Cerebrospinal fluid neurofilament light chain as a potential prognostic biomarker for leptomeningeal metastasis. 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. 2022;14(3):28394. Cancer immunotherapy trial design with cure rate and delayed treatment effect. 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. The https:// ensures that you are connecting to the 2004;60(2):48290. Drugs. 2013;33(4):165760. J Neurooncol. Design issues of randomized phase II trials and a proposal for phase II screening trials. 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. Alternatively, novel surrogates can be used instead of RR and PFS6. 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. Phase 0 clinical trials: recommendations from the task force on methodology for the development of innovative cancer therapies. BMC Med Res Methodol. Furthermore, all trials except one trial did not explain how they chose the acceptable response rate. 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. eCollection 2019 Jul 2. Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04560166. 2022 Feb 20;41(4):786-797. doi: 10.1002/sim.9258. Pharm Stat. The primary endpoint was safety. We systematically reviewed published single-arm two-stage Phase 2 trials for patients with glioblastoma and high-grade gliomas (including newly diagnosed or recurrent). J Neurooncol. 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. Disclaimer, National Library of Medicine 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. HHS Vulnerability Disclosure, Help IEAC-assessed median DOR was not reached (NR; 95% CI, 1.87 months to NR). Intraventricular methotrexate therapy of leptomeningeal metastasis from breast carcinoma. 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. Bethesda, MD 20894, Web Policies Treatment-emergent adverse events with a fatal outcome occurred in eight (6%) of 145 patients; none were considered related to loncastuximab tesirine. 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. 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. Modified Simon's minimax and optimal two-stage designs for single-arm phase II cancer clinical trials. Dhakal A, Van Swearingen AED, O'Regan R, Anders CK. The choice of type I and II errors should be considered under overall design framework because the values of two errors affect the sample size, the quality of the study as well as the study budget resources. Second, if the patient accrual rate is low, the minimax design is more attractive because it requires the smaller number of patients in total (n). The 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]. The site is secure. 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. Murgo AJ, et al. Bendamustine treatment of Chinese patients with relapsed indolent non-Hodgkin lymphoma: a multicenter, open-label, single-arm, phase 3 study. Cancer 124, 2135 (2018). Epub 2020 Jun 5. An International, Single-Arm, Multicenter Phase 2 Trial. 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. 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. Sanai N. Phase 0 clinical trial strategies for the neurosurgical oncologist. WebThis multicenter phase 2 trial (NCT04102150; https://clinicaltrials.gov/ct2/show/NCT04102150; DS3201-A-J201) enrolled patients with Vanderbeek AM, et al. eCollection 2020 Dec. BMC Med Res Methodol. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. Compressing drug development timelines in oncology using phase 0 trials. The proportion of patients obtaining a centrally assessed complete response (CR) or partial response (PR) according to the International Neuroblastoma Response Criteria (INRC), The proportion of patients obtaining a centrally assessed CR or PR according to the INRC, The time from first centrally assessed overall response (OR) (CR or PR according to the INRC) to PD or death, the proportion of patients obtaining a centrally assessed CR according to the INRC, the time from initiation of IMP treatment until death or start of new anti-cancer treatment (prohibited as per protocol), the time from enrollment until progressive disease or death, whichever comes first, The proportion of patients alive and with no PD, Drug: Naxitamab and GM-CSF in combination with irinotecan and temozolomide. Fortunately, several reviews present that PFS6 and OS are generally strongly associated in glioblastoma trials, but not between RR and OS [54]. 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. PLoS One. Epub 2017 May 24. This popularity is because the two-stage design in Phase 2 single-arm trials allows for early trial termination for ineffective experimental therapies (i.e., futility). 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. 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 (\({p}_{0}, {p}_{1}\)). [56] proposed modified PFS (mPFS) for immune-oncology trials. Eur J Cancer. FOIA Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme. Zhou H, Lee JJ, Yuan Y. BOP2: Bayesian optimal design for phase II clinical trials with simple and complex endpoints. Right implementation for two-stage design and sample size calculation, transparency of historical control and experimental rates, appropriate selection on primary endpoint, potential incorporation of adaptive designs, and utilization of Phase 0 paradigm might help overcoming the challenges on glioblastoma therapeutic trials in Phase 2 trials. Unable to load your collection due to an error, Unable to load your delegates due to an error. This site needs JavaScript to work properly. Eastern Cooperative Oncology Group. Oncol. 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 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]. Le Rhun, E. et al. Current Status of Novel Agents for the Treatment of B Cell Malignancies: What's Coming Next? 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. 2019;85:105807. The most widely used endpoints were PFS6 (n=18) and ORR (n=8) in Phase 2 single-arm trials. Ananda S, et al. Stat Biopharma Res. Efficacy and safety of nimotuzumab in addition to radiotherapy and temozolomide for cerebral glioblastoma: a phase II multicenter clinical trial. 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. Disclaimer, National Library of Medicine Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. 1975;43(1):45-57. 2021;372:n160. And 7 trials were used with (1) 5% and 20% (2) 10% and 10% as their type 1 and 2 errors respectively. Finkelstein DM, Muzikansky A, Schoenfeld DA. 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)? Gehan EA. Phase II trials in journal of clinical oncology. Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases. Fifty-six of the 70 (80%) participants became desensitized to peanuts. Biometrics. Bayesian hierarchical modeling of patient subpopulations: efficient designs of Phase II oncology clinical trials. 2014;1(2):345. Using 2014;33(12):2004-2016. A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. J Neurooncol. Two types of errors (\(\alpha , \beta\)) are key information for all study designs. 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]. Optimal, minimax and admissible two-stage design for phase II oncology clinical trials. 2015;121(2):297302. MS reports grants from ADC Therapeutics, during the conduct of the study; and personal fees from Amgen and Celgene, outside of the submitted work. 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]. Biometrics. Racine-Poon A, et al. 2022;169:107420. Clin Cancer Res. J. Clin. Webmultiple myeloma: a multicenter, single-arm phase 2 trial Thilo Zander 1, Thomas Pabst 2, Smi Schr 3, Stefan Aebi 1,2, Ulrich Mey 4, Urban Novak2, Erika Lerch 5, Galle Rhyner Agocs 6, We evaluated the efficacy and safety of valemetostat, a potent EZH1 and EZH2 inhibitor, in treating relapsed/refractory (R/R) ATL. 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. 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. 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. Article Diagnosis and treatment patterns for patients with leptomeningeal metastasis from solid tumors across Europe. Berry SM, et al. 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. MeSH 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 sharing sensitive information, make sure youre on a federal J. Neurooncol. Valemetostat demonstrated promising efficacy and tolerability in heavily pretreated patients, warranting further investigation in treating R/R ATL. We enrolled patients aged 18 years with HER2-positive breast cancer and newly WebIn the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. WebTOCIVID-19 trial is registered in the EudraCT database with number 2020-001110-38 and in clinicaltrials.gov with ID NCT04317092. 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. J Neurooncol. 2020 Jul;21(7):978-988. doi: 10.1016/S1470-2045(20)30225-4. End of study was approximately 8 1 weeks (57 7 days) after the first drug administration. Refining Therapy in Patients with HER2-Positive Breast Cancer with Central Nervous System Metastasis. 2021 Oct 12;12(1):5954. doi: 10.1038/s41467-021-25859-y. Multistage designs for phase II clinical trials: statistical issues in cancer research. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial Summary 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. 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. Due to duplicates (n=10), 71 articles were eligible to assess. 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 When there is uncertainty among endpoints as a surrogate for OS, several primary endpoints can be employed together. 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)). Neuro Oncol. 1996 Oct;74(8):1317-20. doi: 10.1038/bjc.1996.537. FOIA WebThe trial ended after accrual completion; the database lock was Dec 31, 2019. Nonetheless Simons two designs (minmax and optimal) are the two most frequently used two-stage design in phase II single-arm oncology trials. Cancer Med. Please check for further notifications by email. CNS Drugs. Friends of Cancer Research is a 501 (C)(3) non-profit organization.Our tax ID number is 52-1983273. Weighted log-rank test for time-to-event data in immunotherapy trials with random delayed treatment effect and cure rate. Di Nunno V, et al. Please enable it to take advantage of the complete set of features! Cite this article. Terms and Conditions, Overly optimistic results obtained from Phase 2 trials might be a major reason of negative Phase 3 results in randomized studies. 2023 Jan;37(1):45-67. doi: 10.1007/s40263-022-00975-5. Stat Med. 2021 Jan;20(1):117-128. doi: 10.1002/pst.2060. Santoni M, et al. 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. 2018;74(2):529-537. For instance, in Case 3, the 10% and 50% reductions of p0 are 0.45 (=0.50.9) and 0.25 (=0.50.5). -, Grossman, S. A. et al. Accessibility in Central Nervous System Metastasis, the Biological Basis and Clinical Consideraiton (ed. OPTIM-ARTSAn adaptive phase II open platform trial design with application to a metastatic melanoma study. Pellegatta S, et al. Evaluation of two-stage designs of Phase 2 single-arm trials in glioblastoma: a systematic review, https://doi.org/10.1186/s12874-022-01810-7, Two-stage design of phase 2 single-arm trials in glioblastoma, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, bmcmedicalresearchmethodology@biomedcentral.com. JAMA. 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. Secondary endpoints included best response in disease compartments, duration of response (DOR), pharmacokinetics, and safety. The https:// ensures that you are connecting to the However, it is important that efficient and valid study designs be applied successfully and adequately to reach the aims of phase 2 oncology trials. official website and that any information you provide is encrypted Read our, ClinicalTrials.gov Identifier: NCT04560166, Interventional We conducted a single-arm, phase 2 study of pembrolizumab in patients with solid tumor malignancies and LMD (NCT02886585). Curr Treat Options Oncol. Epub 2021 Oct 17. We evaluated the efficacy and safety of valemetostat, a potent EZH1 and EZH2 inhibitor, in treating relapsed/refractory (R/R) ATL. A systematic review of surrogate endpoints (SEPs) for overall survival (OS) in metastatic colorectal cancer mCRC. Fleming TR. A Phase I Study of ADCT-402 (Loncastuximab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma. 2011;11(5):65760. Ivy Brain Tumor Center, Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, 85013, USA, Karmanos Cancer Institute, Department of Oncology, School of Medicine, Wayne State University, Detroit, MI, 48201, USA, Department of Radiation Oncology, Barrow Neurological Institute, Phoenix, AZ, 85013, USA, You can also search for this author in 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. and transmitted securely. Shaverdian N, Lisberg AE, Bornazyan K, Veruttipong D, Goldman JW, Formenti SC, Garon EB, Lee P. Lancet Oncol. FOIA Most trials (90%) used Simons two-stage designs. Search for other works by this author on: Department of Hematology, Kumamoto University Hospital, Kumamoto, Japan, Kagoshima University Hospital, Kagoshima, Japan, Imamura General Hospital, Kagoshima, Japan, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, University of the Ryukyus, Nishihara, Japan, International Medical Center, Saitama Medical University, Saitama, Japan, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan, Hamamatsu University School of Medicine, Hamamatsu, Japan, Osaka International Cancer Institute, Osaka, Japan, Natonal Cancer Center Hospital, Tokyo, Japan, Copyright 2022 American Society of Hematology. Epub 2020 Sep 1. WebAn increasing fraction of patients with metastatic cancer develop leptomeningeal dissemination of disease (LMD), and survival is dismal 1-3. Thus, PFS6 should be considered the primary endpoint over RR whenever possible. Twenty patients-17 with breast cancer, two with lung cancer and one with ovarian cancer-were enrolled into the pre-specified evaluation group having received at least one dose of pembrolizumab. 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. BMJ. WebZhao, Y., Zhang, X., Jin, C.X., et al. Findings: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 2013;111(2):20512. By using this website, you agree to our Would you like email updates of new search results? 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. 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 Childs Nerv Syst. 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. J Cancer. For instance, Silvani et al. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. 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. 2011;105(3):52330. Except for three clinical trials that didnt provide the methods used, almost all articles were Simons two-stage designs (n=23, 90%). Rai SN, Ray H, Pan J, Barnes C, Cambon AC, Wu X, Bonassi S, Srivastava DK. doi: 10.1371/journal.pone.0271094. Adult T-cell leukemia/lymphoma (ATL) is an aggressive non-Hodgkin lymphoma with poor prognosis and few treatment options for patients with relapsed, recurrent, or refractory disease. 2019 Jul 2;10(42):4255-4261. doi: 10.18632/oncotarget.26981. The other three trials used two-stage designs like Inadmissible design, Fleming and Gehan designs. Wang Z-X, et al. The Bayesian basket design for genomic variant-driven phase II trials. Suh CH, et al. 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. The underestimation rate of p0 was ranged from 0.1 (i.e., 10% reduction) to 0.5 (i.e., 50% reduction). Would you like email updates of new search results? (Clinical Trial). 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. Lassen U, et al. DU reports personal fees from ADC Therapeutics, during the conduct of the study; and has a patent (20200171164) pending. 2012;4(4):799801. These factors are recommended to be considered carefully when planning a Phase 2 single-arm study. 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. 2019;93(19):1799806. Only three studies have been completed for both stages and two out of the three completed studies had shown the efficacy. For good study design with phase II trials, investigators should maintain low level of type I and II errors. 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. BMC Med Res Methodol 22, 327 (2022). Publisher Correction: Single-arm, open-label phase 2 trial of pembrolizumab in patients with leptomeningeal carcinomatosis. Phase 0 clinical trials in cancer drug development: from FDA guidance to clinical practice. Please remove one or more studies before adding more. Please enable it to take advantage of the complete set of features! Oncotarget. 2001 May;32(2):155-62. doi: 10.1016/s0169-5002(00)00220-8. 2022 Dec;17(6):524-532. doi: 10.1159/000526431. 2017 Jul;18(7):895-903. doi: 10.1016/S1470-2045(17)30380-7. 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]. (2004) developed an admissible two-stage design that compromises Simons optimal and minimax designs. Hematology Am Soc Hematol Educ Program. WebDive into the research topics of 'MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial'. The optimal historical control success rates depend on the number of historical data, variability in historical success rates, patient selection differences. Phase II open-label study of nintedanib in patients with recurrent glioblastoma multiforme. Combining progression-free survival and overall survival as a novel composite endpoint for glioblastoma trials. Simons optimal design for a one-sided significance level of 0.05 and a power of 0.80 includes 11 patients in the first stage. HHS Vulnerability Disclosure, Help Nat Med. Hu J, et al. By doing so, the chance to capture the effectiveness of a treatment can be increased. 2022 Nov;82(16):1621-1627. doi: 10.1007/s40265-022-01800-5. Please enable it to take advantage of the complete set of features! 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.
Why Does Kayce Dutton Have A Brand, Articles S