Trabectedin is an FDA-approved DNA minor groove binder that has activity against 
translocation-associated sarcomas. Lurbinectedin is a next-generation minor 
groove binder with preclinical activity against myeloid leukemia cells. A 
dose-finding phase 1 clinical trial was performed in patients with acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS) with further assessment of 
safety and tolerability. Forty-two patients with relapsed/refractory AML/MDS 
received lurbinectedin administered as a 1-hour intravenous infusion in a 3 + 3 
study design. Two dosing schedules were used: 3.5, 5, 7, or 6 mg on days 1 and 8 
or 2, 3, 1, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients 
experienced dose-limiting toxicities of rhabdomyolysis (grade 4), 
hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the day 1 and 8 
schedule. Otherwise, adverse events mainly consisted of gastrointestinal 
manifestations (n = 11), febrile neutropenia/infections (n = 4), pulmonary 
toxicity (n = 2), and renal failure (n = 2). The most common laboratory 
abnormalities observed were an increase in creatinine (93%) and anemia, 
neutropenia, and thrombocytopenia (100%). Overall, 33 of 42 patients (79%) had 
reduction in blasts in peripheral blood or bone marrow. One patient achieved a 
partial response and 2 patients a morphologic leukemia-free state. Most (n = 30, 
71%) were discontinued due to progressive disease. Early deaths occurred from 
disease-related causes that were not attributable to lurbinectedin. Four 
patients with a chromosome 11q21-23 abnormality had significantly greater bone 
marrow blast reduction than those without such abnormality, with decrease of 
31 ± 14% (n = 4) vs 8 ± 8% (n = 16), respectively (P = .04). Overall, 
lurbinectedin was safe and tolerated using the schedules and dose levels tested. 
While no sustained remissions were observed, single-agent lurbinectedin was 
transiently leukemia suppressive for some patients.