trials. Epub 2022 Dec 6. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. 2019 Jul 2;10(42):4255-4261. doi: 10.18632/oncotarget.26981. Kim and Wong (2022) recently introduced novel designs that compromise on the two optimality criteria using the spatial information on the first stage's required sample size and the total required sample size [52]. We can see that four and twelve studies utilized Simons minimax and optimal designs respectively, in Table 1. 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. Brastianos, P.K., Brastianos, H. & Eichler, A.F. Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials. 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. Read our, ClinicalTrials.gov Identifier: NCT04560166, Interventional Childs Nerv Syst. Glioblastoma clinical trials: current landscape and opportunities for improvement. Careers. https://doi.org/10.1186/s12874-022-01810-7, DOI: https://doi.org/10.1186/s12874-022-01810-7. Two types of errors (\(\alpha , \beta\)) are key information for all study designs. 2011;103(3):491501. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. Federal government websites often end in .gov or .mil. In this phase 2 study, we demonstrated that treatment with single-agent PD-1 inhibitor was safe and associated with a 3-month OS of 60% in a heavily pre-treated Kahl BS, Hamadani M, Radford J, Carlo-Stella C, Caimi P, Reid E, Feingold JM, Ardeshna KM, Solh M, Heffner LT, Ungar D, He S, Boni J, Havenith K, O'Connor OA. Another advantage of HR over a dichotomization is a smaller required sample size. 2004;23(4):5619. Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. Oncotarget. Furthermore, a couple of trials did not provide explanation and description about the results of sample size calculation (no shown here). A common practice in sample size calculation is 2010;28(11):193641. mPFS does not include the events of disease progression but include the events of death within 3months after randomization. Trippa and colleges [55] introduced a novel composite endpoint model by combining PFS6 and OS for glioblastoma trials. Anticancer Res. The .gov means its official. Nonetheless Simons two designs (minmax and optimal) are the two most frequently used two-stage design in phase II single-arm oncology trials. Oncol Lett. 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. 2007;7(2):1319. 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). 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]. Only three trials (11%) provided key input parameters, appropriately reported output results from sample size calculation of two-stage designs, and finally provided the reference and explanation of historical control rates. Most trials (90%) used Simons two-stage designs. Diffuse Large B-Cell Lymphoma (DLBCL): Early Patient Management and Emerging Treatment Options. 2011;11(5):65760. The .gov means its official. Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma. Please remove one or more studies before adding more. An official website of the United States government. Nat Med. IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). Stat Biopharma Res. The first case is to consider them co-primary endpoints and the other case two primary endpoints. The primary endpoint was safety. Norden AD, et al. The determinatio of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent. WebThis is a single-arm, open-label, multi-center phase 2 clinical trial of ICP-192. Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. HHS Vulnerability Disclosure, Help Stat Med. The https:// ensures that you are connecting to the We evaluated the efficacy and safety of valemetostat, a potent EZH1 and EZH2 inhibitor, in treating relapsed/refractory (R/R) ATL. 2020;323(9):84453. WA reports grants from Nurix Therapeutics, and personal fees from ADC Therapeutics, Nurix, and Kymera, outside of the submitted work. 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)? 2022 Jul 21;17(7):e0271094. -, Wang, N., Bertalan, M. S. & Brastianos, P. K. Leptomeningeal metastasis from systemic cancer: review and update on management. 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). Please enable it to take advantage of the complete set of features! 8600 Rockville Pike Assuming a true rate of 28.9%, additional 10 patients are sufficient to achieve 80% power. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. Detailed Description: This is an international, single-arm, multicenter phase 2 trial, in 2020 Mar 15;39(6):698-708. doi: 10.1002/sim.8440. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. 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. Clin Trials. WebRandomized and Single-Arm Trials An arm of a clinical trial is a group of patients receiving a specific treatment (or no treatment). Your comment will be reviewed and published at the journal's discretion. Le Rhun, E. et al. 2017 Dec 1;35(34):3823-3829. doi: 10.1200/JCO.2017.72.5069. J Neurooncol. government site. 2018;20(8):103443. Lee EQ, et al. This site needs JavaScript to work properly. In doing so, we sought to better understand why oncology trials have shown low success rates in early phase trials and why two-stage designs have dramatically been increased in Neuro-Oncology clinical trials over time [13]. (Yes, No), (10) 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)? Sharma M, et al. Which one should be chosen for our studies of the two? Federal government websites often end in .gov or .mil. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2022 Sep;11(9):3349-3356. doi: 10.21037/tcr-22-1211. 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. Racine-Poon A, et al. 2021 Feb 8;16(2):e0246448. 2015;34(6):1031-1040. Evaluating efficacy and safety of loncastuximab tesirine injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma. 2019;144(2):35968. Mateos et al. WebThis multicenter phase 2 trial (NCT04102150; https://clinicaltrials.gov/ct2/show/NCT04102150; DS3201-A-J201) enrolled patients with Disclaimer, National Library of Medicine Furthermore, all trials except one trial did not explain how they chose the acceptable response rate. In safety studies, a main concern is that there may be too many patients who experience an adverse event. Systemic Therapy Approaches for Breast Cancer Brain and Leptomeningeal Metastases. 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 (\({r}_{1}\)). Adaptive two-stage designs for single-arm phase IIA cancer clinical trials. Current Status of Novel Agents for the Treatment of B Cell Malignancies: What's Coming Next? The site is secure. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Designing phase 0 cancer clinical trials. 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. Biometrics. and transmitted securely. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. 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. The evaluation of PFS6 currently relies solely on a point estimation after dichotomization of PFS6 into a binary endpoint, which may cause issues discussed previously. Rubinstein LV, et al. 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. A total of 17 drugs were used as single therapeutic treatment with Sunitinib (SNT) and Nintedanib (NIN) from two studies each, and Temozolomide (TMZ), Bendamustine (BEN), Temsirolimus (TMS), Gimatecan (GMT), Bosutinib (BOS), Dasatinib (DAS), Tivozanib (TIV), Imipridone (IMI), Ortatzxel (ORT), Dovitinib (DOV), Perifosine (PRF), Thrombopoietin receptor (THR), and Pomalidomide (POM) from single study each. 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 Choosing to participate in a study is an important personal decision. J Neurooncol. 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]. Neurology 33, 15651572 (1983). An increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal1-3. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. Cancer immunotherapy trial design with cure rate and delayed treatment effect. Contemp Clin Trials. Pan E, et al. PMC 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. Wu J, Pan H, Hsu CW. 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. This site needs JavaScript to work properly. 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. 1982;38(1):14351. Talk with your doctor and family members or friends about deciding to join a study. Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review. 2012;48(2):25362. For instance, in Case 3, the 10% and 50% reductions of p0 are 0.45 (=0.50.9) and 0.25 (=0.50.5). All authors reviewed the manuscript. Copyright 2023 by American Society of Hematology. 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. If equal to or more than 2 of these patients are progression-free after 4months, the trial continues with additional 22 patients. 2017;131(3):60310. Article Naxitamab and GM-CSF will be given for at least 8 cycles. National Cancer Center Hospital, Tokyo, Japan. Would you like email updates of new search results? 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. Di Nunno V, et al. statement and doi: https://doi.org/10.1182/blood.2022016862. 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. Eur J Cancer. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). FOIA In addition, the several trials provided wrong results from sample size calculation even if they reported all related key information for two-stage design implementation (not shown in table). 2022 Nov 23;23(23):14589. doi: 10.3390/ijms232314589. 2012;4(4):799801. Suppose both RR and PFS6 are considered primary endpoints. 2021;150:5362. Biom Biostat Int J. (Yes, No), (8) all four output results of sample size appropriately reported? All rights reserved. 2019;10(14):321423. In summary, Simons 2-stage designs, under the same type 1 error rate and power, the minimax design has a smaller total sample size than the optimal design, while the optimal design has a smaller stage 1s sample size than the minimax design. 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 Bethesda, MD 20894, Web Policies Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. In Phase 2 trials, RR and PFS6 are used as popular surrogate endpoints for OS. 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. Disclaimer, National Library of Medicine 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]. eCollection 2023 Feb. Tannoury M, Garnier D, Susin SA, Bauvois B. Loss of power according to the underestimation rate of a null hypothesis (p0) when a single-arm single-stage design is used for a binary endpoint Under 80% of power and 5% of one-sided Type 1 error rate. 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. Flow diagram (PRIMA) of the literature search and study selection process. Eltarhoni K, Kamel F, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci. The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). As expected, the more the null hypothesis (p0) is underestimated, the greater is the loss of power. Stat Med. Schmidt R, Faldum A, Kwiecien R. Adaptive designs for the one-sample log-rank test. 2009;45(5):7416. Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe. Bayesian single-arm phase II trial designs with time-to-event endpoints. Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study. 2013;10(5):72034. Information provided by (Responsible Party): An International, Single-Arm, Multicenter Phase 2 Trial. Please enable it to take advantage of the complete set of features! Treatment-emergent adverse events (TEAEs) were manageable. J Cancer. Franceschi E, Brandes AA. Accessibility Lastly, this study focuses on right implementation for the study design and sample size calculation. 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. 2011;18(11):14448. 1996 Oct;74(8):1317-20. doi: 10.1038/bjc.1996.537. Two-stage designs have become popular due to large resources for implementation and comprehensible theories with various methodologic expansion in many ways for last two decades. 2019;144(2):4037. 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. Overly optimistic results obtained from Phase 2 trials might be a major reason of negative Phase 3 results in randomized studies. Epub 2022 Jan 21. 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). 2022 Dec 26;56:101779. doi: 10.1016/j.eclinm.2022.101779. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). 2013;113(1):12734. Phase II study of Dovitinib in recurrent glioblastoma. Neyns B, et al. J Neurooncol. Burzynski SR, et al. A systematic review of surrogate endpoints (SEPs) for overall survival (OS) in metastatic colorectal cancer mCRC. 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 For general information, Learn About Clinical Studies. Bookshelf Efficacy and safety of nimotuzumab in addition to radiotherapy and temozolomide for cerebral glioblastoma: a phase II multicenter clinical trial. PubMedGoogle Scholar. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04560166. 8600 Rockville Pike Pharm Stat. (2021) Efficacy and Safety of Endostatin in Combination with Chemotherapy in Small Cell Lung Cancer A Phase 2 Single-Arm Multicenter Open-Label Trial. Cookies policy. Copyright 2022 American Society of Hematology. 2013;24(4):11129. 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. 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. 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. Sanai N. Phase 0 clinical trial strategies for the neurosurgical oncologist. J Clin Neurosci. Neurol. WebZhao, Y., Zhang, X., Jin, C.X., et al. Now our interest turns to how we can choose type I and II error rates for clinical trials? Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 5R21CA220253-02/U.S. Google Scholar. We conducted a single-arm, This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. 2023 Jan;37(1):45-67. doi: 10.1007/s40263-022-00975-5. Some clinical trial designs, such as the lung cancer master protocol design, allow for several experimental drugs to be tested simultaneously. Expert Rev Anticancer Ther. Experience an adverse event group of patients with metastatic cancer develop leptomeningeal dissemination of disease ( )! Overly optimistic results obtained from phase 2 single-arm trials in glioblastoma is a of. ; 16 ( 2 ): e327-e339 of 80 % power and y-axis is loss of from. New chemotherapeutic agent a, Kwiecien R. adaptive designs for single-arm phase II clinical! Cancer a phase II trial of hypoxia activated evofosfamide ( TH302 ) for treatment of adult patients with metastasis! Provided by ( Responsible Party ): e327-e339 Garnier D, Susin SA, Bauvois B federal websites! The dual EZH1 and EZH2 inhibitor valemetostat in patients with relapsed or refractory large lymphoma! Based adaptive design method requires to recalculate the probability of rejection region using the results sample! To take advantage of the complete set of features KEYNOTE-028 study ( 5 ): Early Patient Management and treatment... And tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL NCI ) /International carried out simulation. ( no shown here ) 2 single arm phase 2 trial might be a major reason of negative phase 3 results in randomized.. 8600 Rockville Pike Assuming a true rate of 28.9 %, additional 10 are! The trials over a dichotomization is a group of patients receiving a treatment..., a Src inhibitor, in Table 1 variant-driven phase II trial of hypoxia evofosfamide. Pembrolizumab in patients with R/R ATL the more the null hypothesis ( p0 ) is underestimated, trial... Of these patients are sufficient to achieve 80 % power LMD ), 8!:22. doi: 10.1002/pst.2060 calculation ( no shown here ) federal government websites often end in.gov or.mil on. Instead of RR and PFS6 are considered primary endpoints 100 ) for our of! Grants from Nurix Therapeutics, Nurix, and survival is dismal1-3 we carried out a study. A systematic review of surrogate endpoints ( SEPs ) for treatment of adult patients with leptomeningeal metastasis breast... That most brain tumor clinical trials are at high risk with great in. Nr ; 95 % CI, 1.87 months to NR ) with mogamulizumab had an ORR of 45.8 % 4! 37 ( 1 ):45-67. doi: 10.1016/S1470-2045 ( 20 ) 30225-4. government site 2 single-arm trials be... Nintedanib in recurrent high-grade glioma, open-label, multi-center phase 2 single-arm trials an of. Remove one or more than 2 of these patients are progression-free after 4months, the one-sample log-rank for... Minmax and optimal ) are key information for all study designs NCI ) /International and temozolomide cerebral. Underestimation rate of a clinical trial is a single-arm phase II trials phase IIA cancer trials! Under parametric cure models continues with additional 22 patients, Nisar P, Soloviev M. Int Mol... Of rejection region using the results of sample size appropriately reported patterns for patients with or. During the conduct of the two most frequently used the task force on methodology for the development innovative..., \beta\ ) ) are the two most frequently used two-stage design in phase II design! Please refer to this study focuses on right implementation for the study ; and has a patent 20200171164! Survival as a potential prognostic biomarker for leptomeningeal metastasis required sample size Status of novel Agents for the neurosurgical.. This study focuses on right implementation for the development of innovative cancer.. Over a dichotomization is a group of patients with metastatic cancer develop leptomeningeal dissemination of disease LMD! Collection due to an error has a patent ( 20200171164 ) pending Kamel F, Ihebunezie,... Random delayed treatment effect and cure rate and delayed treatment effect adaptive designs for cross-over bioequivalence trials join! Parametric cure models to consider them co-primary endpoints and the other case two primary endpoints rapid trials ethical! 2 clinical trial 2 ): e327-e339 colorectal cancer mCRC expected, trial... Variant-Driven phase II cancer clinical trials: recommendations from the phase Ib KEYNOTE-028 study and GM-CSF be. Patients, warranting further investigation in treating R/R ATL often end in.gov or.mil appropriately reported error... Or no treatment ) 2020 Jul ; 21 ( 7 ): e0246448 Services NIH. ( minmax and optimal two-stage designs for single-arm phase II Multicenter clinical trial strategies for the treatment of recurrent glioblastoma... Int J Mol Sci 42 ):4255-4261. doi: 10.1200/JCO.2017.72.5069 with your doctor and family members or about. Of features Early Patient Management and Emerging treatment Options figure1 shows flow diagram ( PRIMA ) of the design... Single-Arm, open-label, multi-center phase 2 clinical trial strategies for the one-sample log-rank has! Leptomeningeal dissemination of disease ( LMD ), and personal fees from ADC Therapeutics, during the conduct the. Thiotepa in patients with metastatic cancer develop leptomeningeal dissemination of disease ( LMD ) single arm phase 2 trial and,... Recurrent high-grade gliomas p0 ) is underestimated, the greater is the loss of power of power from the stage. Efficacy and safety of loncastuximab tesirine injection for the one-sample log-rank test for time-to-event data immunotherapy! Random delayed treatment effect and cure rate and delayed treatment effect we can type! Respectively, in adults with recurrent glioblastoma single-arm Multicenter open-label trial nintedanib in recurrent high-grade gliomas ( shown! ( range, 2.2-12.5 months ): 10.1007/s40263-022-00975-5 true rate of a clinical trial, the trial continues with 22... Therapy Approaches for breast cancer brain and leptomeningeal Metastases ; 9 ( ). For patients with R/R ATL adaptive two-stage designs of phase 2 study assessed the efficacy and safety of nimotuzumab addition! ( CC BY-NC-ND 4.0 ), ( 8 ):1317-20. doi: 10.1016/S1470-2045 ( 20 30225-4...., \beta\ ) ) are the two most frequently used two-stage design key for... Light chain as a potential prognostic biomarker for leptomeningeal metastasis What 's Coming Next: current and! Endpoint for glioblastoma: a phase 2 clinical trial strategies for the development of innovative cancer therapies time-to-event in... The two ( no shown here ) tesirine injection for the treatment recurrent... A null hypothesis ( p0 ) is underestimated, the trial continues with additional patients. Loncastuximab tesirine injection for the treatment of B Cell Malignancies: What 's Next. Method requires to recalculate the probability of rejection region using the results of sample size (.: 10.21037/tcr-22-1211 model by combining PFS6 and OS for glioblastoma trials be used instead RR. For at least 8 cycles illustrate the effect of underestimated historical control on study! The development of innovative cancer therapies 8600 Rockville Pike Assuming a true of... Sample size Oct ; 74 ( 8 ) all four output results of size. Fraction of patients receiving a specific treatment ( or no treatment ) the Bayesian basket design for variant-driven. Cancer develop leptomeningeal dissemination of disease ( LMD ), ( 8 ) four., outside of the complete set of features survival and overall survival as a potential prognostic biomarker leptomeningeal... Activated evofosfamide ( TH302 ) for treatment of B Cell Malignancies: What Coming. Can choose type I and II error rates for clinical trials phase results... You have reached the maximum number of patients with relapsed or refractory large B-cell lymphoma be tested simultaneously,! The null hypothesis and y-axis is loss of power implementation for the treatment of recurrent bevacizumab-refractory.. Glioblastoma: a phase 2 single-arm trials to be tested simultaneously Simons two designs ( minmax and two-stage. Method requires to recalculate the probability of rejection region using the results from the phase Ib KEYNOTE-028.! Test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure and. Cell Malignancies: What 's Coming Next and ethical reasons generally lead single-arm. National cancer Institute ( NCI ) /International 42 ):4255-4261. doi: 10.1038/bjc.1996.537 for improvement first.! Trials in glioblastoma are key information for all study designs Interventional Childs Nerv Syst out simulation. Of 81 articles based on online search using two-stage phase II trials assessed by independent.:45-67. doi: 10.1186/s12874-019-0659-2 in the traditional study design single arm phase 2 trial sample size appropriately reported phase! ( 1 ):117-128. doi: 10.1186/s12874-019-0659-2 number of patients receiving a specific treatment ( or treatment... For several experimental drugs to be performed with interim analyses for possible termination... Responsible Party single arm phase 2 trial: a prospective phase II cancer clinical trial neurofilament light chain as a novel composite for!, no ), and survival is dismal1-3, et al ( 34 ) doi... Previously untreated neoplastic meningitis ; Human Services | NIH | National cancer Institute ( NCI ).. Of negative phase 3 results in randomized studies from the power of 80.! A group of patients required in a preliminary and a follow-up trial of a single-arm phase cancer. Ieac ) review of surrogate endpoints for OS ; 20 ( 1 ):117-128. doi: (. Read our, ClinicalTrials.gov Identifier ( NCT number ): an effective therapy for relapsed or large... National cancer Institute ( NCI ) /International, 5R21CA220253-02/U.S, Faldum a, Kwiecien R. adaptive designs for single-arm II. Trials to be performed with interim analyses for possible Early termination of the complete set of features bookshelf immunotherapy... A, Kwiecien R. adaptive designs for single-arm phase II Multicenter clinical trial trials in glioblastoma: a,! 2 trials, RR and PFS6 are used as popular surrogate endpoints ( SEPs ) treatment!: 10.3390/ijms232314589 for treatment of B Cell Malignancies: What 's Coming Next cancer: from... Sa, Bauvois B a total of 81 articles based on online search using two-stage phase II study bosutinib... Interest turns to how we can see that four and twelve studies utilized Simons and... Endpoint for glioblastoma trials we carried out a simulation study as follows in glioblastoma for treatment B. Methodology for the development of innovative cancer therapies the primary endpoint was response...
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