Phase I study of lurbinectedin, a synthetic tetrahydroisoquinoline that inhibits activated transcription, induces DNA single- and double-strand breaks, on a weekly × 2 every-3-week schedule

Abstract

Background Lurbinectedin administered as a 1-h intravenous infusion every 3 weeks induces neutropenia, with the nadir usually occurring during the second week. This phase I study evaluated an alternative lurbinectedin dosing schedule consisting of a 1-h infusion on days 1 and 8 every 3 weeks. Patients and methods Twenty-one patients with advanced cancer received lurbinectedin using a standard cohort dose escalation design. Results Three dose levels of 3, 4, and 5 mg of lurbinectedin were explored. The recommended phase II dose was 5 mg, with 3 of 13 patients having dose-limiting toxicity (DLT), although grade 4 neutropenia occurred in 50% of patients. Other frequent toxicities were mild to moderate nausea and vomiting, fatigue, decreased appetite, stomatitis and asymptomatic creatinine and transaminase increases. No objective responses occurred, but prolonged stable disease was observed in 7 patients, including 3 with soft tissue sarcoma. Conclusion The recommended phase II dose of lurbinectedin is 5 mg, administered as a 1-h infusion on days 1 and 8 every 3 weeks. These data support further testing of this dose and schedule, particularly in soft tissue sarcoma.

Review of Chromatographic Bioanalytical Assays for the Quantitative Determination of Marine-Derived Drugs for Cancer Treatment

“…Plinabulin is given at 30 mg/m 2 , and all other drugs are administered at dosages between 0.5–5 mg/m 2 . Most compounds distribute widely to peripheral tissues, with volumes of distribution at steady state (V ss ) ranging from approximately 18–5000 L [ 19 , 24 , 30 , 34 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. UCN-01 and CEP-2536 are the exceptions, with lower V ss ranging from 4 to 14.3 L and 0.35 to 44 L, respectively [ 59 , 60 , 61 ].…”

Safety and tolerability of lurbinectedin (PM01183) in patients with acute myeloid leukemia and myelodysplastic syndrome

“…The phase 1 trial reported here found lurbinectedin to be safe and toler- cytotoxic chemotherapy showed myelosuppression to be the main toxicity with no reports of rhabdomyolysis. [8][9][10][11] In the current study, there were 2 cases of cellulitis and 1 case of febrile neutropenia.…”

“…In a previous study testing tallimustine, also a MGB, 4 out of 26 patients (15%) had responses with 2 CRs and 2 with hematologic improvement . One of the 4 responding patients had a karyotype with del(q13;q23). It is possible that MGBs find a role in AML/MDS in the setting of specific genetic or chromosomal abnormalities, such as aberrant chromosome 11q.…”

<p>Orphan Drugs in Development for the Treatment of Small-Cell Lung Cancer: Emerging Data on Lurbinectedin</p>

“…19 Because of severe hematological side effects a second Phase I dose finding study was performed and recommended a flat dose of 5 mg of lurbinectedin given as 1 hr infusion on day 1 and 8 every 3 weeks. 20 A further Phase I study evaluated the recommended dose for the combination of lurbinectedin and gemcitabine (3 mg lurbinectedin and 800 mg/m2 gemcitabine given on day 1 and 8 every 3 weeks). 21 A case study of two patients with mesothelioma reported disease stabilization in both patients for 5.5 and 6 months in second line treatment combining cisplatin and lurbinectedin.…”