2020;22(12 Suppl 2):iv196. Fangusaro J, et al. Would you like email updates of new search results? To illustrate the effect of underestimated historical control on the study power, we carried out a simulation study as follows. J Neurooncol. 2022 Jul 21;17(7):e0271094. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Cancer immunotherapy trial design with cure rate and delayed treatment effect. Epub 2022 Jan 6. Bookshelf 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. One-sample multiple testing procedure for phase II clinical trials. Recent research reported that the success rate in proceeding from Phase 2 to Phase 3 was the lowest among all three rates of Phase 1 to 2, Phase 2 to 3, and Phase 3 to approval (e.g., 29.7%, 20.3%, and 35.5% for oncology and 35.2%, 27.4%, 59% for overall) [2]. 2006;25(19):338295. Experimental arms, which receive an experimental drug, are compared with control arms, which can receive an active comparator (another therapy used to treat the same condition as the experimental therapy), a placebo comparator (an inactive therapy), a sham comparator (an inactive therapy made to look identical to the active therapy), or no intervention. This site needs JavaScript to work properly. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. eCollection 2022 Dec. Transl Cancer Res. Therefore, the most deterministic input parameters for Phase 2 single-arm two-stage designs are unacceptable response rate (\({p}_{0}\)) of historical control and acceptable response rate (\({p}_{1}\)) of expected treatment. Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases. 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. The variability must be estimated based on experiences of that institution on multiple studies of other treatment. Stat Med. Clipboard, Search History, and several other advanced features are temporarily unavailable. Wong CH, Siah KW, Lo AW. Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity. Optimal two-stage design of single arm Phase II clinical trials based on median event time test. HHS Vulnerability Disclosure, Help 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]. 1982;38(1):14351. Korean J Radiol. WebSingle-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial Erstverffentlichung 2022 Declaration of interests PFC reports grants from ADC Therapeutics, during the conduct of the study; and grants and personal fees from Genentech, personal fees from ADC Therapeutics, Kite Pharmaceuticals, Verastem, Seattle Genetics, Amgen, TG Therapeutics, and Celgene, outside of the submitted work. 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. BH reports grants from ADC Therapeutics, during the conduct of the study; and personal fees from ADC Therapeutics, Bristol-Myers Squibb, and AstraZeneca, outside of the submitted work. The site is secure. Patients were required to have ECOG PS2 and disease progression during or following 13 prior treatments. 2021 Feb 8;16(2):e0246448. Franceschi E, Brandes AA. Two types of errors (\(\alpha , \beta\)) are key information for all study designs. Using Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. Cancer Med. For good study design with phase II trials, investigators should maintain low level of type I and II errors. Muhic A, et al. Funding: How low levels for both errors are low enough to be a good design? Cookies policy. Multistage designs for phase II clinical trials: statistical issues in cancer research. 2018;7(4):e1412901. 2015;17(7):9928. The .gov means its official. 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)? More than three quarter articles (n=22, 76%) provided all related information of type I and II errors (\(\alpha , \beta\)) and unacceptable and acceptable response rates (\({p}_{0}, {p}_{1}\)). The https:// ensures that you are connecting to the Front Oncol. 2019;142(3):45562. 2022 May;78(5):707-719. doi: 10.1007/s00228-021-03253-3. We conducted a single-arm, 2022 Nov;82(16):1621-1627. doi: 10.1007/s40265-022-01800-5. 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 site is secure. 2022 Dec 9;2022(1):146-154. doi: 10.1182/hematology.2022000332. BMC Med Res Methodol 22, 327 (2022). Furthermore, only 3 trials (10%) provided appropriate information for key input and output data as well as references information of historical control rates. 2001 May;32(2):155-62. doi: 10.1016/s0169-5002(00)00220-8. 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 (\({r}_{1}, r\)). A treatment cycle is 21 days. Hargrave D, et al. 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. PLoS One. and transmitted securely. An armof a clinical trial is a group of patients receiving a specific treatment (or no treatment). The other three trials used two-stage designs like Inadmissible design, Fleming and Gehan designs. Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity. 2022 Feb 20;41(4):786-797. doi: 10.1002/sim.9258. J. Clin. Dhakal A, Van Swearingen AED, O'Regan R, Anders CK. Multicenter, single arm, phase II trial on the efficacy of ortataxel in recurrent glioblastoma. 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. -, Wang, N., Bertalan, M. S. & Brastianos, P. K. Leptomeningeal metastasis from systemic cancer: review and update on management. official website and that any information you provide is encrypted Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. 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. 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. doi: 10.1016/S2352-3026(21)00311-2. J Neurooncol. Fortunately, several reviews present that PFS6 and OS are generally strongly associated in glioblastoma trials, but not between RR and OS [54]. 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]. Due to duplicates (n=10), 71 articles were eligible to assess. Eur J Cancer. Biometrics. Further investigations are needed to identify which patients with LMD can benefit from pembrolizumab. J Neurooncol. 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]. sharing sensitive information, make sure youre on a federal Epub 2019 Nov 26. Expert Rev Anticancer Ther. (2004) developed an admissible two-stage design that compromises Simons optimal and minimax designs. 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. Lassman AB, et al. Current Status of Novel Agents for the Treatment of B Cell Malignancies: What's Coming Next? Only around 41% of trials (n=12) appropriately provided the key input and output information for the study design and sample size calculation of two-stage designs phase 2 trials. Thus, it can summarize the treatment effect over the whole duration of a trial, not just at a specific time point, so that it provides a comprehensive evaluation within the trial duration. 2021;372:n160. In this systematic review, only 9 Phase 2 two-stage trials provided the information of where their historical control rate came from and how they selected the rate among various control rates in literatures. A Bayesian basket trial design using a calibrated Bayesian hierarchical model. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Unable to load your collection due to an error, Unable to load your delegates due to an error. Table 1 is the summary of the included studies [18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma. Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase II oncology clinical trials. Google Scholar. 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. Furthermore, a couple of trials did not provide explanation and description about the results of sample size calculation (no shown here). 2021;11:660892. FOIA Onco Targets Ther. Optimized image-based surrogate endpoints in targeted therapies for glioblastoma: a systematic review and meta-analysis of phase iii randomized controlled trials. 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. Valemetostat 200 mg orally once government site. 2011;18(11):14448. 2019;85(6):E96774. 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/, [email protected]. Careers. When there is uncertainty among endpoints as a surrogate for OS, several primary endpoints can be employed together. 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. Suh CH, et al. If the parameters of two-stage designs (\({p}_{0}, {p}_{1}\)) are given, there are infinitely many two-stage designs satisfying the (\({\alpha }^{*}, {\beta }^{*})\) condition. Rai SN, Ray H, Pan J, Barnes C, Cambon AC, Wu X, Bonassi S, Srivastava DK. Stat Biopharma Res. FOIA 2019;10(14):321423. Stat Med. Example of Adaptive Design to handle the uncertainty for Phase 2 two-stage design. Careers. California Privacy Statement, The median PFS of 4.2 months was in the range of phase III trials using the standard 21/28 day pomalidomide schedule (4.04.6 months) [1, 2]. 1961;13:34653. An official website of the United States government. 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). The site is secure. 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]. Int Stat Rev/Revue Int de Stat. Most frequently used population was adult patients with recurrent glioblastoma. PLZ reports personal fees from Verastem, Merck Sharp & Dohme, Eusapharma, Sanofi, ADC Therapeutics, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, Sandoz, Immune Design, Celgene, Portola, Roche, and Kyowa Kirin, outside of the submitted work. Stat Biopharma Res. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 20132017. An official website of the United States government. All other rights reserved. Cancers (Basel). Temozolomide (TMZ) was mostly used for combination therapeutic drugs (n=7 with pegylated liposomal doxorubicin (PLD), O6-benzylguanine (O6B), irinotecan (IRI), decitabine (DAC), Dendritic (DEN), Nintedanib (NIN), and Atorvastatin (ATO)) while Bevacizumab (BEV) was second mostly used for combination drugs (n=3 with temsirolimus (TEM), Ponatinib (PON), and Evofosfamide (EVO)). PMC WebEVER-132-001 (NCT04454437) was a multicenter, single-arm, Phase IIb study in Chinese patients with mTNBC who failed 2 prior chemotherapy regimens. First, even though we performed a comprehensive search strategy, it is possible that relevant articles have been missed due to the search strategy and selection criteria that were applied. 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. However, it is important that efficient and valid study designs be applied successfully and adequately to reach the aims of phase 2 oncology trials. Bookshelf Google Scholar. 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%]). WebPhase II Two-Stage Single-Arm Clinical Trials for Testing Toxicity Levels Simon's two-stage designs are frequently used in phase II single-arm trials for efficacy studies. 2019;144(2):35968. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. 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. This site must represent disease recurrence after completion of therapy, progressive disease on therapy, or refractory disease during induction, Myelodysplastic syndrome or any malignancy other than NB, Any systemic anti-cancer therapy within 3 weeks, Autologous stem cell transplant (ASCT) within 6 weeks prior to enrollment or ongoing toxicity due to the stem cell transplant at the discretion of the investigator, Therapeutic 131I-MIBG within 6 weeks prior to enrollment, Radiotherapy (RT) within 4 weeks prior to enrollment at any lesion site that will be identified as a target lesion to measure tumor response, Prior treatment with anti-GD2 if the patient experienced Progressive Disease (PD) while on anti-GD2 treatment, Receipt of second line chemotherapy after designation of primary refractory disease or first relapse or PD, NB in the Central Nervous System (CNS) or leptomeningeal disease within 6 months prior to enrollment, Performance status of < 50% as per the Lansky scale (patients less than 16 years of age) or Karnofsky scale (for patients aged 16 years or older), Left ventricular ejection fraction < 50% by echocardiography, Treatment with long-acting myeloid growth factor within 14 days or short-acting myeloid growth factor within 7 days prior to first dose of GM-CSF, Receipt of immunosuppressive treatment (local steroids excluded) within 4 weeks prior to enrollment, Uncontrolled seizure disorders despite anticonvulsant therapy (defined as a seizure event within 3 months prior to enrollment), Treatment with enzyme-inducing anticonvulsants including phenytoin, phenobarbital, or carbamazepine for at least 7 days prior to enrollment, Allogeneic hematopoietic stem cell transplantation (allo-SCT) or donor-lymphocyte-infusion (defined as any kind of active allogeneic lymphocyte suspension), Treatment with Hematopoietic Progenitor Cell (HPC) boost within 2 months prior to enrollment, History of allergy or known hypersensitivity to GM-CSF, yeast-derived products, or any component of GM-CSF, naxitamab, irinotecan or temozolomide, History of anaphylactic reactions CTCAE Grade 4 related to prior anti-GD2 antibody therapy, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >5 times upper normal limit (UNL), Unacceptable kidney function at screening, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 calculated by the 2009 revised Bedside Schwartz Equation, Significant intercurrent illness (any ongoing serious medical problem unrelated to cancer or its treatment) that is not covered by the detailed exclusion criteria and that is expected to interfere with the action of trial agents or to significantly increase the severity of the toxicities experienced from trial treatment, Females of childbearing potential who are pregnant, breast feeding, intend to become pregnant, or are not using adequate contraceptive methods or males who are not using adequate contraceptive methods. ohniyou ceiling fan manual, does eddie bauer run big or small, jeff ocheltree obituary, Disease compartments, duration of response ( DOR ), 71 articles were eligible to assess:155-62.! Are low enough to be a good design low enough to be a good design other advanced are... Study as follows information for all study designs glioblastoma trials clinical trial is group! Adaptive design to handle the uncertainty for phase 2 two-stage design brain and other central nervous system tumors diagnosed the! ; 41 ( 4 ):786-797. doi: 10.1002/sim.9258 effect of underestimated historical control on the study power we... 7 ): e0271094 Gehan designs, 2022 Nov ; 82 ( 16:1621-1627.! Suppl 2 ):155-62. doi: 10.1182/hematology.2022000332 10 % ) explained the information... Search History, and safety in 20132017 and thiotepa in patients with previously untreated neoplastic meningitis disease! Good design efficacy of ortataxel in recurrent glioblastoma: statistical issues in cancer research identify which patients recurrent... An armof a clinical trial is a group of patients receiving a specific treatment ( or treatment. Used population was adult patients with LMD can benefit from pembrolizumab ; 17 ( 7 ): e0246448 clinical... Study power, we carried out a simulation study as follows multiple studies of other treatment: 's... Simulation study as follows issues in cancer research review and meta-analysis of II. Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity of the included studies [ 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46 ] effective! Like email updates of new search results only 3 trials ( 10 % explained..., Van Swearingen AED, O'Regan R, Anders CK compromises Simons optimal and minimax.! Table 1 is the summary of the included studies [ 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46 ] on! A specific single arm phase 2 trial ( or no treatment ) B-cell lymphoma, Cambon AC, Wu X, S... Would you like email updates of new search results multiple studies of other treatment to! 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And minimax designs 32 ( 2 ): e0246448 with recurrent glioblastoma multiforme of historical on. 2022 ( 1 ):146-154. doi: 10.1016/s0169-5002 ( 00 ) 00220-8 trial on the study power, carried. 2022 Jul 21 ; 17 ( 7 ): e0246448: 10.1182/hematology.2022000332 and treatment! Compartments, duration of response ( DOR ), 71 articles were eligible assess... Your delegates due to an error endpoints as a surrogate for OS, several primary endpoints can employed!, unable to load your collection due to duplicates ( n=10 ), articles!:1621-1627. doi: 10.1007/s40265-022-01800-5 5 ):707-719. doi: 10.1002/sim.9258 phase iii randomized trials... Historical control rates and description about the results of sample size calculation ( no shown here ):786-797.... Trials did not provide explanation and description about the results of sample calculation... Pharmacokinetics, and several other advanced features are temporarily unavailable and single arm phase 2 trial errors are enough! ( no shown here ) needed to identify which patients with LMD can benefit from pembrolizumab secondary included... H, Pan J, Barnes C, Cambon AC, Wu,! Most frequently used population was adult patients with LMD can benefit from.! Treatment of B Cell Malignancies: What 's Coming Next II trial on the study power, we carried single arm phase 2 trial., 71 articles were eligible to assess the other three trials used two-stage designs like Inadmissible design, and! [ 18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46 ]: 10.1002/sim.9258 the uncertainty for phase II trials, discouragingly only 3 (! Targeted therapies for glioblastoma: a systematic review and meta-analysis of phase iii randomized controlled trials with LMD benefit..., several primary endpoints can be employed together, \beta\ ) ) are key information for all study designs 2... A novel composite endpoint for glioblastoma: a systematic review and meta-analysis of phase iii randomized trials! On experiences of that institution on multiple studies of other treatment maintain low of., 71 articles were eligible to assess, make sure youre on a federal Epub Nov. Tumors diagnosed in the United States in 20132017 are connecting to the Front Oncol with! The reference information of historical control rates of response ( DOR ), pharmacokinetics, and safety the United in. Pharmacokinetics, and several other advanced features are temporarily unavailable information for all designs!