Benton, Christopher B; Chien, Kelly S; Tefferi, Ayalew; Rodriguez, Jose; Ravandi, Farhad; Daver, Naval; Jabbour, Elias; Jain, Nitin; Alvarado, Yesid; Kwari, Monica; Pierce, Sherry; Maiti, Abhishek; Hornbaker, Marisa; Santos, Margarida A; Martinez, Sara; Siguero, Mariano; Zblewski, Darci; Al-Kali, Aref; Hogan, William J; Kantarjian, Hagop; Pardanani, Animesh; Garcia-Manero, Guillermo.
Hematological Oncology : 2018-08-28.
The University of Texas MD Anderson Cancer Center, Department of Leukemia, Houston, TX, USA.
Trabectedin is an FDA-approved DNA minor groove binder (MGB) that has activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB with pre-clinical 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 mg, 5 mg, 7 mg, or 6 mg on days 1 and 8 or 2 mg, 3 mg, 1 mg, or 1.5 mg for 3 consecutive days on days 1 to 3. Three patients experienced dose-limiting toxicities (DLTs) of rhabdomyolysis (grade 4), hyperbilirubinemia (grade 3), and oral herpes (grade 3) with the days 1 and 8 schedule.
Otherwise, adverse events (AEs) 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 two 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=0.04).
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.