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

Abstract

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.

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

“…Moreover, it is used in non-operable liposarcomas and leiomyosarcomas [ 9 , 10 ], breast cancer with Breast Cancer type 1 Susceptibility Protein (BRCA1) loss [ 11 ], soft-tissue osteosarcoma and has been assessed in a phase II study of extraskeletal myxoid chondrosarcoma and a phase III study of mesenchymal chondrosarcoma [ 12 ]. Lurbinectedin (LUR) was approved by the Food and Drug Administration (FDA) in June 2020 after a phase II/III trial for the treatment of small cell lung carcinoma [ 13 ] and had previously been evaluated for ovarian cancer, breast cancer, sarcoma and acute myeloid leukemia (AML) [ 14 , 15 , 16 , 17 ].…”

Lurbinectedin-Induced Tumor Lysis Syndrome in Small Cell Neuroendocrine Cancer of the Cecum: A First-Ever Case Report

“…There are no reports of TLS in neuroendocrine cancers or any other solid tumor type. One case of TLS was reported in a phase I trial (n=42) that tested various doses of Lurbi ranging from 1 to 7 mg in non-solid tumor type, ie, acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) [ 11 ]. One incident of G-4 TLS was reported in a patient with 3 mg of Lurbi, although there were even higher doses given in other patients without developing TLS.…”

Emerging agents and regimens for treatment of relapsed and refractory acute myeloid leukemia

“…One patient achieved a partial response and two patients reached morphologic leukemia-free state. Lurbinectedin was safe and well tolerated in both treatment designs [89].…”