single arm phase 2 trialsingle arm phase 2 trial

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 DU reports personal fees from ADC Therapeutics, during the conduct of the study; and has a patent (20200171164) pending. Eastern Cooperative Oncology Group. Copyright 2022 American Society of Hematology. [56] proposed modified PFS (mPFS) for immune-oncology trials. Expert Rev Anticancer Ther. Epub 2015 Apr 1. The Follow-Up period ends 2 years after End of Treatment. Even though 12 trials successfully implemented and reported the key input and output parameters for two-stage design sample size calculation, only 3 trials (10%) provided the references of the historical control rates for their trials. Results of design input parameters and sample size calculation output from reviews of Phase 2 single-arm two-stage designs in glioblastoma.

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. 2015;121(3):55763. Kwak M, Jung S-H. Bethesda, MD 20894, Web Policies Due to duplicates (n=10), 71 articles were eligible to assess. Vanderbeek AM, et al. Curr Treat Options Oncol. Muhic A, et al. 1975;43(1):45-57.

official website and that any information you provide is encrypted CAS Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. This site needs JavaScript to work properly. 2022;14(3):28394. 2020 Aug;26(8):1309. doi: 10.1038/s41591-020-0978-1. Epub 2018 Jul 29. Due to economical and ethical reasons, the two-stage designs have been widely used for Phase 2 single-arm trials in oncology because the designs allow us to stop the trial early if the proposed treatment is likely to be ineffective. PubMedGoogle Scholar. MeSH Refining Therapy in Patients with HER2-Positive Breast Cancer with Central Nervous System Metastasis. 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. Expert Rev Anticancer Ther. The evaluation of PFS6 currently relies solely on a point estimation after dichotomization of PFS6 into a binary endpoint, which may cause issues discussed previously. Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed or refractory follicular lymphoma: a cohort of a multicentre, single-arm, phase 1b/2 study. Cite this article. Such an unexpected situation cannot be appropriately handled with the current system of two-stage designs because current designs require to prespecify the design information like sample size for each stage and stopping rules in the study protocol. Bethesda, MD 20894, Web Policies Example of Adaptive Design to handle the uncertainty for Phase 2 two-stage design. An official website of the United States government. J Neurooncol. Breslow NE.

We study the relationship between a two-stage design with a safety endpoint and an efficacy endpoint and use simulation studies to ascertain their properties. Bagley SJ, et al. Protracted low doses of temozolomide for the treatment of patients with recurrent glioblastoma: a phase II study. Clipboard, Search History, and several other advanced features are temporarily unavailable. MeSH government site. Treatment-emergent adverse events (TEAEs) were manageable. sharing sensitive information, make sure youre on a federal 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. official website and that any information you provide is encrypted Brief Summary: An International, Single-Arm, Multicenter Phase 2 Trial. Adaptive two-stage designs in phase II clinical trials. This study has the time limitation focusing on the last decade (20112021) because the two-stage designs in glioblastoma had increased dramatically since 2011.

Invest New Drugs. eCollection 2022 Dec. Transl Cancer Res. WebClinical Trials A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants with Previously Treated Glioblastoma 2010;28(11):193641. Reference curve sampling variability in one-sample log-rank tests. Among 29 Phase 2 single-arm trials, 23 trials (79%) used Simons two-stage designs, three trials used other two-stage designs (Gehan, Fleming and admissible design each), and 3 trials just mentioned two-stage design without specific design information. and transmitted securely. Federal government websites often end in .gov or .mil. 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.

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PMC 2019;93(19):1799806. mPFS does not include the events of disease progression but include the events of death within 3months after randomization. 2001 May;32(2):155-62. doi: 10.1016/s0169-5002(00)00220-8. Federal government websites often end in .gov or .mil. 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. 2018;7(4):e1412901. Only three trials (11%) provided key input parameters, appropriately reported output results from sample size calculation of two-stage designs, and finally provided the reference and explanation of historical control rates. 14. Phase II trials in journal of clinical oncology. Lin Y, Shih WJ. A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. 2021 Jan;20(1):117-128. doi: 10.1002/pst.2060. Valemetostat 200 mg orally once daily demonstrated promising efficacy and manageable toxicity in heavily pretreated patients. Int Stat Rev/Revue Int de Stat. Results. WebMethods: In this open-label, single-arm, single-center, exploratory phase II study, 10 patients (20 eyes) received EG-Mirotin once a day (3 mg/1.5 mL sterile saline) for 5 days Yoo, W., Kim, S., Garcia, M. et al. Before 2011;2(1):1322. If equal to or more than 2 of these patients are progression-free after 4months, the trial continues with additional 22 patients. The outcomes of simulation are depicted in Fig. Phase II clinical trials: issues and practices.

Please enable it to take advantage of the complete set of features! Google Scholar. 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.

Survival gain in glioblastoma patients treated with dendritic cell immunotherapy is associated with increased NK but not CD8(+) T cell activation in the presence of adjuvant temozolomide. Patients received valemetostat 200 mg/day until progressive disease or unacceptable toxicity. and transmitted securely. Stat Med. Bookshelf Clin Trials. Eur J Cancer. MeSH Neuro Oncol. 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. Loncastuximab tesirine has substantial single-agent antitumour activity and produces durable responses with an acceptable safety profile, potentially offering a new therapeutic option for heavily pretreated patients with relapsed or refractory DLBCL. Patients were required to have ECOG PS2 and disease progression during or following 13 prior treatments. Pasqualini C, et al. A common practice in sample size calculation is 2013;33(4):165760. Since the two-stage design of Phase 2 trials aims to make a conclusion of go or no-go to the next second stage, the sample size calculation of two-stage designs produces the number of patients in first stage (\({n}_{1}\)) and the response number which is eligible to move to the second stage (\({r}_{1}\)). Epub 2019 Feb 11. Brastianos PK, Lee EQ, Cohen JV, Tolaney SM, Lin NU, Wang N, Chukwueke U, White MD, Nayyar N, Kim A, Alvarez-Breckenridge C, Krop I, Mahar MK, Bertalan MS, Shaw B, Mora JL, Goss N, Subramanian M, Nayak L, Dietrich J, Forst DA, Nahed BV, Batchelor TT, Shih HA, Gerstner ER, Moy B, Lawrence D, Giobbie-Hurder A, Carter SL, Oh K, Cahill DP, Sullivan RJ.

The percentage of patients who experienced one (or more) grade 3 or higher adverse events at least possibly related to treatment was 40%, the most frequent being hyperglycemia (n = 6), nausea (n = 7) and vomiting (n = 7). BMC Medical Research Methodology WebTOCIVID-19 trial is registered in the EudraCT database with number 2020-001110-38 and in clinicaltrials.gov with ID NCT04317092. Epub 2020 Jun 5. The primary endpoint was safety. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial Summary 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. 2012;11(3):2419. 2020 Nov 28;20:100678. doi: 10.1016/j.conctc.2020.100678. 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. View this study on Beta.ClinicalTrials.gov, Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Interpretation: 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.

The followings were key words for the literature search as index terms or free-text words: phase II trials, glioblastoma, and two-stage design.

Epub 2016 Sep 30. Cookies policy. PMC Using the cumulative binomial probability distribution, we could find the probability that the number of progression-free patients are three or more in the second stage was 0.4357. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. statement and The site is secure.

This implies that most brain tumor clinical trials are at high risk with great uncertainty in trial outcomes. In A total of four scenarios were examined according to null (p0) and alternative (p1) response rates such as Case 1: p0=0.1 and p1=0.3, Case 2: p0=0.3 and p1=0.5, Case 3: p0=0.5 and p1=0.7, and Case 4: p0=0.7 and p1=0.9. Lassman AB, et al. 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. Epub 2022 Jan 6. 2021 Dec;21(12):1313-1320. doi: 10.1080/14737140.2021.1988853. 2021 May 6;134(11):1299-1309. doi: 10.1097/CM9.0000000000001463. 2007;7(2):1319. Trials involving several arms, or randomized trials, treat randomly-selected groups of patients with different therapies in order to compare their medical outcomes. Careers. None Created on Jan 16, 2023 Publication details Reviews All publications My publications Add new publication Import from PubMed More Geoerger B, et al. The https:// ensures that you are connecting to the WebEVER-132-001 (NCT04454437) was a multicenter, single-arm, Phase IIb study in Chinese patients with mTNBC who failed 2 prior chemotherapy regimens. 2016 Dec;34(34):4086-4093. doi: 10.1200/JCO.2016.67.7732. 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]. Ott PA, Elez E, Hiret S, Kim DW, Morosky A, Saraf S, Piperdi B, Mehnert JM. The site is secure. Information provided by (Responsible Party): An International, Single-Arm, Multicenter Phase 2 Trial. doi: 10.1016/S2352-3026(22)00072-2. Hu J, et al. An official website of the United States government. 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. 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. The patients will receive irinotecan 50 mg/m2/day IV and temozolomide 100 mg/m2/day orally (both on Days 1-5) in combination with naxitamab 2.25 mg/kg/day IV (Days 2, 4, 8 and 10) (total 9 mg/kg per cycle), and GM-CSF 250 ug/m2/day sc, (Days 6-10). California Privacy Statement, Before Oncotarget. J Clin Oncol. Optimized image-based surrogate endpoints in targeted therapies for glioblastoma: a systematic review and meta-analysis of phase iii randomized controlled trials. 2021 Dec;8(12):e891-e901. 2019;144(2):35968. 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. This phase 2 study assessed the efficacy and safety of the dual EZH1 and EZH2 inhibitor valemetostat in patients with R/R ATL. 2019;10(14):321423. 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. Banerjee A, Tsiatis AA. Neuro Oncol. (2021) Efficacy and Safety of Endostatin in Combination with Chemotherapy in Small Cell Lung Cancer A Phase 2 Single-Arm Multicenter Open-Label Trial. 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. The .gov means its official. 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]. Among 29 reviewed articles, majority study types were glioblastoma (n=20, 69% over high-grade glioma, n=9, 31%) with recurrent patients (n=23, 79% over newly diagnosed patients, n=6 and 21%) and adult patients (n=22, 76% over pediatric population, n=7, 24%). 2011;11(5):65760. Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma. Except for three clinical trials that didnt provide the methods used, almost all articles were Simons two-stage designs (n=23, 90%). 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. Article This site needs JavaScript to work properly. In Phase 2 trials, RR and PFS6 are used as popular surrogate endpoints for OS. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until definitive progression or unacceptable toxicity. Accessibility By doing so, the chance to capture the effectiveness of a treatment can be increased. FOIA Accessibility Before 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 (\({p}_{0}, {p}_{1}\)). 2017;36(21):330214. 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. MeSH 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. The two types of errors (\(\alpha , \beta\)) and unacceptable and acceptable response rates (\({p}_{0}, {p}_{1}\)) are key input information for successful sample size calculation of two-stage design. 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. Cancer immunotherapy trial design with cure rate and delayed treatment effect. The https:// ensures that you are connecting to the 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 government site. 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. 3). In this research, we proposed a piecewise proportional hazards cure rate model with random delayed treatment effect to design single-arm phase II immunotherapy cancer trials. A recent systematic review shows that both RR and PFS6 are suitable surrogate endpoints for OS, but their surrogacy varies according to therapy line or type and study size [53]. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. Springer Nature. Let us now assume that 4 (36.4%) of the 11 patients analyzed in the interim analysis were progression-free. One-sample multiple testing procedure for phase II clinical trials. J Clin Neurosci. 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. Epub 2013 Apr 16. J Clin Oncol. 2021 Oct 12;12(1):5954. doi: 10.1038/s41467-021-25859-y. volume22, Articlenumber:327 (2022) WebThis single-arm, phase I trial evaluated NHS-IL12 12 g/kg SC q2w or 16.8g/kg SC q2w in patients with metastatic solid tumors. 2021;13(15):3750. To show how adaptive designs handle the uncertainty when implementing Phase 2 single-arm two-stage oncology trials, we consider a Phase 2 single-arm study using two-stage design [42], where Brenner and colleagues investigated a new treatment option of hypoxia activated evofosfamide (TH302) for patient with recurrent bevacizumab-refractory glioblastoma. Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. 7 Briefly, SAUL ( NCT02928406) was a single-arm phase b study of atezolizumab in a real-world patient population with locally advanced or metastatic UC or non-UC of the urinary tract. Your comment will be reviewed and published at the journal's discretion. HHS Vulnerability Disclosure, Help Cancer Med. Comput Stat Data Anal. Chamberlain MC, Johnston SK. J Neurooncol. Oncol. Epub 2022 Apr 1. All rights reserved. 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. Loncastuximab tesirine: an effective therapy for relapsed or refractory diffuse large B-cell lymphoma. Study record managers: refer to the Data Element Definitions if submitting registration or results information. Optimal, minimax and admissible two-stage design for phase II oncology clinical trials. Phase 0 clinical trials in oncology new drug development.

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis. 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. Mol Interv. 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. 2022 May;9(5):e327-e339. Stat Biopharma Res. The Bayesian basket design for genomic variant-driven phase II trials. 2004;23(4):5619. Bethesda, MD 20894, Web Policies Admissible two-stage designs for phase II cancer clinical trials. 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). Pellegatta S, et al. This systematic review has some limitations. Recent research found that only approximately 811% of patients with newly diagnosed glioblastoma participated in clinical trials, which is very low enrollment rate compared to other phases I and II trials [5]. 2006;25(19):338295. 2021 Jun;22(6):741-742. doi: 10.1016/S1470-2045(21)00191-1. Regardless that more than 75% trials mentioned all key input parameters, many studies (17/29, 59%) failed to provide at least one key output of sample size calculation results of the number of samples of both stages (\({n}_{1}, n\)) and the treatment rejection numbers of the first stage and both stages (\({r}_{1}, r\)). JAMA.

If advanced to stage 2, the number of patients in both stages (\(n\)) and the response number (\(r\)) of the efficacy for the Phase 2 trial are provided. 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. Provided by the Springer Nature SharedIt content-sharing initiative. This site needs JavaScript to work properly.

Neurosurg. The purpose of this study is to evaluate the efficacy and safety in patients with FGFR2-Rearranged unresectable or metastatic intrahepatic cholangiocarcinoma who failed prior therapy Arms and Interventions Arm: Experimental Drug ICP-192 Outcome Measures 2008;14(12):367582. A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. J Neurooncol. Palmieri, D.) 187201 (Springer, 2013). This site needs JavaScript to work properly. 2019;37(15_suppl):1820618206. Evaluating efficacy and safety of loncastuximab tesirine injection for the treatment of adult patients with relapsed or refractory large B-cell lymphoma. 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. 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.

We systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). Neurology 33, 15651572 (1983). Accessibility There was no language restriction, but only complete papers published in peer-reviewed journals were considered. Korean J Radiol. Blood 2022; blood.2022016862. An official website of the United States government. 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]. BMC Med Res Methodol. Phase II study of Dovitinib in recurrent glioblastoma. 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. 2015;121(2):297302. 2022;28(4):594602. Epub 2021 Nov 15. 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.

2015;17(7):9928. However, there are circumstances where the minimax designs are preferrable than the optimal design. Wang et al. J Neurooncol. Particularly, a recent research of the phase 2 basket trials has extended the two-stage design for multiple heterogeneous indications, which is an important tool to identify the effective drug through a generalized framework of an optimal basket design. 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. 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. Safety and efficacy of decitabine in combination with temozolomide in metastatic melanoma: a phase I/II study and pharmacokinetic analysis. 2011;18(11):14448. 2019;85(6):E96774. Warren KE, et al. Kalpathy-Cramer J, et al. National Cancer Center Hospital, Tokyo, Japan. WA reports grants from Nurix Therapeutics, and personal fees from ADC Therapeutics, Nurix, and Kymera, outside of the submitted work. 1996 Oct;74(8):1317-20. doi: 10.1038/bjc.1996.537. Comparing survival of a sample to that of a standard population. PLoS One. Treatment-emergent adverse events (TEAEs) were manageable. A treatment cycle is 21 days. The site is secure. Santoni M, et al. 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. Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis. Thus, the key input parameters (\(\alpha , \beta , {p}_{0}, {p}_{1}\)) and output results (\({n}_{1}, n, {r}_{1}, r\)) were investigated to assess the appropriate usage and report of the two-stage phase 2 trials.