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Phase I Clinical Trial of DNA Methyltransferase Inhibitor Decitabine and PARP Inhibitor Talazoparib Combination Therapy in Relapsed/Refractory Acute Myeloid Leukemia.
Baer, Maria R; Kogan, Aksinija A; Bentzen, Søren M; Mi, Tian; Lapidus, Rena G; Duong, Vu H; Emadi, Ashkan; Niyongere, Sandrine; O'Connell, Casey L; Youngblood, Benjamin A; Baylin, Stephen B; Rassool, Feyruz V.
Afiliación
  • Baer MR; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
  • Kogan AA; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland.
  • Bentzen SM; Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland.
  • Mi T; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland.
  • Lapidus RG; Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland.
  • Duong VH; Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee.
  • Emadi A; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
  • Niyongere S; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland.
  • O'Connell CL; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
  • Youngblood BA; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland.
  • Baylin SB; Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland.
  • Rassool FV; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland.
Clin Cancer Res ; 28(7): 1313-1322, 2022 04 01.
Article en En | MEDLINE | ID: mdl-35091444
PURPOSE: Patients with acute myeloid leukemia (AML) unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTi). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance PARP1 recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair, and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo. Here, we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in relapsed/refractory AML. PATIENTS AND METHODS: Decitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on cycle 1 days 1 (pretreatment), 5 and 8 blood blasts. RESULTS: Doses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3-5 events included fever in 19 patients and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) and hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased γH2AX foci, and decreased HR activity in responders. γH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m2 decitabine. CONCLUSIONS: Decitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Inhibidores de Poli(ADP-Ribosa) Polimerasas / Decitabina Límite: Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Leucemia Mieloide Aguda / Inhibidores de Poli(ADP-Ribosa) Polimerasas / Decitabina Límite: Humans Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos