Epub 2022 Aug 10. -. 1982;38(1):14351. 2020 Jul;21(7):978-988. doi: 10.1016/S1470-2045(20)30225-4. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. Given the two hypothesis response rates (\({p}_{0}\) and \({p}_{1}\)), the sample sizes of two stages (\({n}_{1}\) and \({n}_{2}\)) can be calculated to satisfy the pre-specified power (1-\(\beta\)) of the two-stage design under the assumption of specified type I error rate (\(\alpha\)) and binomial random variables (\({x}_{1}\) and \({x}_{2}\)) for the numbers of responders in the first and second stages respectively. 2015;17(8):110613. 2021;13(3):28694. 2019;144(2):4037. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial Summary 2018;7(4):e1412901. 2020;20(1):126. Simon R. Optimal two-stage designs for phase II clinical trials. Naxitamab and GM-CSF will be given for at least 8 cycles. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 5R21CA220253-02/U.S. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Study design input information and output results from sample size calculation related to two-stage design implementation were examined. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International. The .gov means its official. Taylor JW, et al. 2019;85:105807. While Phase 3 trials are frequently randomized in order to provide more precise data on safety and effectiveness outcomes, a Phase 3 trial might use a single arm if a small target population makes conducting a randomized trial impractical. Comparing survival of a sample to that of a standard population. Epub 2018 Jul 29. J Clin Oncol. 2019 Jul 2;10(42):4255-4261. doi: 10.18632/oncotarget.26981. 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. Leptomeningeal carcinomatosis. IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). Some clinical trial designs, such as the lung cancer master protocol design, allow for several experimental drugs to be tested simultaneously. Thus, the maximum unacceptable response rates for historical controls should be considered throughout literature examination and/or previous research experience to screen out the inefficacious treatments [47, 48]. Annals of Palliative Medicine, 10, 3277-3285. Detailed Description: This is an international, single-arm, multicenter phase 2 trial, in 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]. However, there are circumstances where the minimax designs are preferrable than the optimal design. The most common grade 3 or higher treatment-emergent adverse events were neutropenia (37 [26%] of 145 patients), thrombocytopenia (26 [18%]), and increased gamma-glutamyltransferase (24 [17%]). Warren KE, et al. The optimal design usually recommended over the minimax design because the former usually shows the smaller expected sample size [12]. Schmidt R, Kwiecien R, Faldum A, Berthold F, Hero B, Ligges S. Sample size calculation for the one-sample log-rank test. Qin F, et al. 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 Sci Rep. 2021;11(1):2306. Epub 2022 Apr 1. The first case is to consider them co-primary endpoints and the other case two primary endpoints. 2017;8(45):79298304. Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme. Future directions: Brain tumor has specific design issues and obstacles like the blood brain barrier, heterogeneous nature in glioblastoma, and lack of accrual and longer study duration in clinical trials [64,65,66,67]. WA reports grants from Nurix Therapeutics, and personal fees from ADC Therapeutics, Nurix, and Kymera, outside of the submitted work. Table 1 shows the summary of the included studies for Phase 2 single-arm two-stage clinical trials in glioblastoma. J Neurooncol. 2011;103(3):491501. 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%). 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. Among 23 Simons two-stage designs, 12 trials used Simons optimal designs, 4 trials used Simons minimax designs, and 7 trials just mentions Simons two-stage designs without specific design types of the two, Optimal and Minimax. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. A better way to avoid the potential issues is to use a hazard ratio (HR). This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. Englert S, Kieser M. Adaptive designs for single-arm phase II trials in oncology. eCollection 2020 Dec. BMC Med Res Methodol. 2021;39(1):22631. Contemp Clin Trials. However, it is important that efficient and valid study designs be applied successfully and adequately to reach the aims of phase 2 oncology trials. Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe. Disclaimer, National Library of Medicine 2018;15(2):14958. Valemetostat 200 mg orally once 2015;17(7):9928. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. Optimal two-stage designs for exploratory basket trials. Accessibility 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. Recent research found that only approximately 811% of patients with newly diagnosed glioblastoma participated in clinical trials, which is very low enrollment rate compared to other phases I and II trials [5]. WebMethods We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. An official website of the United States government. Careers. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. 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. Gupta UC, et al. For general information, Learn About Clinical Studies. In A common practice in sample size calculation is J Neurooncol. Jung SH, et al. 2022 Dec 9;2022(1):146-154. doi: 10.1182/hematology.2022000332. 2022 May;9(5):e327-e339. Comput Stat Data Anal. Hargrave D, et al. J Clin Oncol. Let us now assume that 4 (36.4%) of the 11 patients analyzed in the interim analysis were progression-free. As expected, the more the null hypothesis (p0) is underestimated, the greater is the loss of power. 2019 Jan 28;19(1):22. doi: 10.1186/s12874-019-0659-2. Wong CH, Siah KW, Lo AW. 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. Pharm Stat. Phase 2 study of Pomalidomide (CC-4047) monotherapy for children and young adults with recurrent or progressive primary brain tumors. Analysis of survival data under the proportional hazards model. 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. Epub 2019 Feb 11. The primary endpoint was rate of overall survival at 3 months (OS3). Treatment-emergent adverse events (TEAEs) were manageable. 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. Pharm Stat. Please enable it to take advantage of the complete set of features! Phase 2 single-arm trial designs typically allow Type 1 and 2 error rates up to 20% [50]. Unable to load your collection due to an error, Unable to load your delegates due to an error. -, Wang, N., Bertalan, M. S. & Brastianos, P. K. Leptomeningeal metastasis from systemic cancer: review and update on management. 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. WebZhao, Y., Zhang, X., Jin, C.X., et al. 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. Kinders R, et al. 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]. The therapeutic areas in oncology and immune-modulatory drugs were the most expensive, with a median of $2.8 billion and a mean of $4.5 billion [3]. Phase II trials in journal of clinical oncology. An official website of the United States government. Shi YK, Hong XN, Yang JL, Xu W, Huang HQ, Xiao XB, Zhu J, Zhou DB, Han XH, Wu JQ, Zhang MZ, Jin J, Ke XY, Li W, Wu DP, Yang SM, Du X, Jia YQ, Liu AC, Liu DH, Shen ZX, Zhang LS, James L, Hellriegel E. Chin Med J (Engl). CNS Drugs. Multistage designs for phase II clinical trials: statistical issues in cancer research. 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. The Bayesian basket design for genomic variant-driven phase II trials. Optimal two-stage design of single arm Phase II clinical trials based on median event time test. J. Clin. 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. 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. PLoS One. 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. Suh CH, et al. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. 2015 May-Jun;14(3):226-32. doi: 10.1002/pst.1678. 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 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]. Unable to load your collection due to an error, Unable to load your delegates due to an error. J Neurooncol. Pan E, et al. Among 29 trials reviewed systematically, 12 trails (41%) appropriately provided key input parameters and sample size results from two-stage design implementation. J Clin Neurosci. Brastianos, P.K., Brastianos, H. & Eichler, A.F. 2019;10(14):321423. 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. Palmieri, D.) 187201 (Springer, 2013). 2013;113(1):12734. 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]. 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. Funding: 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. Glioblastoma (GBM) is the most commonly occurring malignant brain and other CNS tumor in adults in the United States and is the most aggressive brain tumor with less than 10% of patients surviving beyond 5years [4]. Keywords: BMC Med Res Methodol. Cookies policy. official website and that any information you provide is encrypted The median follow-up of surviving patients was 6.3 months (range, 2.2-12.5 months). 2018;20(8):103443. 2021 Dec;21(12):1313-1320. doi: 10.1080/14737140.2021.1988853. Eltarhoni K, Kamel F, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci. Optimized image-based surrogate endpoints in targeted therapies for glioblastoma: a systematic review and meta-analysis of phase iii randomized controlled trials. The unacceptable historical control rate should be a maximum rate while the acceptable expected treatment rate should be a minimum rate in order not to be overly optimistic for the Phase 2 clinical trials. Grade 3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. 8600 Rockville Pike The primary endpoint was safety. 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]. MeSH The site is secure. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. 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. 2004;23(4):5619. 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. WebIn the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. For the trial, 70 children aged 618 years old with peanut allergies received 12-hour boiled peanuts for 12 weeks, 2-hour boiled peanuts for 20 weeks, and roasted peanuts for 20 weeks, to a target maintenance dose of 12 roasted peanuts daily. 8600 Rockville Pike Anticancer Res. 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? The x-axis is underestimation rate of a null hypothesis and y-axis is loss of power from the power of 80%. 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