A Phase I Study of Carfilzomib with Cyclophosphamide and Etoposide in Relapsed and Refractory Leukemia and Solid Tumors Journal Article
| Authors: | Boklan, J.; Langevin, A. M.; Bielamowicz, K.; Neville, K.; Trippett, T.; Brown, V.; Dubois, S. G.; Eshun, F.; Gelfond, J.; Zomet, A.; Narendran, A.; Lacayo, N. J. |
| Article Title: | A Phase I Study of Carfilzomib with Cyclophosphamide and Etoposide in Relapsed and Refractory Leukemia and Solid Tumors |
| Abstract: | <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 <30 years with relapsed/refractory leukemia (stratum A) or a relapsed/refractory non-CNS solid tumor (stratum B), Karnofsky/Lansky score >= 50, and adequate organ function. A 5-day regimen of cyclophosphamide 440 mg/m(2)/day, etoposide 100 mg/m(2)/day, and carfilzomib was administered every 28 days with growth factor support. The carfilzomib starting dose was 11 mg/m(2)/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/m(2)/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/m(2)/days 1-2 and 36 mg/m(2)/days 3-5 for cycle 1, then 36 mg/m(2) for days 1-5 of all subsequent cycles. There was a single DLT of PRES. A dose expansion for additional toxicity data was conducted. Overall, twenty patients received >= 2 cycles (range, 2-14). 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.</p> |
| Keywords: | bortezomib; inhibitor; children; criteria; trials; escalation; low-dose dexamethasone; pediatric phase 1; carfilzomib with cyclophosphamide/etoposide; pr-171 |
| Journal Title: | Cancers |
| Volume: | 17 |
| Issue: | 17 |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Date Published: | 2025-09-01 |
| Language: | English |
| ACCESSION: | WOS:001571278200001 |
| DOI: | 10.3390/cancers17172924 |
| PROVIDER: | wos |
| Notes: | Article -- 2924 -- Source: Wos |
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