{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:11:14Z","timestamp":1779927074262,"version":"3.53.1"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T00:00:00Z","timestamp":1623110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002491","name":"Bristol-Myers Squibb","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002491","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Treatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg\/m<jats:sup>2<\/jats:sup>\/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon\u2019s Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3\/4 adverse event.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Treatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p><jats:uri>ClinicalTrials.gov<\/jats:uri>, identifier NCT03257631; EudraCT, identifier 2016-002903-25.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2021.660892","type":"journal-article","created":{"date-parts":[[2021,6,8]],"date-time":"2021-06-08T13:31:35Z","timestamp":1623159095000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Phase 2 Study of Pomalidomide (CC-4047) Monotherapy for Children and Young Adults With Recurrent or Progressive Primary Brain Tumors"],"prefix":"10.3389","volume":"11","author":[{"given":"Jason","family":"Fangusaro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giuseppina","family":"Cefalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Luisa","family":"Garr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynley V.","family":"Marshall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maura","family":"Massimino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bouchra","family":"Benettaib","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noha","family":"Biserna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Poon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackie","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin","family":"Conlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Lewandowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathew","family":"Simcock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neelum","family":"Jeste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren R.","family":"Hargrave","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Doz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine E.","family":"Warren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"key":"B1","unstructured":"SocietyTAC Key Statistics for Brain and Spinal Cord Tumors in Children2018"},{"key":"B2","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.cppeds.2011.12.002","article-title":"Brain tumors in children","volume":"42","author":"Fleming","year":"2012","journal-title":"Curr Probl Pediatr Adolesc Health Care"},{"key":"B3","doi-asserted-by":"publisher","first-page":"x1","DOI":"10.1093\/neuonc\/nou327","article-title":"Alex\u2019s Lemonade Stand Foundation infant and childhood primary brain and central nervous system tumors diagnosed in the United States in 2007-2011","volume":"16","author":"Ostrom","year":"2015","journal-title":"Neuro Oncol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"v1","DOI":"10.1093\/neuonc\/nos218","article-title":"CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009","volume":"14","author":"Dolecek","year":"2012","journal-title":"Neuro Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1177\/0883073809341668","article-title":"Medulloblastoma","volume":"24","author":"Dhall","year":"2009","journal-title":"J Child Neurol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1177\/0883073809339212","article-title":"Ependymoma: an update","volume":"24","author":"Zacharoulis","year":"2009","journal-title":"J Child Neurol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/0883073809338960","article-title":"Pediatric high-grade gliomas and diffuse intrinsic pontine gliomas","volume":"24","author":"Fangusaro","year":"2009","journal-title":"J Child Neurol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e0209193","DOI":"10.1371\/journal.pone.0209193","article-title":"Late vertebral side effects in long-term survivors of irradiated childhood brain tumor","volume":"13","author":"Jussila","year":"2018","journal-title":"PloS One"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.05.009","article-title":"Towards immunotherapy for pediatric brain tumors","volume":"40","author":"Wang","year":"2019","journal-title":"Trends Immunol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1007\/s00381-010-1385-6","article-title":"Morbidity and tumor-related mortality among adult survivors of pediatric brain tumors: a review","volume":"27","author":"Vinchon","year":"2011","journal-title":"Childs Nerv Syst"},{"key":"B11","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.ejpn.2009.12.006","article-title":"Long-term survivors of childhood central nervous system malignancies: the experience of the Childhood Cancer Survivor Study","volume":"14","author":"Armstrong","year":"2010","journal-title":"Eur J Paediatr Neurol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1037\/a0016674","article-title":"Neurocognitive status in long-term survivors of childhood CNS malignancies: a report from the Childhood Cancer Survivor Study","volume":"23","author":"Ellenberg","year":"2009","journal-title":"Neuropsychology"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1177\/0883073809341709","article-title":"Late effects of therapy for pediatric brain tumor survivors","volume":"24","author":"Turner","year":"2009","journal-title":"J Child Neurol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11095","article-title":"Endocrine and cardiovascular late effects among adult survivors of childhood brain tumors: Childhood Cancer Survivor Study","volume":"97","author":"Gurney","year":"2003","journal-title":"Cancer"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-314278","article-title":"IMiD immunomodulatory compounds block C\/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM","volume":"117","author":"Li","year":"2011","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-2317","article-title":"Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells","volume":"67","author":"Verhelle","year":"2007","journal-title":"Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.048496","article-title":"Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs","volume":"305","author":"Schafer","year":"2003","journal-title":"J Pharmacol Exp Ther"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.12708","article-title":"Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4CRBN","volume":"164","author":"Gandhi","year":"2014","journal-title":"Br J Haematol"},{"key":"B19","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.163.1.380","article-title":"Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha","volume":"163","author":"Corral","year":"1999","journal-title":"J Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2005.25.604","article-title":"Immunomodulatory drugs (IMiDs) increase the production of IL-2 from stimulated T cells by increasing PKC-theta activation and enhancing the DNA-binding activity of AP-1 but not NF-kappaB, OCT-1, or NF-AT","volume":"25","author":"Payvandi","year":"2005","journal-title":"J Interferon Cytokine Res"},{"key":"B21","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1016\/j.mvr.2008.08.003","article-title":"The anti-cancer drug lenalidomide inhibits angiogenesis and metastasis via multiple inhibitory effects on endothelial cell function in normoxic and hypoxic conditions","volume":"77","author":"Lu","year":"2009","journal-title":"Microvasc Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.9.4082","article-title":"Thalidomide is an inhibitor of angiogenesis","volume":"91","author":"D\u2019Amato","year":"1994","journal-title":"Proc Natl Acad Sci USA"},{"key":"B23","article-title":"S-3-Amino-phthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice","volume":"62","author":"Lentzsch","year":"2002","journal-title":"Cancer Res"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e71754","DOI":"10.1371\/journal.pone.0071754","article-title":"Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models","volume":"8","author":"Li","year":"2013","journal-title":"PloS One"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.31.3601","article-title":"Phase I trial of lenalidomide in pediatric patients with recurrent, refractory, or progressive primary CNS tumors: Pediatric Brain Tumor Consortium study PBTC-018","volume":"29","author":"Warren","year":"2011","journal-title":"J Clin Oncol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"e28756","DOI":"10.1002\/pbc.28756","article-title":"Phase 1 study of pomalidomide in children with recurrent, refractory, and progressive central nervous system tumors: A Pediatric Brain Tumor Consortium trial","volume":"68","author":"Fangusaro","year":"2021","journal-title":"Pediatr Blood Cancer"},{"key":"B27","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s11060-018-2791-y","article-title":"Phase I trial of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory central nervous system tumors","volume":"138","author":"Robison","year":"2018","journal-title":"J Neurooncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1172\/JCI137181","article-title":"Immune profiling of pediatric solid tumors","volume":"130","author":"Terry","year":"2020","journal-title":"J Clin Invest"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3171\/2018.9.PEDS18419","article-title":"Impact of the H3K27M mutation on survival in pediatric high-grade glioma: a systematic review and meta-analysis","volume":"23","author":"Lu","year":"2018","journal-title":"J Neurosurg Pediatr"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.08.024","article-title":"Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma","volume":"22","author":"Sturm","year":"2012","journal-title":"Cancer Cell"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.31583","article-title":"Advances in the classification of pediatric brain tumors through DNA methylation profiling: From research tool to frontline diagnostic","volume":"124","author":"Kumar","year":"2018","journal-title":"Cancer"},{"key":"B32","doi-asserted-by":"publisher","first-page":"eaaw0064","DOI":"10.1126\/scitranslmed.aaw0064","article-title":"Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening","volume":"11","author":"Lin","year":"2019","journal-title":"Sci Transl Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"e0173507","DOI":"10.1371\/journal.pone.0173507","article-title":"Enhancement of pomalidomide anti-tumor response with ACY-241, a selective HDAC6 inhibitor","volume":"12","author":"North","year":"2017","journal-title":"PloS One"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.Am2017-5060","article-title":"Abstract 5060: Activity of the EZH2 inhibitor tazemetostat as a monotherapy and in combination with multiple myeloma therapies in preclinical models","volume":"77","author":"Drew","year":"2017","journal-title":"Cancer Res"},{"key":"B35","doi-asserted-by":"publisher","first-page":"29","DOI":"10.20517\/2347-8659.2018.35","article-title":"Immunotherapy for pediatric brain tumors","volume":"5","author":"Landi","year":"2018","journal-title":"Neuroimmunol Neuroinflamm"},{"key":"B36","doi-asserted-by":"publisher","first-page":"10504","DOI":"10.1200\/JCO.2017.35.15_suppl.10504","article-title":"A phase II prospective study of selumetinib in children with recurrent or refractory low-grad glioma (LGG): a pediatric brain tumor consortium (PBTC) study","volume":"35","author":"Fangusaro","year":"2017","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.660892\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T17:24:09Z","timestamp":1699118649000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.660892\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,8]]},"references-count":36,"alternative-id":["10.3389\/fonc.2021.660892"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.660892","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,8]]},"article-number":"660892"}}