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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.

SUBMITTER: Benton CB

PROVIDER: S-EPMC6386594 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Benton Christopher B CB Chien Kelly S KS Tefferi Ayalew A Rodriguez Jose J Ravandi Farhad F Daver Naval N Jabbour Elias E Jain Nitin N Alvarado Yesid Y Kwari Monica M Pierce Sherry S Maiti Abhishek A Hornbaker Marisa M Santos Margarida A MA Martinez Sara S Siguero Mariano M Zblewski Darci D Al-Kali Aref A Hogan William J WJ Kantarjian Hagop H Pardanani Animesh A Garcia-Manero Guillermo G

Hematological oncology 20181205 1

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 administere ...[more]

PMID: 30153704

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Project description:Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome.In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312.Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose-escalation cohorts, and 11 patients with acute myeloid leukaemia and four patients with myelodysplastic syndrome in the twice-weekly dose-escalation cohorts. The most common grade 3 or higher adverse events were febrile neutropenia (38 [41%] of 93 patients), pneumonia (27 [29%] of 93 patients), thrombocytopenia (23 [25%] of 93 patients), anaemia (23 [25%] of 93 patients), and sepsis (16 [17%] of 93 patients). The most common serious adverse events were febrile neutropenia (29 [31%] of 93 patients), pneumonia (26 [28%] of 93 patients), and sepsis (16 [17%] of 93 patients). Six of the 74 patients with acute myeloid leukaemia and six of the 19 patients with myelodysplastic syndrome had a clinical response to treatment. Two dose-limiting toxicities were noted in patients with myelodysplastic syndrome at 125 mg/m(2) daily × 5, thus the maximum tolerated dose in patients with myelodysplastic syndrome was 90 mg/m(2) daily × 5. The maximum tolerated dose was not reached in patients with acute myeloid leukaemia. Potent dose-related DNA demethylation occurred on the daily × 5 regimen, reaching a plateau at 60 mg/m(2) (designated as the biologically effective dose).Guadecitabine given subcutaneously at 60 mg/m(2) daily × 5 is well tolerated and is clinically and biologically active in patients with myelodysplastic syndrome and acute myeloid leukaemia. Guadecitabine 60 mg/m(2) daily × 5 is the recommended phase 2 dose, and these findings warrant further phase 2 studies.Astex Pharmaceuticals, Stand Up To Cancer.

Dataset Information

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

Publications

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

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