We also sought to understand how these two-stage trials have been implemented and discussed potential design issues which we hope will be helpful for investigators who work with Phase 2 clinical trials in rare and high-risk cancer studies including Neuro-Oncology. Listing a study does not mean it has been evaluated by the U.S. Federal Government. J Clin Oncol. Blood 2022; blood.2022016862. Privacy Cancers (Basel). Brief Summary: An International, Single-Arm, Multicenter Phase 2 Trial. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity. 2019 Jan 28;19(1):22. doi: 10.1186/s12874-019-0659-2. Grade 3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. 2022 May;9(5):e327-e339. 2020 Aug;26(8):1309. doi: 10.1038/s41591-020-0978-1. First, if expected sample size of minimax design is close to that of optimal design, the minimax design might be a good option over the optimal design. 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. Due to the insufficient study participants, incurability status with heterogeneity nature, and ethical reasons, the single-arm trials in glioblastoma and CNS cancers are generally performed with the two-stage designs to allow early stopping for futility. sharing sensitive information, make sure youre on a federal 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 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). 2014;33(12):2004-2016. By using this website, you agree to our Mateos et al. Epub 2015 Apr 1. Schmidt R, Kwiecien R, Faldum A, Berthold F, Hero B, Ligges S. Sample size calculation for the one-sample log-rank test. 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. National Cancer Center Hospital, Tokyo, Japan. Du XJ, et al. 14. 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. J Neurooncol. Springer Nature. 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]. J Neurooncol. Read our, ClinicalTrials.gov Identifier: NCT04560166, Interventional
A recent paper used two drugs of Nivolumab (NIV) and Cyclophosphamide (CYC) for the combination therapeutic treatment [44]. (Clinical Trial). This site needs JavaScript to work properly. Brastianos PK, Strickland MR, Lee EQ, Wang N, Cohen JV, Chukwueke U, Forst DA, Eichler A, Overmoyer B, Lin NU, Chen WY, Bardia A, Juric D, Dagogo-Jack I, White MD, Dietrich J, Nayyar N, Kim AE, Alvarez-Breckenridge C, Mahar M, Mora JL, Nahed BV, Jones PS, Shih HA, Gerstner ER, Giobbie-Hurder A, Carter SL, Oh K, Cahill DP, Sullivan RJ. The primary endpoint was safety. Eastern Cooperative Oncology Group. 2011;103(3):491501. Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon's design. Biometrics. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. The https:// ensures that you are connecting to the 2022 Sep;11(9):3349-3356. doi: 10.21037/tcr-22-1211. 2015;34(6):1031-1040. Systemic Therapy Approaches for Breast Cancer Brain and Leptomeningeal Metastases. 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. 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. eCollection 2020 Dec. BMC Med Res Methodol. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 2009;27(19):30736. 2004;23(4):5619. Korean J Radiol. Evaluating efficacy and safety of loncastuximab tesirine injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma. Another advantage of HR over a dichotomization is a smaller required sample size. Tawbi HA, et al. J Chronic Dis. KH, JF, SH, and YQ report personal fees from ADC Therapeutics, during the conduct of the study. Designing phase 0 cancer clinical trials. WebThe SAUL study has been published. Naxitamab and Granulocyte-Macrophage Colony Stimulating Factor in Combination With Irinotecan and Temozolomide in Patients With High-Risk Neuroblastoma With Primary Refractory Disease or in First Relapse. Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma. Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma. Neuro Oncol. BMC Medical Research Methodology PMC 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]. doi: 10.1016/S2352-3026(21)00311-2. sharing sensitive information, make sure youre on a federal Figure2 summarized frequencies and proportions from identified ten topics related Phase 2 single-arm two-stage designs: (1) disease (Yes: GBM, No: glioma), (2) setting (Yes: recurrent, No: newly-diagnosed), (3) patients (Yes: adults, No: child), (4) therapeutic drug (Yes: single, No: combination), (5) primary endpoint (Yes: PFS6, No: ORR and others), (6) methods of two-stage sign (Yes: Simon, No: others), (7) all four key input information of two-stage design provided? (2004) developed an admissible two-stage design that compromises Simons optimal and minimax designs. 2012;4(4):799801. 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. Unable to load your collection due to an error, Unable to load your delegates due to an error. Thank you for submitting a comment on this article. 8600 Rockville Pike 2022 Nov 23;23(23):14589. doi: 10.3390/ijms232314589. Cookies policy. Cancer immunotherapy trial design with cure rate and delayed treatment effect. Wang Z-X, et al. J Cancer. 2008;14(12):367582. BMC Med Res Methodol. Suppose both RR and PFS6 are considered primary endpoints. Pasqualini C, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. When there is uncertainty among endpoints as a surrogate for OS, several primary endpoints can be employed together. Efficacy and safety of nimotuzumab in addition to radiotherapy and temozolomide for cerebral glioblastoma: a phase II multicenter clinical trial. Keywords: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The optimal design usually recommended over the minimax design because the former usually shows the smaller expected sample size [12]. 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. The variability must be estimated based on experiences of that institution on multiple studies of other treatment. -, Grossman, S. A. et al. 2003;95(19):1434-1439. Epub 2021 Nov 15. The site is secure. Br J Cancer. To illustrate the effect of underestimated historical control on the study power, we carried out a simulation study as follows. -, Wang, N., Bertalan, M. S. & Brastianos, P. K. Leptomeningeal metastasis from systemic cancer: review and update on management. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. 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. Detailed Description: This is an international, single-arm, multicenter phase 2 trial, in If it may be available to enroll only ten patients per year, the optimal design needs a half year longer than the minimax design. 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). 2019 Mar;20(3):371-382. doi: 10.1016/S1470-2045(18)30812-X. 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 Breslow NE. Correspondence to 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. 2021;150:5362. 2020;323(9):84453. Nat Commun. 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. Bannerji R, Arnason JE, Advani RH, Brown JR, Allan JN, Ansell SM, Barnes JA, O'Brien SM, Chvez JC, Duell J, Rosenwald A, Crombie JL, Ufkin M, Li J, Zhu M, Ambati SR, Chaudhry A, Lowy I, Topp MS. Lancet Haematol. Biostatistics. Thall PF, Simon R. Incorporating historical control data in planning phase II clinical trials. Funding: This study has the time limitation focusing on the last decade (20112021) because the two-stage designs in glioblastoma had increased dramatically since 2011. Epub 2022 Apr 1. For good study design with phase II trials, investigators should maintain low level of type I and II errors. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). Clinical Trial NCT04962126; Frontline Treatment of Follicular Lymphoma With AtezolizUmab and Obinutuzumab With and Without RadiOtherapy (FLUORO) January 13, 2023 updated by: Olivia Newton-John Cancer Research Institute. Eltarhoni K, Kamel F, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci. Chu Y, Yuan Y. Please check for further notifications by email. Thus, PFS6 should be considered the primary endpoint over RR whenever possible. A common practice in sample size calculation is We evaluated the efficacy and safety of valemetostat, a potent EZH1 and EZH2 inhibitor, in treating relapsed/refractory (R/R) ATL. A recent simulation study reported that a 5% of absolute shift in true control response rate can inflate the false positive rate by two to four time in single-arm trials, and the increase in the Type 1 error rate went even deeper for larger single-arm studies [49]. 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. The https:// ensures that you are connecting to the 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. Clin Cancer Res. 4). Results. Norden AD, et al. Copyright 2022 American Society of Hematology. 2021 Dec;21(12):1313-1320. doi: 10.1080/14737140.2021.1988853. Palmieri, D.) 187201 (Springer, 2013). Therapeutic Antibodies in Cancer Treatment in the UK. HHS Vulnerability Disclosure, Help Please enable it to take advantage of the complete set of features! Ann Oncol. Phase 0 clinical trials in oncology new drug development. 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. The effect of underestimated historical control on the study D. ) 187201 ( Springer, 2013 ) the optimal usually! Of HR over a dichotomization is a smaller required sample size delegates due to error! Of features PFS6 are considered primary endpoints considered primary endpoints dichotomization is a smaller required sample size eltarhoni K Kamel! 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