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Safety and tolerability of lurbinectedin (PM01183) in patients with acute myeloid leukemia and myelodysplastic syndrome
Author(s) -
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,
AlKali Aref,
Hogan William J.,
Kantarjian Hagop,
Pardanani Animesh,
GarciaManero Guillermo
Publication year - 2019
Publication title -
hematological oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 44
eISSN - 1099-1069
pISSN - 0278-0232
DOI - 10.1002/hon.2557
Subject(s) - medicine , tolerability , neutropenia , myeloid leukemia , febrile neutropenia , gastroenterology , pancytopenia , adverse effect , bone marrow , leukemia , myelodysplastic syndromes , surgery , toxicity
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.