doi: 10.1371/journal.pone.0271094. Comparing survival of a sample to that of a standard population. FOIA and transmitted securely. 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. Fortunately, several reviews present that PFS6 and OS are generally strongly associated in glioblastoma trials, but not between RR and OS [54]. Epub 2016 Sep 30. 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. This systematic review has some limitations. Unable to load your collection due to an error, Unable to load your delegates due to an error. 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). 2020;323(9):84453. J Neurooncol. 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. Di Nunno V, et al. Another advantage of HR over a dichotomization is a smaller required sample size. Kieser M, Rauch G. Two-stage designs for cross-over bioequivalence trials. BMC Med Res Methodol 22, 327 (2022). -, Grossman, S. A. et al. Biometrics. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Semin Oncol. Lassen U, et al. Accessibility Clipboard, Search History, and several other advanced features are temporarily unavailable. Suppose both RR and PFS6 are considered primary endpoints. 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. 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). 8600 Rockville Pike 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. 2019 Mar;20(3):371-382. doi: 10.1016/S1470-2045(18)30812-X. Franceschi E, Brandes AA. 2009;45(5):7416. None Created on Jan 16, 2023 Publication details Reviews All publications My publications Add new publication Import from PubMed More 2021;372:n160. Epub 2021 Nov 15. Clinical end points in recurrent glioblastoma: are antiangiogenic agents friend or foe? We extracted disease type and setting, population, therapeutic drug, primary endpoint, input parameters and sample size results from two-stage designs, and historical control reference, and study termination status. 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). Ananda S, et al. Serious adverse events were reported in 57 (39%) of 145 patients. Keywords: WebZhao, Y., Zhang, X., Jin, C.X., et al. 2018;15(2):14958. Please remove one or more studies before adding more. 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]. Stat Med. Its interesting to see that most trials without mentioning specific design types (like Simons optimal or minimax, Gehan, Fleming, or admissible designs) failed to provide one or more than one key information for the implementation results of two-stage design sample size calculation. This implies that most brain tumor clinical trials are at high risk with great uncertainty in trial outcomes. 2016;43(1):138. The site is secure. 2014;30(12):205161. 2022 Dec 9;2022(1):146-154. doi: 10.1182/hematology.2022000332. Wang Z-X, et al. 2021 May 6;134(11):1299-1309. doi: 10.1097/CM9.0000000000001463. 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). 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. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. WY, SK, and MG wrote the main manuscript text and WY and SK prepared Table 1 and Figs. J Neurooncol. The .gov means its official. EG-Mirotin safety and efficacy were investigated in patients with type 1 or type 2 diabetes mellitus and moderate to severe NPDR. Pellegatta S, et al. MeSH Stat Med. 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. Trials involving several arms, or randomized Tawbi HA, et al. Single-arm phase II trial design under parametric cure models. Jung SH, et al. official website and that any information you provide is encrypted 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. Nat Commun. sharing sensitive information, make sure youre on a federal 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]. But interestingly almost 60% of studies (17/29, 59%) failed to provide at least one key output results of sample size calculation such as the number of samples of first stage and both stages (\({n}_{1}, n\)) and the treatment rejection numbers of the first stage and both stages (\({r}_{1}, r\)). 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. However, we should acknowledge there exist heterogeneities when we borrow the historical control information from other published studies due to different population conditions and quality of supportive care. Google Scholar. Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy. By doing so, the chance to capture the effectiveness of a treatment can be increased. 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. Expert Rev Anticancer Ther. Lassman AB, et al. Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, Tsukasaki K, Ito S, Yoshimitsu M, Otsuka M, Ogura M, Midorikawa S, Ruiz W, Ohtsu T. J Clin Oncol. Oncotarget. ADC Therapeutics. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. 1996 Oct;74(8):1317-20. doi: 10.1038/bjc.1996.537. Fifty-six of the 70 (80%) participants became desensitized to peanuts. PMC 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. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. Study design input information and output results from sample size calculation related to two-stage design implementation were examined. OPTIM-ARTSAn adaptive phase II open platform trial design with application to a metastatic melanoma study. Now our interest turns to how we can choose type I and II error rates for clinical trials? Manage cookies/Do not sell my data we use in the preference centre. 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. We provide a real-life application and a free R package gen2stage to facilitate direct use of such two-stage designs in a safety study. 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. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. Eur J Cancer. Admissible two-stage designs for phase II cancer clinical trials. Odronextamab, a human CD20CD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Cancer Med. Careers. Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. The site is secure. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. Stat Biopharma Res. 2021 Jan;20(1):117-128. doi: 10.1002/pst.2060. 2012;48(2):25362. 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). 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. Kalpathy-Cramer J, et al. Figure1 shows flow diagram (PRIMA) of the literature search and study selection process. 2013;33(4):165760. Unable to load your collection due to an error, Unable to load your delegates due to an error. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 1R01CA244975-01/U.S. Palmieri, D.) 187201 (Springer, 2013). Fangusaro J, et al. Koji Izutsu, Shinichi Makita, Kisato Nosaka, Makoto Yoshimitsu, Atae Utsunomiya, Shigeru Kusumoto, Satoko Morishima, Kunihiro Tsukasaki, Toyotaka Kawamata, Takaaki Ono, Shinya Rai, Hiroo Katsuya, Jun Ishikawa, Hironori Yamada, Kazunobu Kato, Masaya Tachibana, Yasuyuki Kakurai, Nobuaki Adachi, Kensei Tobinai, Kentaro Yonekura, Kenji Ishitsuka; An Open-Label, Single-Arm, Phase 2 Trial of Valemetostat in Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma. Racine-Poon A, et al. 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. Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study. Grade 3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Taylor JW, et al. 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. JAMA. Burzynski SR, et al. Results. BMJ. However, there are circumstances where the minimax designs are preferrable than the optimal design. Lancet Oncol. Clipboard, Search History, and several other advanced features are temporarily unavailable. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. Phase 2 study of bosutinib, a Src inhibitor, in adults with recurrent glioblastoma. Epub 2020 Jun 5. KH, JF, SH, and YQ report personal fees from ADC Therapeutics, during the conduct of the study. Phase 2 single-arm trial designs typically allow Type 1 and 2 error rates up to 20% [50]. Clin Trials. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. WebEVER-132-001 (NCT04454437) was a multicenter, single-arm, Phase IIb study in Chinese patients with mTNBC who failed 2 prior chemotherapy regimens. 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. CAS WebMethods We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). Batista MFFV, Eiriz I, Fitzpatrick A, Le Du F, Braga S, Alpuim Costa D. Breast Care (Basel). 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. https://doi.org/10.1186/s12874-022-01810-7, DOI: https://doi.org/10.1186/s12874-022-01810-7. Bookshelf 2022;169:107420. 2017;131(3):60310. A common practice in sample size calculation is 2019;93(19):1799806. Curr Treat Options Oncol. Epub 2019 Nov 26. 2019;8(13):598894. The primary endpoint was safety. Epub 2020 Sep 1. Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. 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. Let us now assume that 4 (36.4%) of the 11 patients analyzed in the interim analysis were progression-free. Accessibility The https:// ensures that you are connecting to the Except for three clinical trials that didnt provide the methods used, almost all articles were Simons two-stage designs (n=23, 90%). 2021;20(6):123548. J Neurooncol. Valemetostat 200 mg orally once Second, if we have the stronger interim results of higher activity than assumed in the planning stage, final results may be over-powered without adjusting the sample size [59]. 2008;14(12):367582. Federal government websites often end in .gov or .mil. Biom Biostat Int J. Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: a phase II study. Neuro Oncol. The primary endpoint was overall response rate (ORR) centrally assessed by an independent efficacy assessment committee (IEAC). J Neurooncol. 2021;13(3):28694. and transmitted securely. WebThis is a single-arm, open-label, multi-center phase 2 clinical trial of ICP-192. 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. 2021;150:5362. When there is uncertainty among endpoints as a surrogate for OS, several primary endpoints can be employed together. Anticancer Res. doi: 10.1016/S2352-3026(21)00311-2. A phase II study of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brainstem gliomas: a Pediatric Brain Tumor Consortium study. Stat Med. 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. 2019;142(3):45562. Schmidt R, Faldum A, Kwiecien R. Adaptive designs for the one-sample log-rank test. For instance, Silvani et al. Geoerger B, et al. Would you like email updates of new search results? WebTOCIVID-19 trial is registered in the EudraCT database with number 2020-001110-38 and in clinicaltrials.gov with ID NCT04317092. The site is secure. Vanderbeek AM, et al. This site needs JavaScript to work properly. 8600 Rockville Pike WebThe SAUL study has been published. 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 Thank you for submitting a comment on this article. 8600 Rockville Pike 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)? FOIA 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. Among 29 trials, only three has been completed for both stages and two studies have shown the efficacy. Compressing drug development timelines in oncology using phase 0 trials. 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]. 2020;21(4):47182. Patients pretreated with mogamulizumab had an ORR of 45.8% (4 complete and 7 partial remissions). Systemic Therapy Approaches for Breast Cancer Brain and Leptomeningeal Metastases. J Neurooncol. Br J Cancer. Finkelstein DM, Muzikansky A, Schoenfeld DA. official website and that any information you provide is encrypted 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]. WebThe trial ended after accrual completion; the database lock was Dec 31, 2019. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. An official website of the United States government. The primary endpoint was rate of overall survival at 3 months (OS3).
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