Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia
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ORIGINAL ARTICLE
Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia Jorge Cortes1 · Nikolai Podoltsev2 · Hagop Kantarjian1 · Gautam Borthakur1 · Amer M. Zeidan2 · Maximilian Stahl2 · Tillmann Taube3 · Nora Fagan4 · Sushmita Rajeswari4 · Geoffrey L. Uy5 Received: 17 January 2020 / Revised: 19 June 2020 / Accepted: 7 September 2020 © Japanese Society of Hematology 2020
Abstract Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings. Keywords Volasertib · Decitabine · PLK1 · AML · Phase 1
Introduction As one of the non-microtubule components of mitosis required for complete cell division, polo-like kinase (PLK) 1 has emerged as a promising target for cancer therapy. PLK1 is the best characterized member of a family of five evolutionarily conserved serine/threonine protein kinases that play key roles in cell division and checkpoint regulation of mitosis [1–3]. PLK1 shows peak expression and activity at the G2/M transition and plays an important role in activation * Jorge Cortes [email protected] 1
Department of Leukemia, Anderson Cancer Center, University of Texas, 1515 Holcombe Blvd, Houston, TX 77030, USA
2
Department of Internal Medicine, Hematology Section, Yale University School of Medicine, New Haven, CT, USA
3
Boehringer Ingelheim International GmbH, Biberach, Germany
4
Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA
5
Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA
of the cell division cycle, chromosome segregation, centrosome maturation, bipolar spindle formation, regulation of the anaphase-promoting complex, and execution of cytokinesis [4–6]. High levels of human PLK1 have been noted in various solid tumors, as well as malignant lymphomas and acute myeloid leukemia (AML), and have been associated with poor prognosis [7]. Several studies have revealed that PLK1 depletion by short interfering ribonucleic acid (RNA), or a reduction in PLK1 activity by small molecule inhibitors, preferentially block
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