single arm phase 2 trial

Oncol Lett. 8600 Rockville Pike Figure1 shows flow diagram (PRIMA) of the literature search and study selection process. 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. Systemic Therapy Approaches for Breast Cancer Brain and Leptomeningeal Metastases. 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. Lassen U, et al. Clin Cancer Res. Perspect Clin Res. Before 2022 May;169:107420. doi: 10.1016/j.csda.2021.107420. Before https://doi.org/10.1186/s12874-022-01810-7, DOI: https://doi.org/10.1186/s12874-022-01810-7. 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]. Please check for further notifications by email. 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. Pharm Stat. OPTIM-ARTSAn adaptive phase II open platform trial design with application to a metastatic melanoma study. Taylor JW, et al. J Neurooncol. 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 2022 Sep;11(9):3349-3356. doi: 10.21037/tcr-22-1211. 2021;39(1):22631. Epub 2020 Jun 5. 2014;30(12):205161. WebThe SAUL study has been published. Hematology Am Soc Hematol Educ Program. WebZhao, Y., Zhang, X., Jin, C.X., et al. 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. 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. J Clin Oncol. 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]. 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. Secondary objectives included toxicity, response rate and time to intracranial or extracranial disease progression. 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]. Finally, we can calculate the expected sample sizes of \({n}_{1}\) or \(n\) with a true response rate of the experimental therapy since the sample size of \({n}_{1}\) and \(n\) are random variables [6, 12, 17]. Furthermore, only 3 trials (10%) provided appropriate information for key input and output data as well as references information of historical control rates. This implies that most brain tumor clinical trials are at high risk with great uncertainty in trial outcomes. Simon R. Optimal two-stage designs for phase II clinical trials. Eur J Cancer. 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 Pellegatta S, et al. Their composite endpoint model provides efficiency while still maintaining the clinical relevance of OS. 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. Neurosurg. Qin F, et al. Epub 2018 Jul 29. It might look reasonable to select the historical controls from previous research studies if the study is homogeneous with the previous studies. Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. eCollection 2019 Jul 2. 1800 M Street NW, Suite 1050 South,Washington, DC 20036Phone: (202) 944-6700. 2013;33(4):165760. doi: 10.1371/journal.pone.0246448. Due to duplicates (n=10), 71 articles were eligible to assess. J Neurooncol. And 7 trials were used with (1) 5% and 20% (2) 10% and 10% as their type 1 and 2 errors respectively. 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. Among appropriately implemented 12 trials, discouragingly only 3 trials (10%) explained the reference information of historical control rates. 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. BMC Med Res Methodol 22, 327 (2022). 2013;113(1):12734. 2007;7(6):32534. 2016;43(1):138. 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. 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]. Cancer immunotherapy trial design with random delayed treatment effect and cure rate. Disclaimer, National Library of Medicine Accessibility 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. Neuro Oncol. eCollection 2021. Front Oncol. 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. Oncotarget. 2011;18(11):14448. In Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. Google Scholar. Interpretation: Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. The outcomes of simulation are depicted in Fig. J Neurooncol. Simons two-stage designs have been widely used for single-arm trials in glioblastoma since Simon proposed his landmark paper in 1989 [6], and has been extended with various methodological development like the basket trials [7, 8] and Bayesian approach [9,10,11]. 2019;144(2):4037. 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 To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Stat Biopharma Res. 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. 2018 Sep;17(5):541-554. doi: 10.1002/pst.1878. For instance, Silvani et al. JAMA. Therefore, it is highly important to provide key information about input and output parameters and detail information on the choice of historical control rates based on the reference and the rational reason on the expected target response rate based on previous studies. The Follow-Up period ends 2 years after End of Treatment. 2020;323(9):84453. Epub 2022 Dec 6. Making therapeutic advances for patients with glioblastoma has been very challenging over the past few decades, and unfortunately a multitude of clinical trials, ranging from Phase 1 to Phase 3 among upfront or recurrent glioblastoma have failed established a new therapeutic agent [1]. Clinical end points in recurrent glioblastoma: are antiangiogenic agents friend or foe? Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. Bayesian single-arm phase II trial designs with time-to-event endpoints. 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)? Brief Summary: An International, Single-Arm, Multicenter Phase 2 Trial. Ann Oncol. PMC The x-axis is underestimation rate of a null hypothesis and y-axis is loss of power from the power of 80%. Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis. J Neurooncol. Would you like email updates of new search results? 2013;111(2):20512. Bagley SJ, et al. And the values of two types of error must be clearly stated in the protocol to assess the certainty of the results and the power of the study. Hyun JW, Kim Y, Kim KH, Kim SH, Park EY, Youn JH, Yoo H, Gwak HS, Kim HJ. 2023 BioMed Central Ltd unless otherwise stated. 14. Cancer immunotherapy trial design with long-term survivors. End of study was approximately 8 1 weeks (57 7 days) after the first drug administration. Another option of two-stage designs is admissible design or spatial design, which came from an idea Can we find a good alternative design between the minimax and optimal design. Assuming a true rate of 28.9%, additional 10 patients are sufficient to achieve 80% power. Would you like email updates of new search results? Friends of Cancer Research is a 501 (C)(3) non-profit organization.Our tax ID number is 52-1983273. Zhou H, et al. Copyright 2022 American Society of Hematology. Ananda S, et al. Phase II study of sunitinib malate in patients with recurrent high-grade glioma. Anand S, et al. 2014;33(12):2004-2016. This single-arm phase II interventional study aims to assess disease response to, and toxicity of, a Careers. 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. Estimation of clinical trial success rates and related parameters. Burzynski SR, et al. 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. Cancer Med. MeSH Two types of errors (\(\alpha , \beta\)) are key information for all study designs. Article 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. Wong CH, Siah KW, Lo AW. Phase II trial of triple tyrosine kinase receptor inhibitor nintedanib in recurrent high-grade gliomas. J Neurooncol. Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma. Suppose a two-stage design with a type I error no larger than \({\alpha }^{*}\) and a power no smaller than (1- \({\beta }^{*}\)) for given (\({p}_{0}\), \({p}_{1}\)). Stat Med. The site is secure. Terms and Conditions, PMC 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. Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis. safety; single-stage design; tolerability; toxicity; two-stage design. 2020 Aug;26(8):1309. doi: 10.1038/s41591-020-0978-1. 2019 Dec 1;25(23):6986-6994. doi: 10.1158/1078-0432.CCR-19-0711. and transmitted securely. Glioblastoma clinical trials: current landscape and opportunities for improvement. 2017 Dec 1;35(34):3823-3829. doi: 10.1200/JCO.2017.72.5069. [37] used Simons two-stage optimal design to evaluate the target PFS6 of 35% against the null PFS6 of 20% to achieve 90% power at a 1-sided 10% level, resulting in the required sample size of 58 patients. 2021 May 6;134(11):1299-1309. doi: 10.1097/CM9.0000000000001463. Rubinstein LV, et al. Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study. Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases. 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. The site is secure. Single-arm studies have been traditionally used in Phase II oncology clinical 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. Twenty-five patients (median age, 69.0) with a median of 3 prior lines of therapy were enrolled; 24 had prior mogamulizumab treatment. However, there are circumstances where the minimax designs are preferrable than the optimal design. Copyright 2020 Friends of Cancer Research. 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). 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 .gov means its official. For instance, in Case 3, the 10% and 50% reductions of p0 are 0.45 (=0.50.9) and 0.25 (=0.50.5). Funding: 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. Kwak M, Jung S-H. Springer Nature. doi: 10.1016/S2352-3026(22)00072-2. PubMedGoogle Scholar. Eastern Cooperative Oncology Group. Eltarhoni K, Kamel F, Ihebunezie K, Nisar P, Soloviev M. Int J Mol Sci. Read our, ClinicalTrials.gov Identifier: NCT04560166, Interventional This systematic review has some limitations. 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. Thall PF, Simon R. Incorporating historical control data in planning phase II clinical trials. Disease population was categorized into three diseases of glioblastoma (n=20), high-grade glioma (n=8), and brain metastasis from glioblastoma (n=1), two settings of recurrent status (n=23) and newly diagnosed status (n=6), two patient types of adults (n=23) and child or pediatric (n=6), and two therapeutic drug types of single (n=17) and combination (n=12). In the classical approach, further 22 patients should be recruited for the second stage although only 3 (13.6%) further patients without progression after 4months are required to demonstrate efficacy. Comput Stat Data Anal. Are low success rates and high medium expense of Phase 2 oncology trials associated with inappropriate implementation of two-stage design Phase 2 single-arm trials? CNS Drugs. Sort by Weight Alphabetically Medicine and Dentistry Patient This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. Leptomeningeal carcinomatosis. Semin Oncol. We can see that four and twelve studies utilized Simons minimax and optimal designs respectively, in Table 1. 2021 Jan;20(1):117-128. doi: 10.1002/pst.2060. In this manner, the two-stage designs allow stopping of a futile trial early. How low levels for both errors are low enough to be a good design? 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 (\({p}_{0}, {p}_{1}\)). In the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. 2019 Jul 2;10(42):4255-4261. doi: 10.18632/oncotarget.26981. 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. Neurology 33, 15651572 (1983). BMC Med Res Methodol. Dhakal A, Van Swearingen AED, O'Regan R, Anders CK. FOIA Based on this, we tested the activity and safety of alternate-day dosing of 4 mg pomalidomide on a 28/28 day schedule in a multicenter, open-label phase 2 trial 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]. TACE-HAIC Plus Lenvatinib for Patients With Unresectable HCC: an Open-label, Single-arm, Phase 2 Trial (Thalen) The safety and scientific validity of this study Loss of power according to the underestimation rate of a null hypothesis (p0) when a single-arm single-stage design is used for a binary endpoint Under 80% of power and 5% of one-sided Type 1 error rate. The https:// ensures that you are connecting to the 7]); 35 had complete response and 35 had partial response. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. 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. 2008;14(12):367582. volume22, Articlenumber:327 (2022) Multistage designs for phase II clinical trials: statistical issues in cancer research. Epub 2020 Sep 1. 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. Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: a phase II study. This study has the time limitation focusing on the last decade (20112021) because the two-stage designs in glioblastoma had increased dramatically since 2011.

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