{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:33:48Z","timestamp":1783384428286,"version":"3.54.6"},"reference-count":31,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Amgen Inc.","award":["486277"],"award-info":[{"award-number":["486277"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Novel therapies are needed for children, adolescents, and young adults with relapse\/refractory leukemia or solid tumors. The proteasome inhibitor carfilzomib has demonstrated pre-clinical activity against several pediatric malignancies when used alone or in combination. Therefore, a multicenter dose-escalation phase 1 study of carfilzomib administered in combination with cyclophosphamide and etoposide was conducted. Methods: Study eligibility included an age of 6 months to &lt;30 years with relapsed\/refractory leukemia (stratum A) or a relapsed\/refractory non-CNS solid tumor (stratum B), Karnofsky\/Lansky score \u2265 50, and adequate organ function. A 5-day regimen of cyclophosphamide 440 mg\/m2\/day, etoposide 100 mg\/m2\/day, and carfilzomib was administered every 28 days with growth factor support. The carfilzomib starting dose was 11 mg\/m2\/day, and dose escalation followed a rolling-six design, managed independently for each stratum. Dose-limiting toxicity (DLT) was assessed during the first cycle, and disease response was assessed after one cycle (stratum A) or two cycles (stratum B). Results: Thirty-eight patients were treated (14 in stratum A; 24 in stratum B). For stratum A, the maximum tolerated dose (MTD) for carfilzomib was 11 mg\/m2\/day. Three DLTs were observed: thrombocytopenia, pericarditis, and posterior reversible encephalopathy syndrome (PRES). Most patients received one cycle. For stratum B, an MTD was not reached. The highest dose level administered and recommended in phase 2 (RP2D) was 20 mg\/m2\/days 1\u20132 and 36 mg\/m2\/days 3\u20135 for cycle 1, then 36 mg\/m2 for days 1\u20135 of all subsequent cycles. There was a single DLT of PRES. A dose expansion for additional toxicity data was conducted. Overall, twenty patients received \u2265 2 cycles (range, 2\u201314). Conclusions: A 5-day schedule of carfilzomib\/cyclophosphamide\/etoposide was well-tolerated in patients with solid tumors. Patients with sarcomas benefited most, warranting further evaluation.<\/jats:p>","DOI":"10.3390\/cancers17172924","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T10:29:07Z","timestamp":1757327347000},"page":"2924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Phase I Study of Carfilzomib with Cyclophosphamide and Etoposide in Relapsed and Refractory Leukemia and Solid Tumors"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4251-8484","authenticated-orcid":false,"given":"Jessica","family":"Boklan","sequence":"first","affiliation":[{"name":"College of Medicine, University of Arizona, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4218-8120","authenticated-orcid":false,"given":"Anne-Marie","family":"Langevin","sequence":"additional","affiliation":[{"name":"Health Science Center at San Antonio, University of Texas, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Bielamowicz","sequence":"additional","affiliation":[{"name":"Arkansas Children\u2019s Hospital, Little Rock, AR 72202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Neville","sequence":"additional","affiliation":[{"name":"Arkansas Children\u2019s Hospital, Little Rock, AR 72202, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya","family":"Trippett","sequence":"additional","affiliation":[{"name":"Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Brown","sequence":"additional","affiliation":[{"name":"Penn State Hershey Children\u2019s Hospital, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0882-738X","authenticated-orcid":false,"given":"Steven G.","family":"DuBois","sequence":"additional","affiliation":[{"name":"Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorder Center, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Eshun","sequence":"additional","affiliation":[{"name":"Phoenix Children\u2019s Hospital, Phoenix, AZ 85016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Gelfond","sequence":"additional","affiliation":[{"name":"Health Science Center at San Antonio, University of Texas, San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ativ","family":"Zomet","sequence":"additional","affiliation":[{"name":"Stanford Cancer Institute, Lucile Packard Children\u2019s Hospital at Stanford, Stanford University, 750 Welch Rd., Ste. 224, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4898-477X","authenticated-orcid":false,"given":"Aru","family":"Narendran","sequence":"additional","affiliation":[{"name":"Alberta Children\u2019s Hospital, Calgary, AB T3B 6A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4573-5118","authenticated-orcid":false,"given":"Norman J.","family":"Lacayo","sequence":"additional","affiliation":[{"name":"Stanford Cancer Institute, Lucile Packard Children\u2019s Hospital at Stanford, Stanford University, 750 Welch Rd., Ste. 224, Palo Alto, CA 94304, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6383","DOI":"10.1158\/0008-5472.CAN-06-4086","article-title":"Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome","volume":"67","author":"Demo","year":"2007","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2657","DOI":"10.1182\/blood.V112.11.2657.2657","article-title":"Non-Proteosomal Targets of Proteasome Inhibitors Bortezomib and Carfilzomib","volume":"112","author":"Shenk","year":"2008","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"740","DOI":"10.3389\/fonc.2021.740796","article-title":"Carfilzomib: A Promising Proteasome Inhibitor for the Treatment of Relapsed and Refractory Multiple Myeloma","volume":"11","author":"Jayaweera","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1182\/blood-2012-10-459883","article-title":"Carfilzomib","volume":"121","author":"Kortuem","year":"2013","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2248","DOI":"10.1158\/1078-0432.CCR-12-3352","article-title":"Phase Ib dose-escalation study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma","volume":"19","author":"Niesvizky","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"804","DOI":"10.2174\/1568009621666210504085527","article-title":"Cytotoxicity and Target Modulation in Pediatric Solid Tumors by the Proteasome Inhibitor Carfilzomib","volume":"21","author":"Thakur","year":"2021","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2902","DOI":"10.1158\/1078-0432.CCR-05-0308","article-title":"The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide","volume":"12","author":"Smith","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"46","DOI":"10.3324\/haematol.2019.237230","article-title":"Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: A report from the Children\u2019s Oncology Group phase III study AALL0433","volume":"106","author":"Lew","year":"2021","journal-title":"Haematologica"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"480","DOI":"10.5435\/JAAOS-21-08-480","article-title":"Sarcoma chemotherapy","volume":"21","author":"Walczak","year":"2013","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7085","DOI":"10.1158\/1078-0432.CCR-09-0822","article-title":"A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies","volume":"15","author":"Stewart","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.3109\/10428194.2012.663915","article-title":"Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients","volume":"53","author":"Miano","year":"2012","journal-title":"Leuk. Lymphoma"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e29999","DOI":"10.1002\/pbc.29999","article-title":"Phase 1b study of carfilzomib with induction chemotherapy in pediatric relapsed\/refractory acute lymphoblastic leukemia","volume":"69","author":"Burke","year":"2022","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2576","DOI":"10.1200\/JCO.2000.18.13.2576","article-title":"Fractionated cyclophosphamide and etoposide for children with advanced or refractory solid tumors: A phase II window study","volume":"18","author":"Mantadakis","year":"2000","journal-title":"J. Clin. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1002\/(SICI)1097-0142(19970801)80:3<489::AID-CNCR17>3.0.CO;2-T","article-title":"A dose-intensive, cyclophosphamide-based regimen for the treatment of recurrent\/progressive or advanced solid tumors of childhood: A report from the Australia and New Zealand Children\u2019s Cancer Study Group","volume":"80","author":"Carpenter","year":"1997","journal-title":"Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1200\/JCO.2013.52.3522","article-title":"Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and\/or refractory multiple myeloma","volume":"33","author":"Papadopoulos","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1182\/blood-2014-02-556308","article-title":"A phase 2 single-center study of carfilzomib 56 mg\/m2 with or without low-dose dexamethasone in relapsed multiple myeloma","volume":"124","author":"Lendvai","year":"2014","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.3324\/haematol.2022.282225","article-title":"High-dose carfilzomib achieves superior anti-tumor activity over low-dose and recaptures response in relapsed\/refractory multiple myeloma resistant to lowdose carfilzomib by co-inhibiting the \u03b22 and \u03b21 subunits of the proteasome complex","volume":"108","author":"Zhou","year":"2023","journal-title":"Haematologica"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e30715","DOI":"10.1097\/MD.0000000000030715","article-title":"Efficacy and toxicity of carfilzomib- or bortezomib-based regimens for treatment of transplant-ineligible patients with newly diagnosed multiple myeloma: A meta-analysis","volume":"101","author":"Xie","year":"2022","journal-title":"Medicine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"920","DOI":"10.2174\/1871520616666160902101622","article-title":"Second Generation Proteasome Inhibitors in Multiple Myeloma","volume":"17","author":"Gozzetti","year":"2017","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1200\/JCO.2007.12.7712","article-title":"Shortening the timeline of pediatric phase I trials: The rolling six design","volume":"26","author":"Skolnik","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1200\/JCO.2006.09.2403","article-title":"Revised Response Criteria for Malignant Lymphoma","volume":"25","author":"Cheson","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1159\/000524500","article-title":"Poor Treatment Outcomes with Second-Line Chemotherapy in Advanced Synovial Sarcoma","volume":"100","author":"Kojima","year":"2022","journal-title":"Oncology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2484","DOI":"10.1200\/JCO.2007.10.9991","article-title":"Dexamethasone-induced posterior reversible encephalopathy syndrome","volume":"25","author":"Irvin","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.3324\/haematol.2019.220962","article-title":"Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: A report from the Children\u2019s Oncology Group","volume":"105","author":"Aplenc","year":"2020","journal-title":"Haematologica"},{"key":"ref_26","unstructured":"Narendran, A., Boklan, J., Bielamowicz, K., Trippett, T., Brown, V., DuBois, S., Eshun, F., Gelfond, J., Zomet, A., and Lacayo, N. (2023). Abstract 1123: POE14-01: A Phase I Study of Carfilzomib in Combination with Cyclophosphamide and Etoposide for Children, Adolescents and Young Adults with Relapsed\/Refractory Leukemias or Solid Tumors, Wiley."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"100402","DOI":"10.1016\/j.esmoop.2022.100402","article-title":"Patterns of care and outcomes of 417 patients with METAstatic SYNovial sarcoma (METASYN): Real-life data from the French Sarcoma Group (FSG)","volume":"7","author":"Campion","year":"2022","journal-title":"ESMO Open"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.ejca.2017.01.005","article-title":"Phase-II trials in osteosarcoma recurrences: A systematic review of past experience","volume":"75","author":"Omer","year":"2017","journal-title":"Eur. J. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e26896","DOI":"10.1002\/pbc.26896","article-title":"Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma","volume":"65","author":"Guenther","year":"2018","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3031","DOI":"10.1200\/JCO.2015.65.5381","article-title":"Outcome of Patients with Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children\u2019s Cancer Group, Pediatric Oncology Group, and Children\u2019s Oncology Group: Learning From the Past to Move Forward","volume":"34","author":"Lagmay","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"529","DOI":"10.4236\/jct.2018.97044","article-title":"Cyclophosphamide and Etoposide as a Salvage Treatment in Metastatic Osteosarcoma Patients","volume":"9","author":"Akl","year":"2018","journal-title":"J. Cancer Ther."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2924\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:41:20Z","timestamp":1760035280000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2924"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,6]]},"references-count":31,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cancers17172924"],"URL":"https:\/\/doi.org\/10.3390\/cancers17172924","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,6]]}}}