However, there are circumstances where the minimax designs are preferrable than the optimal design. WebARTICLE Clinical Trials 2011; 8: 260269 Quantitative evaluation of single-arm versus randomized phase II cancer clinical trials Gregory R Ponda,b and Saqib Abbasia Background There is a debate among cancer researchers about the use of single-arm or randomized phase II clinical trial designs; however, there is limited published Department of Health & Human Services | NIH | National Cancer Institute (NCI)/International, 1R01CA244975-01/U.S. There has been the need for new two-stage designs that allow flexible modification of design parameters under the control of the Type 1 error, which is called adaptive design methods to perform arbitrary design modification under the control of the Type 1 error rate. Burzynski SR, et al. Single-arm phase II trial design under parametric cure models. 2009;27(19):30736. 2022 May;169:107420. doi: 10.1016/j.csda.2021.107420. 2019;85:105807. Br J Cancer. A common practice in sample size calculation is Hematology Am Soc Hematol Educ Program. Pellegatta S, et al. Figure1 shows flow diagram (PRIMA) of the literature search and study selection process. 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 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. Wu X, Wu C, Liu F, Zhou H, Chen C. A generalized framework of optimal two-stage designs for exploratory basket trials. 2014;33(12):2004-2016. 2015;34(16):240316. JAMA. https://doi.org/10.1186/s12874-022-01810-7, DOI: https://doi.org/10.1186/s12874-022-01810-7. 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. 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. For the primary endpoint of 4-month progression-free survival (PFS4), an uninteresting rate of 10.9% obtained from historical controls and an anticipated rate of 28.9% were assumed. Biostatistics. Your comment will be reviewed and published at the journal's discretion. Accessibility First, it is usually difficult to stop patient recruitment exactly when the number of patients for the interim or final analysis is achieved, which might result to over- or under-running. National Cancer Center Hospital, Tokyo, Japan. Kaley TJ, et al. 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). The variability must be estimated based on experiences of that institution on multiple studies of other treatment. Designing phase 0 cancer clinical trials. BMC Med Res Methodol 22, 327 (2022). Before Phase 2 study of Pomalidomide (CC-4047) monotherapy for children and young adults with recurrent or progressive primary brain tumors. 2017;131(3):60310. J Clin Oncol. Unable to load your collection due to an error, Unable to load your delegates due to an error. Contemp Clin Trials. J Neurooncol. 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. 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. Several important topics related to the design issues will be followed to handle the design issues by increasing the precision of efficacy from targeted therapeutic trials of Phase 2 two-stage designs in brain tumor. We enrolled patients aged 18 years with HER2-positive breast cancer and newly California Privacy Statement, WebIn the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. official website and that any information you provide is encrypted Dhakal A, Van Swearingen AED, O'Regan R, Anders CK. 2019;37(15_suppl):1820618206. Le Rhun, E. et al. doi: 10.1371/journal.pone.0246448. 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. 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. Oncol. 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]. How low levels for both errors are low enough to be a good design? 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. 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. 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 optimal design usually recommended over the minimax design because the former usually shows the smaller expected sample size [12]. Mol Interv. 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. 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. 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]. WebThe trial ended after accrual completion; the database lock was Dec 31, 2019. Control Clin Trials. Epub 2022 Jan 6. Pharm Stat. 2021 Jun;22(6):741-742. doi: 10.1016/S1470-2045(21)00191-1. Suppose both RR and PFS6 are considered primary endpoints. Epub 2022 Dec 6. 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. 8600 Rockville Pike Wouters OJ, McKee M, Luyten J. J Neurooncol. Bookshelf 2011;2(1):1322. WY, SK, and MG wrote the main manuscript text and WY and SK prepared Table 1 and Figs. 2021 Feb 8;16(2):e0246448. Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase II oncology clinical trials. 2021;372:n160. Neurology 33, 15651572 (1983). 1989;10(1):110. Chu Y, Yuan Y. Stat Med. Epub 2021 May 11. Suh CH, et al. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. 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. Grade 3 TEAEs included thrombocytopenia, anemia, lymphopenia, leukopenia, and neutropenia. Would you like email updates of new search results? Blood 2022; blood.2022016862. The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design. Talk with your doctor and family members or friends about deciding to join a study. 2010;28(11):193641. 2021;9(4):e002114. and transmitted securely. Vanderbeek AM, et al. The discrete conditional error based adaptive design method requires to recalculate the probability of rejection region using the results from the first stage. AS reports grants from ADC Therapeutics, during the conduct of the study; and grants from Bayer, Eli Lilly, Roche, Pfizer, Merck, Novartis, MEI Pharma, and personal fees from Abbvie and PharmaMar, 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)? The .gov means its official. HHS Vulnerability Disclosure, Help 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 (\({r}_{1}, r\)). Stat Med. 2019 Jan 28;19(1):22. doi: 10.1186/s12874-019-0659-2. This site needs JavaScript to work properly. 2017;36(21):330214. Neurol. Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review. Hyun JW, Kim Y, Kim KH, Kim SH, Park EY, Youn JH, Yoo H, Gwak HS, Kim HJ. 2020;21(4):47182. 2015 May-Jun;14(3):226-32. doi: 10.1002/pst.1678. Jung et al. Brief Summary: An International, Single-Arm, Multicenter Phase 2 Trial. 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. Cancer immunotherapy trial design with cure rate and delayed treatment effect. 2020;20(1):126. and transmitted securely. Some clinical trial designs, such as the lung cancer master protocol design, allow for several experimental drugs to be tested simultaneously. This multicenter phase 2 trial (NCT04102150; https://clinicaltrials.gov/ct2/show/NCT04102150; DS3201-A-J201) enrolled patients with R/R aggressive ATL (acute, lymphoma, unfavorable chronic type). Neuro Oncol. 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]. The primary endpoint was rate of overall survival at 3 months (OS3). 2015;34(6):1031-1040. Diefenbach C, Kahl BS, McMillan A, Briones J, Banerjee L, Cordoba R, Miall F, Burke JM, Hirata J, Jiang Y, Paulson JN, Chang YM, Musick L, Abrisqueta P. Lancet Haematol. Spatial Two-stage Designs for Phase II Clinical Trials. The site is secure. Drugs. Epub 2022 Apr 1. Clipboard, Search History, and several other advanced features are temporarily unavailable. Murgo AJ, et al. Wonsuk Yoo. 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. Even though Simons two-stage designs have been popularly in oncology Phase 2 trials during last two decades, none, to our knowledge, has examined the usage for published articles that had applied the two-stage designs in Phase 2 single-arm trials in brain tumors. Stat Med. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Assuming a true rate of 28.9%, additional 10 patients are sufficient to achieve 80% power. Englert S, Kieser M. Adaptive designs for single-arm phase II trials in oncology. Epub 2019 Nov 26. government site. Results. WebA Single-arm, Multicenter, Phase 2 Trial to Evaluate Efficacy and Safety of Lenvatinib in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic This site needs JavaScript to work properly. Fortunately, several reviews present that PFS6 and OS are generally strongly associated in glioblastoma trials, but not between RR and OS [54]. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04560166. Bethesda, MD 20894, Web Policies Among 29 trials, only three has been completed for both stages and two studies have shown the efficacy. J Chronic Dis. Zagouri F, Sergentanis TN, Bartsch R, Berghoff AS, Chrysikos D, de Azambuja E, Dimopoulos MA, Preusser M. Breast Cancer Res Treat. Google Scholar. 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. Chamberlain MC, Johnston SK. MH reports grants from Takeda, Spectrum Pharmaceuticals, Astellas Pharma, and personal fees from Janssen, Incyte Corporation, ADC Therapeutics, Celgene, Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio, Sanofi Genzyme, BeiGene, and AstraZeneca, outside of the submitted work. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Fifty-six of the 70 (80%) participants became desensitized to peanuts. 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. 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. Our simulation study showed that the proposed log-rank test performs well and is robust of misspecified weight and the sample size calculation formula also performs well. 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. Phase II trial of ponatinib in patients with bevacizumab-refractory glioblastoma. Fangusaro J, et al. Better understanding on the study drug information and targeted molecular information might help the understanding of why the two-stage trials had been terminated after the stage 1 and ineffective after successful completion of both stages. Optimal, minimax and admissible two-stage design for phase II oncology clinical trials. Ostrom QT, et al. 1982;38(1):14351. Nat Med. Lastly, this study focuses on right implementation for the study design and sample size calculation. Clipboard, Search History, and several other advanced features are temporarily unavailable. This single-arm phase II interventional study aims to assess disease response to, and toxicity of, a Overly optimistic results obtained from Phase 2 trials might be a major reason of negative Phase 3 results in randomized studies. PMC 2021 Dec;8(12):e891-e901. 1975;43(1):45-57. Using four key input parameters of two types of error (\(\alpha , \beta\)) and two hypothesis rates of unacceptable maximum response rate of historical control (\({p}_{0}\)) and acceptable minimum response rate of study expectation (\({p}_{1}\)), we can implement the sample size calculation of the two-stage designs. 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. The two-stage design tests efficacy using the number of responses at the end of first stage of the trial and only if an efficacy threshold is met can the trial proceed to the second stage. 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. Except for three clinical trials that didnt provide the methods used, almost all articles were Simons two-stage designs (n=23, 90%). 2012;11(3):2419. BMJ. 2013;33(4):165760. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. J Neurooncol. 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. 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