James Nam, PharmD // September 05, 2018.
Previous preclinical in vitro and in vivo studies have demonstrated that lurbinectedin, a next-generation minor groove binder (MGB), has good antitumor activity in solid tumors; its efficacy in AML however, is unknown.
For this phase 1 dose-finding study, investigators enrolled 42 patients with relapsed/refractory AML or MDS. Patients were treated with 2 dosing schedules of lurbinectedin 1-hour IV infusions in a 3+3 design.
Of the 42 patients, 24 received 3.5 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8. Overall, 3 patients experienced dose-limiting toxicities (DLT) including grade 4 rhabdomyolysis, grade 3 hyperbilirubinemia, and grade 3 oral herpes. Due to DLTs and an elevated dropout rate from early disease progression, the dose schedule was switched to 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. No DLTs were observed at this schedule.
Other frequently observed adverse events (AEs) included gastrointestinal AEs, febrile neutropenia/infections, pulmonary AEs, and renal failure. Common laboratory abnormalities included increased creatinine, anemia, neutropenia, and thrombocytopenia.
Thirty-three of 42 (79%) patients had a decrease in blasts in the peripheral blood or bone marrow, and 1 and 2 patients achieved a partial response or a morphologic leukemia-free state, respectively. All participants discontinued treatment prior to study cutoff, primarily due to progressive disease (30 patients; 71%).
Patients with a chromosome 11q21-23 abnormality had significantly greater reductions in bone marrow blast compared with patients who did not.
The authors concluded that “while no sustained remissions were observed, single-agent lurbinectedin was transiently leukemia suppressive for some patients.”